Journal articles on the topic 'Human diet-switch'

Today, the demand for quality food is increasing and genetically modified food has become part of the Asian diet. Based on the potential of GM food products and Malaysia’s plan to expand its biotechnology industry, the market for GMO will surge if Malaysian consumers are well-informed on the advantages of GM food products. Therefore, this study proposed nine hypothesis to understand Malaysia consumers’ preference for switch from conventional food to genetically modified food. The result indicates that utilitarian, aversive and informational reinforcement will increase consumers’ preference towards genetic modified food if they are aware that genetically modified food brings more advantages than disadvantages to human being. In addition, result shows that consumer who switch will have higher intention to recommend GMO food to others and willing to pay more for GMO food.

Maternal metabolic disorders such as obesity and metabolic syndrome are linked to decreased oocyte and embryo quality and thus reproductive failure. Overweight and obese patients are advised to lose weight before conception to increase the chance of a healthy pregnancy. Human studies show conflicting results and are often underpowered, leading to a lack of scientifically substantiated advice. Furthermore, the effects of significant weight loss, due to caloric restriction, on oocyte quality are not known. Therefore, we aimed to feed a normal control or low-calorie diet as a preconception care strategy in high-fat-fed obese Swiss mice to improve their metabolic health and oocyte quality. Five-week-old female outbred Swiss mice (as a model for human physiology) were fed a control (CTRL; 10% fat) or a high-fat (HF; 60% fat) diet for seven weeks. Afterward, HF mice were switched to different preconception care interventions (PCCI) for six weeks, resulting in four treatment groups: (1) control diet for 13 weeks (CTRL_CTRL), (2) high fat diet for 13 weeks (HF_HF), (3) switch from a HF to an ad libitum CTRL diet (HF_CTRL), and (4) switch to a 30% caloric restriction diet (HF_CR). Change in bodyweight (twice a week, n=156 mice), metabolic health (glucose and insulin tolerance tests; n=32 mice), oocyte quality and pregnancy rates (n=32 mice) were studied. To assess oocyte quality, mature oocytes were collected after hormonal stimulation (10IU equine chorionic gonadotrophin followed by 10IU human chorionic gonadotrophin 48h later, IP injected) to evaluate oocyte lipid content (Bodipy staining; 11-12 oocytes/group) and to examine mitochondrial ultrastructure by transmission electron microscopy (4-5 oocytes/group). All data were analysed using analysis of variance and Bonferroni corrected. In comparison with the CTRL group, HF diet increased bodyweight after seven weeks (40.01±0.54g vs. 32.01±0.47 g; P<0.05). After 2 weeks of PCCI, both HF_CTRL and HF_CR mice had lost weight, reaching similar weights as control mice. Overall, the deteriorated glucose tolerance and insulin sensitivity in the HF_HF group were normalized to levels similar to the CTRL_CTRL group in both PCCI. Transmission electron microscopy of HF_HF oocytes showed higher proportions of mitochondrial ultrastructural abnormalities, e.g. low electron density and rose petal appearance (Boudoures et al. 2016 Reproduction 151(3):261-270) compared with CTRL_CTRL (54.70% vs. 30.52%; P<0.05). After six weeks of PCCI, the proportions of mitochondrial abnormalities were partially reduced in both HF_CTRL (39.64%) and HF_CR (44.47%) groups. The HF_HF diet increased the intracellular lipid content in oocytes with 84.41% compared with the CTRL_CTRL group (P<0.05). However, both PCCI strategies failed to alleviate this effect. The HF_HF-fed mice displayed lower pregnancy rates compared with those on the CTRL_CTRL diet (12.5% vs. 100%; P<0.05). Pregnancy rates were completely restored in the HF_CTRL and HF_CR group. In conclusion, both PCCI improved metabolic health (reduced weight, restored glucose tolerance and insulin sensitivity), partially improved oocyte quality, and restored pregnancy rates in HF-induced obese mice.

Chronic kidney disease (CKD) research is limited by the lack of convenient inducible models mimicking human CKD and its complications in experimental animals. We demonstrate that a soluble oxalate-rich diet induces stable stages of CKD in male and female C57BL/6 mice. Renal histology is characterized by tubular damage, remnant atubular glomeruli, interstitial inflammation, and fibrosis, with the extent of tissue involvement depending on the duration of oxalate feeding. Expression profiling of markers and magnetic resonance imaging findings established to reflect inflammation and fibrosis parallel the histological changes. Within 3 wk, the mice reproducibly develop normochromic anemia, metabolic acidosis, hyperkalemia, FGF23 activation, hyperphosphatemia, and hyperparathyroidism. In addition, the model is characterized by profound arterial hypertension as well as cardiac fibrosis that persist following the switch to a control diet. Together, this new model of inducible CKD overcomes a number of previous experimental limitations and should serve useful in research related to CKD and its complications.

With increasing livestock numbers, competition and avoidance are increasingly shaping resource availability for wild ungulates. Shifts in the dietary niche of wild ungulates are likely and can be expected to negatively affect their fitness. The Mongolian Gobi constitutes the largest remaining refuge for several threatened ungulates, but unprecedentedly high livestock numbers are sparking growing concerns over rangeland health and impacts on threatened ungulates like the Asiatic wild ass (khulan). Previous stable isotope analysis of khulan tail hair from the Dzungarian Gobi suggested that they graze in summer but switch to a poorer mixed C3 grass / C4 shrub diet in winter, most likely in reaction to local herders and their livestock. Here we attempt to validate these findings with a different methodology, DNA metabarcoding. Further, we extend the scope of the original study to the South Gobi Region, where we expect higher proportions of low-quality browse in the khulan winter diet due to a higher human and livestock presence. Barcoding confirmed the assumptions behind the seasonal diet change observed in the Dzungarian Gobi isotope data, and new isotope analysis revealed a strong seasonal pattern and higher C4 plant intake in the South Gobi Region, in line with our expectations. However, DNA barcoding revealed C4 domination of winter diet was due to C4 grasses (rather than shrubs) for the South Gobi Region. Slight climatic differences result in regional shifts in the occurrence of C3 and C4 grasses and shrubs, which do not allow for an isotopic separation along the grazer-browser continuum over the entire Gobi. Our findings do not allow us to confirm human impacts upon dietary preferences in khulan as we lack seasonal samples from the South Gobi Region. However, these data provide novel insight into khulan diet, raise new questions about plant availability versus preference, and provide a cautionary tale about indirect analysis methods if used in isolation or extrapolated to the landscape level. Good concordance between relative read abundance of C4 genera from barcoding and proportion of C4 plants from isotope analysis adds to a growing body of evidence that barcoding is a promising quantitative tool to understand resource partitioning in ungulates.

Snap beans are a significant source of micronutrients in the human diet. Among the micronutrients present in snap beans are phenolic compounds with known beneficial effects on human health, potentially via their metabolism by the gut-associated microbiome. The genetic pathways leading to the production of phenolics in snap bean pods remain uncertain. In this study, we quantified the level of total phenolic content (TPC) in the Bean Coordinated Agriculture Program (CAP) snap bean diversity panel of 149 accessions. The panel was characterized spectrophotometrically for phenolic content with a Folin–Ciocalteu colorimetric assay. Flower, seed and pod color were also quantified, as red, purple, yellow and brown colors are associated with anthocyanins and flavonols in common bean. Genotyping was performed through an Illumina Infinium Genechip BARCBEAN6K_3 single nucleotide polymorphism (SNP) array. Genome-Wide Association Studies (GWAS) analysis identified 11 quantitative trait nucleotides (QTN) associated with TPC. An SNP was identified for TPC on Pv07 located near the P gene, which is a major switch in the flavonoid biosynthetic pathway. Candidate genes were identified for seven of the 11 TPC QTN. Five regulatory genes were identified and represent novel sources of variation for exploitation in developing snap beans with higher phenolic levels for greater health benefits to the consumer.

In hepatocytes, the amount of the Spot 14 (S14) protein is closely related to the full expression of enzymes involved in the glycolytic and lipogenic pathways. In the present study we address the role played by this protein in the control of transcription of the L-type pyruvate kinase (L-PK) gene in primary hepatocytes. We show that human S14, which by itself does not bind to the L-PK promoter, physically interacts with the human chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1) and induces the switch of this factor from a repressor to an activator. However, the enhancing activity of S14 and COUP-TF1 depends on the presence of a proximal GC-rich box (the L0 element) that specifically binds nuclear proteins from the livers of rats fed a glucose-rich diet. Moreover, the L0 element, which strongly binds dephosphorylated specificity protein 1 (Sp1), loses all affinity when this factor is phosphorylated by cAMP-dependent protein kinase. Mutations that affect binding of Sp1 and nuclear proteins to the L0 box also decrease basal transcription and impair glucose responsiveness of the promoter. These results therefore shed light on the mechanism by which the S14 protein, whose concentration rapidly rises after glucose intake, contributes to the full activity of the L-PK promoter.

Abstract Background Induction of goblet cell differentiation during inflammation has been shown to be impaired in ulcerative colitis (UC) but not Crohn’s disease (CD), possibly explaining the intestinal goblet cell and mucus reduction observed in active UC. A metabolic switch from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) is necessary for terminal differentiation of intestinal stem cells towards goblet cells. Interestingly, intestinal energy deficiency in general and reduced level of OXPHOS in specific have been attributed to UC pathogenesis more than 30 years ago. The c1q binding protein (C1QBP; gC1qR) is indispensable for the maintenance of OXPHOS. Nevertheless, experimental evidence linking mitochondrial dysfunction with goblet cell depletion and C1QBP expression are still missing. Methods Goblet cell differentiation was studied in human biopsies from UC patients in remission, in mucus-producing HT29MTX cells and in a conplastic mouse strain with diminished mitochondrial OXPHOS activity. Furthermore, mice were fed an experimental diet to shift cellular energy production from glycolysis to OXPHOS and mucosal cell differentiation was compared with mice on an isocaloric control diet. Results In vitro, siRNA experiments in HT29MTX cells showed that butyrate-induced expression of goblet cell differentiation factor KLF4 is highly dependent on gC1qR expression. Interestingly, the latter was significantly reduced in human ileal and colonic sections of UC patients in remission compared with HN. OXPHOS-deficient conplastic B6-mt FVB mice further confirmed these findings by depicting diminished klf4 expression, lowered goblet cell numbers, a thinned intestinal mucus layer and signs of intestinal inflammation. Finally, via nutritional intervention in C57BL/6 mice we were able to increase gC1qR level and to induce goblet cell differentiation via hath1 and klf4 compared with controls. Conclusion Taken together, we here describe a new pathway linking low intestinal expression of OXPHOS-regulating gC1qR to impaired goblet cell differentiation, mucus reduction and mucosal inflammation, which could be possibly reversed by nutritional intervention.

The study of the burden that parasites can exert upon the bacterial gut microbiota was restricted by the available technologies and their costs. Currently, next-generation sequencing coupled with traditional methodologies allows the study of eukaryotic parasites (protozoa and helminths) and its effects on the human bacterial gut microbiota diversity. This diversity can be altered by a variety of factors such as age, diet, genetics and parasitic infections among others. The disturbances of the gut microbiota have been associated with a variety of illnesses. Children population in developing countries, are especially susceptible to parasitic infections because of the lack of proper sanitation and undernutrition, allowing both, the thriving of intestinal parasites and profound alteration of the gut microbiota. In this work, we have sampled the stool of 23 children from four different children’s care-centers in Medellin, Colombia, and we have identified the eukaryotic parasites by traditional and molecular methodologies coupled with microbial profiling using 16S rDNA sequencing. This mixed methodology approach has allowed us to establish an interesting relationship betweenGiardia intestinalisand helminth infection, having both effects upon the bacterial gut microbiota enterotypes, causing a switch from a type I to a type II enterotype upon infection.

Abstract Objectives The objectives of this research were to determine the protein digestibility corrected amino acid score (PDCAAS) and the digestible indispensable amino acid score (DIAAS) for raw and roasted American pistachio nuts in growing pigs, and to assess the effect of roasting on these measures of protein quality. Methods Twelve ileal cannulated barrows (body weight: 60.9 ± 3.2 kg) were randomly allotted to a 2-period switch-back design with 3 diets and 4 replicate pigs per period. Roasted pistachio nuts and raw pistachio nuts (American cultivated pistachio nuts) were each added to a single diet as the only protein source, and the third diet was a nitrogen-free diet that was used to measure basal endogenous losses of AA. Experimental periods were 9 d with the initial 5 d for adaptation to the diets. On d 6 and 7, fecal samples were collected, and on d 8 and 9, ileal digesta samples were collected for 9 h each day. The PDCAAS and DIAAS were calculated according to the Food and Agriculture Organization. Results The standardized ileal digestibility (SID) of all indispensable AA, except Arg and Phe, was less (P < 0.05) in roasted than in raw pistachio nuts. Raw pistachio nuts had a PDCAAS of 73 and roasted pistachio nuts had a PDCAAS of 81, calculated for children 2 to 5 yr, and the first limiting AA when compared to human requirements was Thr for both pistachio nuts. The DIAAS calculated for children older than 3 years, adolescents, and adults was 86 and 83 for raw and roasted pistachio nuts, respectively. The limiting AA in both raw and roasted pistachio nuts that determined the DIAAS for this age group was Lys. Conclusions Results of this research illustrate that raw and roasted pistachio nuts can be considered a good quality protein source with DIAAS greater than 75, however, heating conditions associated with roasting may decrease the digestibility of AA in pistachio nuts. Funding Sources The U.S. Department of Agriculture's (USDA) Agricultural Marketing Service. Product was supplied by the American Pistachio Growers.

SummaryThe miR-143/145 cluster regulates VSMC specific gene expression, thus controlling differentiation, plasticity and contractile function, and promoting the VSMC phenotypic switch from a contractile/non-proliferative to a migrating/proliferative state. More recently increased miR-145 expression was observed in human carotid atherosclerotic plaques from symptomatic patients. The goal of this study was to investigate the contribution of miR-143/145 during atherogenesis by generating mice lacking miR-143/145 on an Ldlr-deficient background. Ldlr-/- and Ldlr-/--miR-143/145-/- (DKO) were fed a Western diet (WD) for 16 weeks. At the end of the treatment, the lipid profile and the atherosclerotic lesions were assessed in both groups of mice. Absence of miR-143/145 significantly reduced atherosclerotic plaque size and macrophage infiltration. Plasma total cholesterol levels were lower in DKO and FLPC analysis showed decreased cholesterol content in VLDL and LDL fractions. Interestingly miR-143/145 deficiency per se resulted in increased hepatic and vascular ABCA1 expression. We further confirmed the direct regulation of miR-145 on ABCA1 expression by qRT-PCR, Western blotting and 3′UTR-luciferase reporter assays. In summary, miR-143/145 deficiency significantly reduces atherosclerosis in mice. Therapeutic inhibition of miR-145 might be useful for treating atherosclerotic vascular disease.

Adipose tissue (AT) inflammation is crucial to the development of obesity-associated insulin resistance. Our aim was to investigate the contribution of cyclooxygenase-2 (COX-2)/macrophage migration inhibitory factor (MIF)-mediated cross-talk between hypertrophic adipocytes and macrophages to the etiology of AT inflammation and the involvement of CD74 using human SGBS adipocytes, THP-1 macrophages and mice fed a high-fat (HF) diet. The MIF and CD74 mRNA levels in the adipocytes and stromal vascular cells (SVCs) of white fat were highly correlated with body weight (BW), homeostatic model assessment for insulin resistance (HOMA-IR), and adipose macrophage marker expression levels, especially those in SVCs. COX-2 inhibition suppressed the elevation of MIF production in HF white adipocytes as well as palmitate and hypoxic-treated SGBS adipocytes. Treatment of adipocytes transfected with shCOX-2 and siMIF or subjected to MIF depletion in the medium reversed the pro-inflammatory responses in co-incubated THP-1 cells. Inhibition of NF-κB activation reversed the COX2-dependent MIF secretion from treated adipocytes. The targeted inhibition of macrophage CD74 prevented M1 macrophage polarization in the above co-culture model. The COX-2-dependent increases in CD74 gene expression and MIF release in M1-polarized macrophages facilitated the expression of COX-2 and MIF in co-cultured SGBS adipocytes. CD74 shRNA intravenous injection suppressed HF-induced AT M1 macrophage polarization and inflammation as well as insulin resistance in mice. The present study suggested that COX-2-mediated MIF secretion through NF-κB activation from hypertrophic and hypoxic adipocytes as well as M1 macrophages might substantially contribute to the phenotypic switch of AT macrophages through CD74 in obesity. Inhibition of CD74 could attenuate AT inflammation and insulin resistance in the development of HF diet-induced obesity.

Carotenoid pigments, particularly β-carotene and lycopene, are consumed in human foodstuffs and play a vital role in maintaining health. β-carotene is known to quench singlet oxygen and can have strong antioxidant activity. As such, it was proposed that β-carotene might reduce the risk of cancer. Epidemiological studies found inverse relationships between cancer risk and β-carotene intake or blood levels. However, clinical trials failed to support those findings and β-carotene supplementation actually increased lung cancer incidence in male smokers. Early experimental animal studies found dietary β-carotene inhibited UV-induced skin cancers. Later studies found that β-carotene supplementation exacerbated UV-carcinogenic expression. The discrepancies of these results were related to the type of diet the animals consumed. Lycopene has been associated with reduced risk of lethal stage prostate cancer. Other carotenoids, e.g., lutein and zeaxanthin, play a vital role in visual health. Numerous studies of molecular mechanisms to explain the carotenoids’ mode of action have centered on singlet oxygen, as well as radical reactions. In cellular systems, singlet oxygen quenching by carotenoids has been reported but is more complex than in organic solvents. In dietary β-carotene supplement studies, damaging pro-oxidant reactivity can also arise. Reasons for this switch are likely due to the properties of the carotenoid radicals themselves. Understanding singlet oxygen reactions and the anti-/pro-oxidant roles of carotenoids are of importance to photosynthesis, vision and cancer.

ABSTRACTThe lytic cycles of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are induced in cell culture by sodium butyrate (NaB), a short-chain fatty acid (SCFA) histone deacetylase (HDAC) inhibitor. Valproic acid (VPA), another SCFA and an HDAC inhibitor, induces the lytic cycle of KSHV but blocks EBV lytic reactivation. To explore the hypothesis that structural differences between NaB and VPA account for their functional effects on the two related viruses, we investigated the capacity of 16 structurally related short- and medium-chain fatty acids to promote or prevent lytic cycle reactivation. SCFAs differentially affected EBV and KSHV reactivation. KSHV was reactivated by all SCFAs that are HDAC inhibitors, including phenylbutyrate. However, several fatty acid HDAC inhibitors, such as isobutyrate and phenylbutyrate, did not reactivate EBV. Reactivation of KSHV lytic transcripts could not be blocked completely by any fatty acid tested. In contrast, several medium-chain fatty acids inhibited lytic activation of EBV. Fatty acids that blocked EBV reactivation were more lipophilic than those that activated EBV. VPA blocked activation of the BZLF1 promoter by NaB but did not block the transcriptional function of ZEBRA. VPA also blocked activation of the DNA damage response that accompanies EBV lytic cycle activation. Properties of SCFAs in addition to their effects on chromatin are likely to explain activation or repression of EBV. We concluded that fatty acids stimulate the two related human gammaherpesviruses to enter the lytic cycle through different pathways.IMPORTANCELytic reactivation of EBV and KSHV is needed for persistence of these viruses and plays a role in carcinogenesis. Our direct comparison highlights the mechanistic differences in lytic reactivation between related human oncogenic gammaherpesviruses. Our findings have therapeutic implications, as fatty acids are found in the diet and produced by the human microbiota. Small-molecule inducers of the lytic cycle are desired for oncolytic therapy. Inhibition of viral reactivation, alternatively, may prove useful in cancer treatment. Overall, our findings contribute to the understanding of pathways that control the latent-to-lytic switch and identify naturally occurring molecules that may regulate this process.

Objective: Intraplaque neovascularization is an important feature of unstable human atherosclerotic plaques. However, its impact on plaque formation and stability is poorly studied. Because proliferating endothelial cells generate up to 85% of their ATP from glycolysis, we investigated whether pharmacological inhibition of glycolytic flux by the small-molecule 3PO (3-[3-pyridinyl]-1-[4-pyridinyl]-2-propen-1-one) could have beneficial effects on plaque formation and composition. Approach and Results: ApoE −/ − (apolipoprotein E deficient) mice treated with 3PO (50 µg/g, ip; 4×/wk, 4 weeks) showed a metabolic switch toward ketone body formation. Treatment of ApoE −/− Fbn1 C1039G+/− mice with 3PO (50 µg/g, ip) either after 4 (preventive, twice/wk, 10 weeks) or 16 weeks of Western diet (curative, 4×/wk, 4 weeks) inhibited intraplaque neovascularization by 50% and 38%, respectively. Plaque formation was significantly reduced in all 3PO-treated animals. This effect was independent of intraplaque neovascularization. In vitro experiments showed that 3PO favors an anti-inflammatory M2 macrophage subtype and suppresses an M1 proinflammatory phenotype. Moreover, 3PO induced autophagy, which in turn impaired NF-κB (nuclear factor-kappa B) signaling and inhibited TNF-α (tumor necrosis factor-alpha)–mediated VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) upregulation. Consistently, a preventive 3PO regimen reduced endothelial VCAM-1 expression in vivo. Furthermore, 3PO improved cardiac function in ApoE −/− Fbn1 C1039G+/− mice after 10 weeks of treatment. Conclusions: Partial inhibition of glycolysis restrained intraplaque angiogenesis without affecting plaque composition. However, less plaques were formed, which was accompanied by downregulation of endothelial adhesion molecules—an event that depends on autophagy induction. Inhibition of coronary plaque formation by 3PO resulted in an overall improved cardiac function.

The liver X receptors (LXR-α and -β) are nuclear transcription factors that have been implicated in both glucose and lipid metabolism; their activation by oxysterol ligands elicits both a decrease in atherosclerosis and antidiabetic effects. Although synthetic LXR ligands decrease hepatic gluconeogenesis and increase lipogenesis in rodent models, the normal rodent diet lacks cholesterol, which led Mitro et al. to search for other ligands. They found that glucose and glucose derivatives stimulated the transcriptional activation of a Gal4-responsive gene reporter in human HepG2 cells expressing constructs in which LXR ligand-binding domains (LBDs) were fused to the Gal4 DNA binding domain and transcriptionally activated LXR-RXR (retinoid X receptor) targets. Cell-free coactivator recruitment assays and scintillation proximity assays indicated that glucose and glucose-6-phosphate were direct LXR agonists that bound to the LXR LBD. Furthermore, glucose protected LXR-α from proteolytic attack and increased the LXR-β melting temperature. Glucose had effects on the transcription of LXR target genes in HEPG2 cells similar to those of known ligands, stimulating the expression of genes involved in fatty acid synthesis and cholesterol homeostasis and inhibiting expression of gluconeogenic genes; moreover, it potentiated the effects of LXR ligands. Similarly, glucose- or sucrose-feeding stimulated the expression of LXR target genes in the livers of fasted mice, even mice that were insulin deficient. Thus, glucose itself appears to act as a ligand for LXR, leading the authors to propose that LXR acts as a "transcriptional switch" to coordinate carbohydrate and lipid metabolism. N. Mitro, P. A. Mak, L. Vargas, C. Godio, E. Hampton, V. Molteni, A. Kreusch, E. Saez, The nuclear receptor LXR is a glucose sensor. Nature445, 219-223 (2007). [PubMed]

How dietary patterns impact colonic bacterial biosynthesis of vitamins and utilization by humans is poorly understood. Our aim was to investigate whether a reciprocal dietary switch between rural South Africans (traditionally high fibre, low fat) and African Americans (Western diet of low fibre, high fat) affects colonic folate synthesis. Colonic evacuants were obtained from 20 rural South Africans and 20 African Americans consuming their usual diets at baseline. For 2 weeks thereafter, rural South Africans were provided with a Western diet (protein, 27%; fat, 52%; carbohydrate, 20%; and fibre, 8 g/day) and African Americans were provided with a high fibre, low-fat diet (protein, 16%; fat, 17%; carbohydrate, 63%; and fibre, 43 g/day). Colonic evacuants were again collected. No difference between groups at baseline in the folate content of 3-h evacuants was observed. The high-fibre, low-fat diet consumed by African Americans during the intervention produced a 41% increase in mean total folate content compared with baseline values (p = 0.0037). No change was observed in rural South Africans consuming a Western diet. Mean total folate content of colonic evacuants was higher among African Americans at the end of the dietary switch (3107 ± 1811 μg) compared with rural South Africans (2157 ± 1956 μg) (p = 0.0409). In conclusion, consistent with animal studies, switching from a Western diet to one higher in fibre and lower in fat can be expected to result in greater colonic folate content. Future research should confirm that these observations are not transitory and understand the contribution of transit-time to the findings.

A wearable computing system plays a leading role in the ubiquitous computing era, in which computers are used at any place and at any time. Now the mobile multimedia communication technology based devices, such as mobile phone, handy-type PC, etc., have come to be used in such a broad range of areas, the features of wearable hands-free computing system, which people can constantly use in their daily life or workplace while doing some other job, are highly valued more than ever. However, the wearable computing system has not yet spread so widely owing to various factors. Among such factors is the delay in the development of human machine interface, which is applicable to the wearable computing system. Conventional technologies that require either manual manipulation of keyboard, mouse, touch panel, etc., or a large equipment to make use of electroencephalogram, eyeball movements, etc. for realizing hands-free interface, are not suitable for the wearable computing system. We, therefore, developed a human-machine interface for the wearable computing system. This interface makes it easy to manipulate machine with intentional movements of temple. User can constantly use machine with no interference, as well as with hands free. It is compact and lightweight, permitting ease of manufacturing at a low cost. It does not react to daily actions like conversation, diet, etc., other than movements intended to control the machine. This interface consists of one optical distance sensor mounted in the vicinity of the left and right temples each and of one single-chip microcomputer.

In different pathophysiological conditions plasminogen activator inhibitor-1 (PAI-1) plasma concentrations are elevated. As dietary patterns are considered to influence PAI-1 concentration, we aimed to determine active PAI-1 plasma concentrations and mRNA expression in adipose tissue before and after consumption of a high-fat diet (HFD) and the impact of additive genetic effects herein in humans. For 6 weeks, 46 healthy, non-obese pairs of twins (aged 18–70) received a normal nutritionally balanced diet (ND) followed by an isocaloric HFD for 6 weeks. Active PAI-1 plasma levels and PAI-1 mRNA expression in subcutaneous adipose tissue were assessed after the ND and after 1 and 6 weeks of HFD. Active PAI-1 plasma concentrations and PAI-1 mRNA expression in adipose tissue were significantly increased after both 1 and 6 weeks of HFD when compared to concentrations determined after ND (p< .05), with increases of active PAI-1 being independent of gender, age, or changes of BMI and intrahepatic fat content, respectively. However, analysis of covariance suggests that serum insulin concentration significantly affected the increase of active PAI-1 plasma concentrations. Furthermore, the increase of active PAI-1 plasma concentrations after 6 weeks of HFD was highly heritable (47%). In contrast, changes in PAI-1 mRNA expression in fatty tissue in response to HFD showed no heritability and were independent of all tested covariates. In summary, our data suggest that even an isocaloric exchange of macronutrients — for example, a switch to a fat-rich diet — affects PAI-1 concentrations in humans and that this is highly heritable.

AbstractDespite appropriate antiepileptic drug treatment, approximately one-third of humans and dogs with epilepsy continue experiencing seizures, emphasising the importance for new treatment strategies to improve the quality of life of people or dogs with epilepsy. A 6-month prospective, randomised, double-blinded, placebo-controlled cross-over dietary trial was designed to compare a ketogenic medium-chain TAG diet (MCTD) with a standardised placebo diet in chronically antiepileptic drug-treated dogs with idiopathic epilepsy. Dogs were fed either MCTD or placebo diet for 3 months followed by a subsequent respective switch of diet for a further 3 months. Seizure frequency, clinical and laboratory data were collected and evaluated for twenty-one dogs completing the study. Seizure frequency was significantly lower when dogs were fed the MCTD (2·31/month, 0–9·89/month) in comparison with the placebo diet (2·67/month, 0·33–22·92/month, P=0·020); three dogs achieved seizure freedom, seven additional dogs had ≥50 % reduction in seizure frequency, five had an overall <50 % reduction in seizures (38·87 %, 35·68–43·27 %) and six showed no response. Seizure day frequency were also significantly lower when dogs were fed the MCTD (1·63/month, 0–7·58/month) in comparison with the placebo diet (1·69/month, 0·33–13·82/month, P=0·022). Consumption of the MCTD also resulted in significant elevation of blood β-hydroxybutyrate concentrations in comparison with placebo diet (0·041 (sd 0·004) v. 0·031 (sd 0·016) mmol/l, P=0·028). There were no significant changes in serum concentrations of glucose (P=0·903), phenobarbital (P=0·422), potassium bromide (P=0·404) and weight (P=0·300) between diet groups. In conclusion, the data show antiepileptic properties associated with ketogenic diets and provide evidence for the efficacy of the MCTD used in this study as a therapeutic option for epilepsy treatment.

The glucagon-like peptide-1 receptor (GLP1R) is expressed in the renal vasculature and known to be downregulated under hypertensive conditions in rats and humans. However, little is known about the regulation in other types of renal pathology involving vascular changes. This study investigates the expression of the GLP1R in renal vasculature after glomerular injury in the nephrotoxic nephritis mouse model, high cholesterol, and atherosclerosis in the Ldlr-/- mouse on Western diet, and ex vivo injury in an organ culture model. The immunohistochemical signal of the GLP1R was significantly decreased in arteries from mice with nephrotoxic nephritis after 42 days compared to 7 days and saline control (P < 0.05). Histological evaluation of kidneys from Ldlr-/- mice on Western diet showed a decreased GLP1R specific immunohistochemical signal (P < 0.05). The dilatory response to liraglutide was decreased in Western diet fed Ldlr-/- mice compared to C57Bl/6J controls (P < 0.05). Organ culture significantly decreased the immunohistochemical signal of the GLP1R (P <0.05) and the expression of Glp1r mRNA (P < 0.005) compared to fresh. Organ cultured vessels showed vascular smooth muscle cell remodelling as Acta2 expression was decreased (P < 0.005) and Ednrb was increased (P < 0.05). In conclusion, nephrotoxic nephritis and hypercholesterolaemia led to decreased GLP1R specific immunohistochemical signal. Ex vivo vascular injury in the organ culture model leads to a decrease in expression of GLP1R expressionand contractile VSMC specific markers and increase in expression of dedifferentiation markers suggestive of an inverse relationship between phenotypic switch of the VSMC and the expression of the GLP1R; however, the causal relationship remains elusive.

Abstract Introduction. There is increasing interest in therapeutic modulation of metabolic pathways in cancer. Tumor cells preferentially use aerobic glycolysis to meet their energetic demands. However, glycolysis inhibition alone is unable to bring durable responses because of limited therapeutic index and because of previously underappreciated metabolic adaptability in tumor cells, which can switch to alternative substrate usage when specific nutrients are limiting. The molecular basis of metabolic adaptation is poorly understood. Recently, the histone demethylase LSD1 (Lysine-Specific Demethylase 1) has been implicated in the control of oxidative phosphorylation (OXPHOS) in adipocytes through its interaction with NRF1 (Nuclear Respiratory Factor 1), a master regulator of metabolic gene transcription (1). We hypothesized that LSD1 could regulate metabolic adaptability and be a therapeutic target upon metabolic modulation through Caloric Restriction (CR) in Acute Myeloid Leukaemia (AML) and specifically in APL (Acute Promyelocytic Leukaemia), which we showed to be sensitive to body fatness in the clinic (2). Methods. APLs were generated in mice expressing the PML-RARa fusion under the control of the Cathepsin G promoter (3). Primary leukemias were transplanted into recipients subjected to 30% CR or Standard Diet (SD). We scored the effect of CR alone or in combination with the LSD1 inhibitor IEO368 (4) on mouse survival, Leukemia Initiating Cell (LIC) frequency and epigenomic, transcriptomic and metabolic parameters. Results. Compared to SD controls, CR-fed recipients experienced an initial dramatic decrease in the total leukemic burden accompanied by cell cycle slowdown (“adaptation phase”); this was followed by a delayed disease progression that brought animals to death (“terminal phase”) (median survival 91 vs 51 days, p=0.038). Limiting-dilution transplantation of CR-conditioned leukemias revealed increased frequency of LICs (estimated frequency 1/3064 cells in SD vs 1/947 in CR, p=0.003) and increased aggressiveness (median survival reduced to 49 vs 70.5 days with 5000 cells injected, p<0.0001). Thus, CR limits the expansion of leukemic cells but enriches for cells with increased ability to regrow. RNAseq of leukemic cells purified during the terminal phase (but not earlier) showed that a dramatic transcriptional reprogramming in CR, characterized by upregulation of genes controlling OXPHOS, Krebs cycle and nucleotide and protein biosynthesis, and downregulation of insulin signaling and glucose transporters. Flow cytometry with Mitotracker Red confirmed increased mitochondrial activity. Thus, leukemic cells exposed to CR put in place adaptive transcriptional changes to allow survival in a nutrient/growth factor deprived environment. To investigate the basis of these transcriptional changes, we revised ChIPseq analysis of LSD1 binding in human APL cell lines and found a significant enrichment for i) NRF1 consensus binding motif and ii) promoters of genes encoding for OXPHOS and Krebs cycle enzymes. NRF1 binding to OXPHOS/Krebs enzymes was confirmed on mouse leukemias by ChIPseq. These data suggested that the CR-induced adaptive changes could be mediated by LSD1/NRF1. Strikingly, co-treatment of leukemic mice with CR and our LSD1 inhibitor IEO368 (4) resulted in macroscopic and microscopic eradication of disease (see figure, p=0.0018 compared to SD). In these conditions, leukemic cells completely disappeared in 4/6 mice after 4 weeks. LSD1 inhibition alone was also effective but did not produce bona fide disease eradication. Importantly, some of the features of the CR-LSD1 interaction could be modeled by combining LSD1 and an IGF1/Insulin inhibitor. In vivo, this combination was synergistic and led to durable responses (median survival 121 vs 50 days in untreated controls, p=0.0143, vs 65.5 and 78.5 days with Insulin/IGF1 Inhibitor and IEO368 respectively). Conclusion: the combination of LSD1 inhibition and insulin/IGF1 signaling reduction by pharmacological or dietary intervention appears as a highly effective therapeutic strategy and deserves further investigation. Ongoing preclinical studies will verify its applicability to other models of AML. References: 1. Duteil et al, Nat Commun. 2014 Jun 10;5:4093 2. Breccia et al, Blood. 2012 Jan 5;119(1):49-54 3. Westervelt et al, Blood. 2003 Sep 1;102(5):1857-65 4. Varasi et a,l Eur J Cancer Vol 50 supp 6: 185 Figure 1. Figure 1. Disclosures Pelicci: Rasna therapeutics: Membership on an entity's Board of Directors or advisory committees.

Endocrine disruption has been reported in freshwater fish populations around the world. This phenomenon ranges from subtle changes in the physiology and sexual behavior of fish to permanently altered sexual differentiation and impairment of fertility. Despite widespread reports of endocrine disruption in fish (and this is well characterized at the individual level), few studies have demonstrated population-level consequences as a result of exposure to endocrine-disrupting chemicals (EDCs). An exception to this is in Lake Ontario Lake trout where precipitous declines in the population have been linked with periods of high exposure to organochlorine chemicals (known EDCs). Recently, it has been established that roach (Rutilus rutilus) exposed to treated sewage effluent (that contains complex mixtures of EDCs) in UK rivers, have a reduced reproductive capacity. This, in turn, may have population-level consequences. Evidence for a link between exposure to effluents from kraft mill (BKME) and sewage treatment works (STWs) and altered reproductive function in freshwater fish is compelling. In most cases, however, a causal link between a specific chemical and a physiological effect has not been established. Indeed, identifying specific chemical(s) responsible for adverse effects observed in the wild is difficult, given that tens of thousands of man-made chemicals enter the aquatic environment and that mixtures of chemicals can have combination (e.g., additive) effects. Some EDCs are known to act at a number of different body targets to affect a variety of physiological processes, further complicating the identification of the causative agent(s). Endocrine disruption appears to be particularly widespread in freshwater fish populations. There is little evidence, however, to suggest fish are more susceptible to EDCs relative to other wildlife. Notwithstanding this, there are some features of the endocrine physiology of fish that may be particularly susceptible to the effects of EDCs, including the processes of sex-determination and smoltification (in salmonids). Furthermore, their aquatic existence means that fish can be bathed constantly in a solution containing pollutants. In addition, uptake of chemicals readily occurs via the gills and skin, as well as via the diet (the major exposure route for most EDCs in terrestrial animals). The exposure of fish early life stages to the cocktail of EDCs present in some aquatic environments may be of particular concern, given that this is an especially vulnerable period in their development. The challenge, from the point of view of ecological risk assessment, is to determine effects of EDCs on freshwater fish populations and freshwater ecosystems. In order to meet this challenge, high-quality data are required on the population biology of freshwater fish, on the effects of EDCs on their various life history characteristics, and comprehensive and appropriate population models. Basic information on the population biology of most species of wild freshwater fish is, however, extremely limited, and needs significant improvement for use in deriving a sound understanding of how EDCs affect fish population sustainability. Notwithstanding this, we need to start to undertake possible/probable predictions of population level effects of EDCs using data derived from the effects found in individual fish. Furthermore, information on the geographical extent of endocrine disruption in freshwater fish is vital for understanding the impact of EDCs in fish populations. This can be derived using published statistical associations between endocrine disruption in individual fish and pollutant concentration in receiving waters. Simplistic population models, based on the effects of EDCs on the reproductive success of individual fish can also used to model the likely population responses to EDCs. Wherever there is sufficient evidence for endocrine disruption in freshwater fish and the need for remediation has been established, then there is a need to focus on how these problems can be alleviated. Where industrial chemicals are identified as causative agents, a practical program of tighter regulation for their discharge and/or a switch to alternative chemicals (which do not act as EDCs) is needed. There are recent examples where such strategies have been adopted, and these have been successful in reducing the impacts of EDCs from point source discharges on freshwater fish. Where EDCs are of natural origin (e.g., sex steroid hormones from human and animal waste), however, remediation is a more difficult task. Regulation of the release of these chemicals can probably be achieved only by improvements in treatment processes and/or the implementation of systems that specifically remove and degrade them before their discharge into the aquatic environment.

Atherosclerosis is a chronic inflammatory disease of the vasculature commonly leading to myocardial infarction and stroke. We show that IL-33, which is a novel IL-1–like cytokine that signals via ST2, can reduce atherosclerosis development in ApoE−/− mice on a high-fat diet. IL-33 and ST2 are present in the normal and atherosclerotic vasculature of mice and humans. Although control PBS-treated mice developed severe and inflamed atherosclerotic plaques in the aortic sinus, lesion development was profoundly reduced in IL-33–treated animals. IL-33 also markedly increased levels of IL-4, -5, and -13, but decreased levels of IFNγ in serum and lymph node cells. IL-33 treatment also elevated levels of total serum IgA, IgE, and IgG1, but decreased IgG2a, which is consistent with a Th1-to-Th2 switch. IL-33–treated mice also produced significantly elevated antioxidized low-density lipoprotein (ox-LDL) antibodies. Conversely, mice treated with soluble ST2, a decoy receptor that neutralizes IL-33, developed significantly larger atherosclerotic plaques in the aortic sinus of the ApoE−/− mice compared with control IgG-treated mice. Furthermore, coadministration of an anti–IL-5 mAb with IL-33 prevented the reduction in plaque size and reduced the amount of ox-LDL antibodies induced by IL-33. In conclusion, IL-33 may play a protective role in the development of atherosclerosis via the induction of IL-5 and ox-LDL antibodies.

AbstractHumans are unique in their diet, physiology and socio-reproductive behavior compared to other primates. They are also unique in the ubiquitous adaptation to all biomes and habitats. From an evolutionary perspective, these trends seem to have started about two million years ago, coinciding with the emergence of encephalization, the reduction of the dental apparatus, the adoption of a fully terrestrial lifestyle, resulting in the emergence of the modern anatomical bauplan, the focalization of certain activities in the landscape, the use of stone tools, and the exit from Africa. It is in this period that clear taphonomic evidence of a switch in diet with respect to Pliocene hominins occurred, with the adoption of carnivory. Until now, the degree of carnivorism in early humans remained controversial. A persistent hypothesis is that hominins acquired meat irregularly (potentially as fallback food) and opportunistically through klepto-foraging. Here, we test this hypothesis and show, in contrast, that the butchery practices of early Pleistocene hominins (unveiled through systematic study of the patterning and intensity of cut marks on their prey) could not have resulted from having frequent secondary access to carcasses. We provide evidence of hominin primary access to animal resources and emphasize the role that meat played in their diets, their ecology and their anatomical evolution, ultimately resulting in the ecologically unrestricted terrestrial adaptation of our species. This has major implications to the evolution of human physiology and potentially for the evolution of the human brain.

The dietary carotenoids provide photoprotection to photosynthetic organisms, the eye and the skin. The protection mechanisms involve both quenching of singlet oxygen and of damaging free radicals. The mechanisms for singlet oxygen quenching and protection against free radicals are quite different - indeed, under some conditions, quenching of free radicals can lead to a switch from a beneficial anti-oxidant process to damaging pro-oxidative situation. Furthermore, while skin protection involves β-carotene or lycopene from a tomato-rich diet, protection of the macula involves the hydroxyl-carotenoids (xanthophylls) zeaxanthin and lutein. Time resolved studies of singlet oxygen and free radicals and their interaction with carotenoids via pulsed laser and fast electron spectroscopy (pulse radiolysis) and the possible involvement of amino acids are discussed and used to (1) speculate on the anti- and pro-oxidative mechanisms, (2) determine the most efficient singlet oxygen quencher and (3) demonstrate the benefits to photoprotection of the eye from the xanthophylls rather than from hydrocarbon carotenoids such as β-carotene.

Abstract MMP11 overexpression is a bad prognostic factor in various human carcinomas. Interestingly, this proteinase is not expressed in malignant cells themselves but is secreted by adjacent non-malignant mesenchymal/stromal cells, such as cancer associated fibroblasts (CAFs) and adipocytes (CAAs), which favors cancer cell survival and progression. As MMP11 negatively regulates adipogenesis in vitro, we hypothesized that it may play a role in whole body metabolism and energy homeostasis. We used an in vivo gain- (Mmp11-Tg mice) and loss- (Mmp11−/− mice) of-function approach to address the systemic function of MMP11. Strikingly, MMP11 overexpression protects against type 2 diabetes while Mmp11−/− mice exhibit hallmarks of metabolic syndrome. Moreover, Mmp11-Tg mice were protected from diet-induced obesity and display mitochondrial dysfunction, due to oxidative stress, and metabolic switch from oxidative phosphorylation to aerobic glycolysis. This Warburg-like effect observed in adipose tissues might provide a rationale for the deleterious impact of CAA-secreted MMP11, favouring tumor progression. MMP11 overexpression also leads to increased circulating IGF1 levels and the activation of the IGF1/AKT/FOXO1 cascade, an important metabolic signalling pathway. Our data reveal a major role for MMP11 in controlling energy metabolism, and provide new clues for understanding the relationship between metabolism, cancer progression and patient outcome.

OBJECTIVE: To investigate whether the promotion of breakdown of body fat and the increased energy expenditure associated with growth hormone (GH) affect the voluntary food intake of an obese organism. DESIGN: Wistar rats (15 months old) were first fed either a high-fat (HF) or a low-fat (LF) diet for 10 weeks. In the subsequent treatment period, two saline groups continued with either the HF or the LF diet, and rats of three other groups had their diet shifted from HF to LF and were treated with saline, human GH (hGH) or rat GH (rGH). hGH and rGH were given in a dose of 4 mg/kg per day. After 21 days of treatment and registration of food intake, rats were killed, blood was collected and tissues were excised. RESULTS: The HF diet produced a significant (P<0.05) increase in weight of fat pads compared with the LF diet: 69+/-5 g compared with 48+/-2 g. The switch from HF to LF diet combined with injections of saline alone decreased the intake of metabolizable energy, but fat pad weight did not decrease significantly (69+/-5 g compared with 63+/-6 g). The latter value was significantly (P<0.05) decreased (to 37+/-3 g) in groups treated with either hGH or rGH. Both GH treatments increased serum IGF-I and muscle weight, whereas the activity of adipose tissue lipoprotein lipase decreased significantly (P<0.01). During the first 9 days of treatment, food intake was significantly (P<0.01) depressed, from 27+/-1 g/kg per day in control rats to 14+/-2 and 16+/-4 g/kg per day in the hGH and rGH groups respectively. CONCLUSION: This study demonstrates that breakdown of adipose tissue and a transient decrease in voluntary food intake are parallel consequences of GH treatment in old and obese rats, and that the actions of hGH and rGH are very similar.

ABSTRACTWhile a substantial amount of dietary fats escape absorption in the human small intestine and reach the colon, the ability of resident microbiota to utilize these dietary fats for growth has not been investigated in detail. In this study, we used anin vitromultivessel simulator system of the human colon to reveal that the human gut microbiota is able to utilize typically consumed dietary fatty acids to sustain growth. Gut microbiota adapted quickly to a macronutrient switch from a balanced Western diet-type medium to its variant lacking carbohydrates and proteins. We defined specific genera that increased in their abundances on the fats-only medium, includingAlistipes,Bilophila, and several genera of the classGammaproteobacteria. In contrast, the abundances of well-known glycan and protein degraders, includingBacteroides,Clostridium, andRoseburiaspp., were reduced under such conditions. The predicted prevalences of microbial genes coding for fatty acid degradation enzymes and anaerobic respiratory reductases were significantly increased in the fats-only environment, whereas the abundance of glycan degradation genes was diminished. These changes also resulted in lower microbial production of short-chain fatty acids and antioxidants. Our findings provide justification for the previously observed alterations in gut microbiota observed in human and animal studies of high-fat diets.IMPORTANCEIncreased intake of fats in many developed countries has raised awareness of potentially harmful and beneficial effects of high fat consumption on human health. Some dietary fats escape digestion in the small intestine and reach the colon where they can be metabolized by gut microbiota. We show that human gut microbes are able to maintain a complex community when supplied with dietary fatty acids as the only nutrient and carbon sources. Such fatty acid-based growth leads to lower production of short-chain fatty acids and antioxidants by community members, which potentially have negative health consequences on the host.

Abstract Dietary restriction induces beneficial metabolic changes and prevents age-related deterioration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) shows protective effects on cells in various models of degenerative diseases. Here we studied whether circulating concentrations of MANF are associated with fasting-induced positive effects. We quantified the levels of circulating MANF from 40 human subjects before and after therapeutic fasting. As measured by an enzyme-linked immunosorbent assay (ELISA), the mean concentration of plasma MANF increased after an average fasting of 15 days. Plasma MANF levels correlated inversely with adiponectin, a hormone that regulates metabolism, thus suggesting that MANF levels are related to metabolic homeostasis. To study the effects of dietary intervention on MANF concentrations in mice, we developed an ELISA for mouse MANF and verified its specificity using MANF knock-out (KO) tissue. A switch from high-fat to normal diet increased MANF levels and downregulated the expression of unfolded protein response (UPR) genes in the liver, indicating decreased endoplasmic reticulum (ER) stress. Liver MANF and serum adiponectin concentrations correlated inversely in mice. Our findings demonstrate that MANF expression and secretion increases with dietary intervention. The MANF correlation to adiponectin and its possible involvement in metabolic regulation and overall health warrants further studies.

Background: Chronic activation of the innate immune system drives inflammation and contributes directly to atherosclerosis. Previously, we showed that macrophages in the atherogenic plaque undergo RIPK3-MLKL-dependent programmed necroptosis in response to sterile ligands such as oxidized LDL and damage-associated patterns (DAMPs) and necroptosis is active in advanced atherosclerotic plaques. Upstream of the RIPK3-MLKL necroptotic machinery lies RIPK1, which acts as a master switch that controls whether the cell undergoes NFκB-dependent inflammation, caspase-dependent apoptosis or necroptosis in response to extracellular stimuli. We therefore set out to investigate the role of RIPK1 in the development of atherosclerosis, which is largely driven by NFκB-dependent inflammation at early stages. We hypothesize that, unlike RIPK3 and MLKL, RIPK1 primarily drives NFκB-dependent inflammation in early atherogenic lesions and knocking down RIPK1 will reduce inflammatory cell activation and protect against the progression of atherosclerosis. Methods: We examined expression of RIPK1 protein and mRNA in both human and mouse atherosclerotic lesions, and using loss-of-function approaches in vitro in macrophages and endothelial cells to measure inflammatory responses. We administered weekly injections of RIPK1 anti-sense oligonucleotides (ASO) to Apoe -/- mice fed a cholesterol-rich (Western) diet for 8 weeks. Results: We find RIPK1 expression is abundant in early-stage atherosclerotic lesions in both humans and mice. Treatment with RIPK1 ASOs led to a reduction in aortic sinus and en face lesion areas (47.2% or 58.8% decrease relative to control, p<0.01) and plasma inflammatory cytokines (IL-1α, IL-17A, p<0.05) compared to controls. RIPK1 knockdown in macrophages decreased inflammatory genes (NFκB, TNFα, IL-1α) and in vivo LPS- and atherogenic diet-induced NF-κB activation. In endothelial cells, knockdown of RIPK1 prevented NF-κB translocation to the nucleus in response to TNFα, where accordingly there was a reduction in gene expression of IL1B, E-selectin and monocyte attachment. Conclusions: We have identified RIPK1 as a central driver of inflammation in atherosclerosis by its ability to activate the NF-κB pathway and promote inflammatory cytokine release. Given the high levels of RIPK1 expression in human atherosclerotic lesions, our study suggests RIPK1 as a future therapeutic target to reduce residual inflammation in patients at high risk of coronary artery disease.

Abstract Study question Can diet normalization or caloric restriction (CR) for two weeks be used as a preconception care intervention in obese Swiss mice to restore oocyte development and quality Summary answer Diet normalization or CR as short-term preconception care interventions in obese mice only partially restored oocyte quality but did improve overall developmental competence. What is known already Maternal metabolic disorders like obesity and metabolic syndrome may result in decreased oocyte and embryo quality, and thus reproductive failure. Overweight and obese patients are advised to lose weight before conception to increase the chance of a healthy pregnancy. However, as human studies show no univocal guidelines, more fundamental research might provide additional answers. In order to avoid interference with increased maternal age, the question remains if oocyte quality can be restored after only a short preconception care intervention (PCCI). Study design, size, duration Outbred mice were fed a control (CTRL) or high-fat/high-sugar (HF) diet for seven weeks. Afterwards, HF-mice were put on different PCCIs for two weeks, resulting in four treatment groups: control diet (9w; CTRL_CTRL), HF diet (9w; HF_HF), switch from HF (7w) to an ad libitum control diet for 2w (HF_CTRL) or to a 30% CR diet for 2w (HF_CR). Oocyte developmental competence (n = 357) and quality (12-16 oocytes /treatment, scored blinded) were determined, using 6-8 mice/treatment. Participants/materials, setting, methods Body weight changes were recorded. In vivo matured oocytes were collected after superovulation and analysed for quality or in vitro fertilized and cultured. Oocyte quality was determined by staining for lipid content (Bodipy) and mitochondrial inner membrane potential and active mitochondria localization (JC-1). Oocyte developmental competence [cleavage (24h p.i.) and blastocyst rates (5 days p.i.)] was scored. Categorical and numerical data were analysed using binary logistic regression and ANOVA, respectively and corrected for multiple testing. Main results and the role of chance Compared to the CTRL group, HF diet increased body weight after 7 weeks by 24.19% (P &lt; 0.001). After the start of the PCCI, both HF_CTRL and HF_CR mice progressively lost weight and reached values similar to control mice after two weeks. HF_HF diet increased the intracellular lipid content in oocytes with 54.3% compared to the CTRL_CTRL group (P &lt; 0.05). This increased content was (partially) normalized in both preconception care intervention groups, even similar to the control levels in the HF_CTRL group. Both HF_HF and HF_CR oocytes showed a tendency to an increased ratio of active/total mitochondria when compared to the CTRL_CTRL group (P = 0.081, P = 0.083 respectively). In addition, active oocyte mitochondria in the HF_HF group were less pericortically distributed compared to controls. This was also the case in both preconception care intervention groups (P &lt; 0.05). After two weeks of PCCI, oocytes from HF_HF mice displayed lower cleavage rates than those from CTRL_CTRL mice (36.26% vs. 64.52%, P &lt; 0.05) but blastocyst rates (26.37% vs. 35.48%, P &gt; 0.1) were not different. HF_CR, but not HF_CTRL, oocytes showed higher cleavage rates (68.48%, P &lt; 0.001) compared with HF_HF oocytes. Moreover, both HF_CTRL (44.64%, P &lt; 0.05) and HF_CR (59.78%, P &lt; 0.001) oocytes showed improved blastocyst rates when compared to the HF_HF group (26.37%). Limitations, reasons for caution Although using a mouse model has several advantages, translating these results to the human setting is a limitation of this study. However, to improve this translatability, an outbred mouse model was used. Additional data will be collected to gain more information regarding the best preconception care intervention advice. Wider implications of the findings This research aims to provide fundamental insights in order to be able to formulate clear preconception guidelines to obese women planning for pregnancy. In addition, we aim to find the shortest possible intervention period to improve fertility. Trial registration number Not applicable

AbstractRosiglitazone is an effective insulin-sensitizer, however associated with bone loss mainly due to increased bone resorption and bone marrow adiposity. We investigated the effect of the co-administration of fish oil rich in omega-3 fatty acids (FAs) on rosiglitazone-induced bone loss in C57BL/6 mice and the mechanisms underlying potential preventive effect. Mice fed the iso-caloric diet supplemented with fish oil exhibited significantly higher levels of bone density in different regions compared to the other groups. In the same cohort of mice, reduced activity of COX-2, enhanced activity of alkaline phosphatase, lower levels of cathepsin k, PPAR-γ, and pro-inflammatory cytokines, and a higher level of anti-inflammatory cytokines were observed. Moreover, fish oil restored rosiglitazone-induced down-regulation of osteoblast differentiation and up-regulation of adipocyte differentiation in C3H10T1/2 cells and inhibited the up-regulation of osteoclast differentiation of RANKL-treated RAW264.7 cells. We finally tested our hypothesis on human Mesenchymal Stromal Cells differentiated to osteocytes and adipocytes confirming the beneficial effect of docosahexaenoic acid (DHA) omega-3 FA during treatment with rosiglitazone, through the down-regulation of adipogenic genes, such as adipsin and FABP4 along the PPARγ/FABP4 axis, and reducing the capability of osteocytes to switch toward adipogenesis. Fish oil may prevent rosiglitazone-induced bone loss by inhibiting inflammation, osteoclastogenesis, and adipogenesis and by enhancing osteogenesis in the bone microenvironment.

The comprehended knowledge of the metabolic profile of the fecal matter has been recognized as an important point for understanding metabolic changes in the human systemic metabolism and it can provide precious information about host-gut microbiota interactions. However, few analytical strategies have been addressed for a broad analysis of metabolites with different chemical properties to better understand the chemical space of fecal samples. Here we report a systematic pipeline to achieve comprehensive coverage of the fecal metabolome, from high polar to nonpolar metabolites, using dog fecal samples as a proof-of-concept. This pipeline comprises a monophasic (ACN/H2O) and a biphasic extraction (methyl tert-butyl ether (MTBE)/MeOH/H2O) of the sample, followed by three liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS) methods using HILIC-amide, RP-C18 and CSH-C18 columns, and a switch polarity acquisition mode in the electrospray ion source. This approach allowed the annotation of 376 metabolites from 70 different chemical classes. The chemical space analysis by molecular networking and the pathway analysis revealed the complexity of the fecal sample and the importance of combined methods to better understand biochemical pathways. This pipeline can be used as a valuable tool to comprehend the relationship between host-gut microbiota metabolites and the influence of diet, medication, or environmental changes.

Abstract Background and Aims Tumor necrosis factor-α-induced gene/protein (TSG)-6 is a key factor influencing mesenchymal stem cells (MSCs) immunomodulatory properties, but its renoprotective efficacy is unknown. Using a novel swine model of renal artery stenosis (RAS) complicated by metabolic syndrome (Mets), we assessed the therapeutic effects of adipose tissue-derived MSCs-produced TSG-6 and mechanisms underlying the immunomodulatory properties of MSCs. Method Five groups of pigs (n=6 each) were studied after 16 weeks of diet-induced Mets and unilateral RAS (Mets+RAS), either untreated or treated 4 weeks earlier with a single intra-renal delivery of autologous posrcine adipose tissue-derived MSCs (pMSC). Lean, Mets, and RAS shams served as controls. We studied renal function in vivo (using CT imaging) and kidney histopathology and macrophage phenotype ex vivo. In vitro, TSG-6 levels were measured in conditioned media of human MSCs (hMSCs) incubated with or without TNF-α. Additionally, levels of the tubular injury marker LDH were measured in conditioned media after co-culturing macrophages with injured HK-2 cells (achieved by TNF-α and antimycin-A, AMA) with or without addition of TSG-6. The effects of TSG-6 on macrophage phenotype (M1/M2), adhesion, and migration capability were determined. Results Mets+RAS pigs showed increased renal M1 macrophages and renal vein TNF-α levels. After p-MSCs delivery, renal vein TSG-6 increased and TNF-α decreased, M1 macrophage switched to M2 (Fig. A),, renal function improved, and fibrosis alleviated. In vitro, TNF-α increased TSG-6 secretion by h-MSCs. TSG-6 decreased LDH release from injured HK-2, induced a macrophage phenotypic switch from M1 to M2 (Fig. B), and reduced M1 macrophage adhesion and migration (Fig. C). Conclusion TNF-α-induced TSG-6 release from MSCs in vivo and in vitro may decrease renal tubular cells injury, which is associated with and may be at least in part mediated by regulating macrophage function and phenotype.

Replacing SAFAs (saturated fatty acids) for vegetable PUFAs (polyunsaturated fatty acids) has a well documented positive effect on the lipoprotein pattern while the direct effect of dietary fatty acids composition on systemic inflammation remains to be proven. In well controlled randomised cross-over study with 15 overweight/obese postmenopausal women, the effect of dietary switch on systemic inflammation was investigated. A two 3 weeks dietary period either with predominant animal fat (SAFA, 29 caloric % SAFA) or vegetable fat (PUFA 25 % caloric % PUFA) were interrupted by wash-out period. The expected increasing effect on SAFA diet to LDL-C (low density cholesterol) and opposite effect of PUFA diet was documented following changes in fatty acid spectrum in VLDL (very low density cholesterol) particles. The switch from SAFA diet to PUFA diet produced a significant change of CRP (C-reactive protein) concentration (p<0.01) whereas similar trend of IL-18 did not reach statistical significance. In this study, previous in vitro results of different SAFA and PUFA proinflammatory effects with well documented molecular mechanisms were first proven in a clinical study. It could be stated that the substantial change of dietary fatty acid composition might influence proinflammatory effect in addition to traditional cardiovascular risk factors.

Introduction: Gut dysbiosis has been linked to hypertension in both rodents and humans. Microbial metabolites such as propionate have been shown to regulate blood pressure (BP), while butyrate, one of the major fermented end-products of fiber, reportedly produces beneficial anti-inflammatory effects in multiple dysbiosis-related diseases. Therefore, we tested the impact of a fiber-rich, butyrolytic diet on BP regulation and immune responses in the spontaneously hypertensive rats (SHR). Methods: SHR (5 wo) were placed on either the fructooligosaccharides/inulin-rich diet (Fiber, N=6), or its calorie-matched control diet (Control, N=6) (Research Diets, Inc.) for 10 weeks. Baseline BP was measured by tail cuff every week for the duration of the study. Fecal samples were collected for HPLC analysis of butyrate, and Lactobacillus population by QPCR. Manganese-enhanced magnetic resonance imaging was used to monitor neural activity in cardioregulatory brain regions. Blood was analyzed for circulating lymphocyte populations previously implicated in BP control in the SHR (CD3 + CD45 + , CD4 + CD25 + , CD8 + ). Results: Fiber-rich diet produced an increase in fecal butyrate levels as early as five weeks (Control vs. Fiber, 4.9umol/g vs. 9.7umol/g, p=0.068, N=6). This was associated with contraction of fecal Lactobacillus (47.5% vs. 5.9%, p=0.0008, N=6). However, we observed significantly higher systolic BP (181.4mmHg vs. 201.7 mmHg, p=0.0088, N=6) in the fiber group compared with control, beginning with week 9 post-diet switch. Changes in neural activation were observed in the paraventricular nucleus of hypothalamus (PVN) (3.3 voxel vs. 7.3 voxel, p=0.26) and amygdala (93.3 voxel vs. 31 voxel, p=0.0059, N=3). No changes in circulating T-lymphocytes were observed between the two groups: CD3 + CD45 + (32.4% vs. 32.1% lymphocytes); CD4 + CD25 + (1.05% vs. 0.78% lymphocytes); CD8 + (18.7% vs. 16.2% lymphocytes, N=6) at week 10 post-diet switch. Conclusion: Fiber-rich diet suppression of Gut Lactobacillus is associated with increase in BP in the SHR, independently of T-lymphocyte responses. The observed higher neural activity in PVN and lower in amygdala in the fiber group suggest direct effects of gut bacterial metabolites on brain cardioregulatory regions.

Abstract Arc-Pomc knockout mice have a disruption of the two neural enhancers for the Pomc (proopiomelanocortin) gene, resulting in selective loss of Pomc gene expression in the arcuate nucleus of the hypothalamus. This gene targeting strategy leaves pituitary Pomc expression unaffected. These mice are hyperphagic starting at weaning, and develop progressive obesity, infertility and insulin resistance over their lifetime. RM-493 (setmelanotide) is a melanocortin-4 receptor agonist that has shown promise in treating humans with Pomc null mutations. In this preclinical study, we investigated the effects of chronic RM-493 treatment using subcutaneously implanted osmotic minipumps in two groups of male mice: Arc-Pomc knockout mice, fed regular chow throughout the study period, and their wildtype counterparts, fed a 45% high-fat diet. Each of these groups of mice was randomized into three treatment cohorts at weaning: one that was given RM-493 throughout the entire study period (4–24 weeks of age, “RM-493” group), one that was given RM-493 only for the first 4 weeks of the study (4–8 weeks of age, “switch” group) and then switched to vehicle, and one cohort that received vehicle for the entire study (“vehicle” group). We serially measured body weight, food intake, body composition, glucose tolerance, insulin tolerance, and several measures of metabolism using the Comprehensive Lab Animal Monitoring System, including oxygen consumption, energy expenditure, ambulatory activity and lipid and glucose oxidation. Among other results, at the end of the study (24 weeks of age), Arc-Pomc knockout mice in the RM-493 group weighed significantly less than either the switch or vehicle groups (p&lt;0.05). Arc-Pomc knockout mice on RM-493 also had higher energy expenditure when compared to the switch and vehicle groups (p&lt;0.05). In addition, RM-493 improved the glucose-insulin index for Arc-Pomc knockout mice (p&lt;0.05). According to our preliminary results, wildtype mice on high-fat diet, treated chronically with RM-493, did not differ in any of these measurements from their switch and vehicle groups. We conclude that the obesity syndrome caused by a loss of hypothalamic Pomc expression was completely blocked by RM-493 treatment started before the onset of obesity, with no apparent desensitization to the drug’s action over 20 weeks. However, the beneficial effects of a single month’s treatment were steadily reversed within one month after switching to vehicle treatment. In contrast to the dramatic effects of RM-493 in the genetic obesity syndrome, at this time, there does not appear to be any phenotypic changes in wild-type mice with RM-493 administration on the development of obesity or secondary metabolic disruptions in response to high-fat diet consumption.

Background “The sense of taste,” write Nelson and colleagues in a 2002 issue of Nature, “provides animals with valuable information about the nature and quality of food. Mammals can recognize and respond to a diverse repertoire of chemical entities, including sugars, salts, acids and a wide range of toxic substances” (199). The authors go on to argue that several amino acids—the building blocks of proteins—taste delicious to humans and that “having a taste pathway dedicated to their detection probably had significant evolutionary implications”. They imply, but do not specify, that the evolutionary implications are positive. This may be the case with some amino acids, but contemporary tastes, and changes in them, are far from universally beneficial. Indeed, this article argues that modern food production shapes and distorts human taste with significant implications for health and wellbeing. Take the western taste for fried chipped potatoes, for example. According to Schlosser in Fast Food Nation, “In 1960, the typical American ate eighty-one pounds of fresh potatoes and about four pounds of frozen french fries. Today [2002] the typical American eats about forty-nine pounds of fresh potatoes every year—and more than thirty pounds of frozen french fries” (115). Nine-tenths of these chips are consumed in fast food restaurants which use mass-manufactured potato-based frozen products to provide this major “foodservice item” more quickly and cheaply than the equivalent dish prepared from raw ingredients. These choices, informed by human taste buds, have negative evolutionary implications, as does the apparently long-lasting consumer preference for fried goods cooked in trans-fats. “Numerous foods acquire their elastic properties (i.e., snap, mouth-feel, and hardness) from the colloidal fat crystal network comprised primarily of trans- and saturated fats. These hardstock fats contribute, along with numerous other factors, to the global epidemics related to metabolic syndrome and cardiovascular disease,” argues Michael A. Rogers (747). Policy makers and public health organisations continue to compare notes internationally about the best ways in which to persuade manufacturers and fast food purveyors to reduce the use of these trans-fats in their products (L’Abbé et al.), however, most manufacturers resist. Hank Cardello, a former fast food executive, argues that “many products are designed for ‘high hedonic value’, with carefully balanced combinations of salt, sugar and fat that, experience has shown, induce people to eat more” (quoted, Trivedi 41). Fortunately for the manufactured food industry, salt and sugar also help to preserve food, effectively prolonging the shelf life of pre-prepared and packaged goods. Physiological Factors As Glanz et al. discovered when surveying 2,967 adult Americans, “taste is the most important influence on their food choices, followed by cost” (1118). A person’s taste is to some extent an individual response to food stimuli, but the tongue’s taste buds respond to five basic categories of food: salty, sweet, sour, bitter, and umami. ‘Umami’ is a Japanese word indicating “delicious savoury taste” (Coughlan 11) and it is triggered by the amino acid glutamate. Japanese professor Kikunae Ikeda identified glutamate while investigating the taste of a particular seaweed which he believed was neither sweet, sour, bitter, or salty. When Ikeda combined the glutamate taste essence with sodium he formed the food additive sodium glutamate, which was patented in 1908 and subsequently went into commercial production (Japan Patent Office). Although individual, a person’s taste preferences are by no means fixed. There is ample evidence that people’s tastes are being distorted by modern food marketing practices that process foods to make them increasingly appealing to the average palate. In particular, this industrialisation of food promotes the growth of a snack market driven by salty and sugary foods, popularly constructed as posing a threat to health and wellbeing. “[E]xpanding waistlines [are] fuelled by a boom in fast food and a decline in physical activity” writes Stark, who reports upon the 2008 launch of a study into Australia’s future ‘fat bomb’. As Deborah Lupton notes, such reports were a particular feature of the mid 2000s when: intense concern about the ‘obesity epidemic’ intensified and peaked. Time magazine named 2004 ‘The Year of Obesity’. That year the World Health Organization’s Global Strategy on Diet, Physical Activity and Health was released and the [US] Centers for Disease Control predicted that a poor diet and lack of exercise would soon claim more lives than tobacco-related disease in the United States. (4) The American Heart Association recommends eating no more than 1500mg of salt per day (Hamzelou 11) but salt consumption in the USA averages more than twice this quantity, at 3500mg per day (Bernstein and Willett 1178). In the UK, a sustained campaign and public health-driven engagement with food manufacturers by CASH—Consensus Action on Salt and Health—resulted in a reduction of between 30 and 40 percent of added salt in processed foods between 2001 and 2011, with a knock-on 15 percent decline in the UK population’s salt intake overall. This is the largest reduction achieved by any developed nation (Brinsden et al.). “According to the [UK’s] National Institute for Health and Care Excellence (NICE), this will have reduced [UK] stroke and heart attack deaths by a minimum of 9,000 per year, with a saving in health care costs of at least £1.5bn a year” (MacGregor and Pombo). Whereas there has been some success over the past decade in reducing the amount of salt consumed, in the Western world the consumption of sugar continues to rise, as a graph cited in the New Scientist indicates (O’Callaghan). Regular warnings that sugar is associated with a range of health threats and delivers empty calories devoid of nutrition have failed to halt the increase in sugar consumption. Further, although some sugar is a natural product, processed foods tend to use a form invented in 1957: high-fructose corn syrup (HFCS). “HFCS is a gloopy solution of glucose and fructose” writes O’Callaghan, adding that it is “as sweet as table sugar but has typically been about 30% cheaper”. She cites Serge Ahmed, a French neuroscientist, as arguing that in a world of food sufficiency people do not need to consume more, so they need to be enticed to overeat by making food more pleasurable. Ahmed was part of a team that ran an experiment with cocaine-addicted rats, offering them a mutually exclusive choice between highly-sweetened water and cocaine: Our findings clearly indicate that intense sweetness can surpass cocaine reward, even in drug-sensitized and -addicted individuals. We speculate that the addictive potential of intense sweetness results from an inborn hypersensitivity to sweet tastants. In most mammals, including rats and humans, sweet receptors evolved in ancestral environments poor in sugars and are thus not adapted to high concentrations of sweet tastants. The supranormal stimulation of these receptors by sugar-rich diets, such as those now widely available in modern societies, would generate a supranormal reward signal in the brain, with the potential to override self-control mechanisms and thus lead to addiction. (Lenoir et al.) The Tongue and the Brain One of the implications of this research about the mammalian desire for sugar is that our taste for food is about more than how these foods actually taste in the mouth on our tongues. It is also about the neural response to the food we eat. The taste of French fries thus also includes that “snap, mouth-feel, and hardness” and the “colloidal fat crystal network” (Rogers, “Novel Structuring” 747). While there is no taste receptor for fats, these nutrients have important effects upon the brain. Wang et al. offered rats a highly fatty, but palatable, diet and allowed them to eat freely. 33 percent of the calories in the food were delivered via fat, compared with 21 percent in a normal diet. The animals almost doubled their usual calorific intake, both because the food had a 37 percent increased calorific content and also because the rats ate 47 percent more than was standard (2786). The research team discovered that in as little as three days the rats “had already lost almost all of their ability to respond to leptin” (Martindale 27). Leptin is a hormone that acts on the brain to communicate feelings of fullness, and is thus important in assisting animals to maintain a healthy body weight. The rats had also become insulin resistant. “Severe resistance to the metabolic effects of both leptin and insulin ensued after just 3 days of overfeeding” (Wang et al. 2786). Fast food restaurants typically offer highly palatable, high fat, high sugar, high salt, calorific foods which can deliver 130 percent of a day’s recommended fat intake, and almost a day’s worth of an adult man’s calories, in one meal. The impacts of maintaining such a diet over a comparatively short time-frame have been recorded in documentaries such as Super Size Me (Spurlock). The after effects of what we widely call “junk food” are also evident in rat studies. Neuroscientist Paul Kenny, who like Ahmed was investigating possible similarities between food- and cocaine-addicted rats, allowed his animals unlimited access to both rat ‘junk food’ and healthy food for rats. He then changed their diets. “The rats with unlimited access to junk food essentially went on a hunger strike. ‘It was as if they had become averse to healthy food’, says Kenny. It took two weeks before the animals began eating as much [healthy food] as those in the control group” (quoted, Trivedi 40). Developing a taste for certain food is consequently about much more than how they taste in the mouth; it constitutes an individual’s response to a mixture of taste, hormonal reactions and physiological changes. Choosing Health Glanz et al. conclude their study by commenting that “campaigns attempting to change people’s perception of the importance of nutrition will be interpreted in terms of existing values and beliefs. A more promising strategy might be to stress the good taste of healthful foods” (1126). Interestingly, this is the strategy already adopted by some health-focused cookbooks. I have 66 cookery books in my kitchen. None of ten books sampled from the five spaces in which these books are kept had ‘taste’ as an index entry, but three books had ‘taste’ in their titles: The Higher Taste, Taste of Life, and The Taste of Health. All three books seek to promote healthy eating, and they all date from the mid-1980s. It might be that taste is not mentioned in cookbook indexes because it is a sine qua non: a focus upon taste is so necessary and fundamental to a cookbook that it goes without saying. Yet, as the physiological evidence makes clear, what we find palatable is highly mutable, varying between people, and capable of changing significantly in comparatively short periods of time. The good news from the research studies is that the changes wrought by high salt, high sugar, high fat diets need not be permanent. Luciano Rossetti, one of the authors on Wang et al’s paper, told Martindale that the physiological changes are reversible, but added a note of caution: “the fatter a person becomes the more resistant they will be to the effects of leptin and the harder it is to reverse those effects” (27). Morgan Spurlock’s experience also indicates this. In his case it took the actor/director 14 months to lose the 11.1 kg (13 percent of his body mass) that he gained in the 30 days of his fast-food-only experiment. Trivedi was more fortunate, stating that, “After two weeks of going cold turkey, I can report I have successfully kicked my ice cream habit” (41). A reader’s letter in response to Trivedi’s article echoes this observation. She writes that “the best way to stop the craving was to switch to a diet of vegetables, seeds, nuts and fruits with a small amount of fish”, adding that “cravings stopped in just a week or two, and the diet was so effective that I no longer crave junk food even when it is in front of me” (Mackeown). Popular culture indicates a range of alternative ways to resist food manufacturers. In the West, there is a growing emphasis on organic farming methods and produce (Guthman), on sl called Urban Agriculture in the inner cities (Mason and Knowd), on farmers’ markets, where consumers can meet the producers of the food they eat (Guthrie et al.), and on the work of advocates of ‘real’ food, such as Jamie Oliver (Warrin). Food and wine festivals promote gourmet tourism along with an emphasis upon the quality of the food consumed, and consumption as a peak experience (Hall and Sharples), while environmental perspectives prompt awareness of ‘food miles’ (Weber and Matthews), fair trade (Getz and Shreck) and of land degradation, animal suffering, and the inequitable use of resources in the creation of the everyday Western diet (Dare, Costello and Green). The burgeoning of these different approaches has helped to stimulate a commensurate growth in relevant disciplinary fields such as Food Studies (Wessell and Brien). One thing that all these new ways of looking at food and taste have in common is that they are options for people who feel they have the right to choose what and when to eat; and to consume the tastes they prefer. This is not true of all groups of people in all countries. Hiding behind the public health campaigns that encourage people to exercise and eat fresh fruit and vegetables are the hidden “social determinants of health: The conditions in which people are born, grow, live, work and age, including the health system” (WHO 45). As the definitions explain, it is the “social determinants of health [that] are mostly responsible for health iniquities” with evidence from all countries around the world demonstrating that “in general, the lower an individual’s socioeconomic position, the worse his or her health” (WHO 45). For the comparatively disadvantaged, it may not be the taste of fast food that attracts them but the combination of price and convenience. If there is no ready access to cooking facilities, or safe food storage, or if a caregiver is simply too time-poor to plan and prepare meals for a family, junk food becomes a sensible choice and its palatability an added bonus. For those with the education, desire, and opportunity to break free of the taste for salty and sugary fats, however, there are a range of strategies to achieve this. There is a persuasive array of evidence that embracing a plant-based diet confers a multitude of health benefits for the individual, for the planet and for the animals whose lives and welfare would otherwise be sacrificed to feed us (Green, Costello and Dare). Such a choice does involve losing the taste for foods which make up the lion’s share of the Western diet, but any sense of deprivation only lasts for a short time. The fact is that our sense of taste responds to the stimuli offered. It may be that, notwithstanding the desires of Jamie Oliver and the like, a particular child never will never get to like broccoli, but it is also the case that broccoli tastes differently to me, seven years after becoming a vegan, than it ever did in the years in which I was omnivorous. When people tell me that they would love to adopt a plant-based diet but could not possibly give up cheese, it is difficult to reassure them that the pleasure they get now from that specific cocktail of salty fats will be more than compensated for by the sheer exhilaration of eating crisp, fresh fruits and vegetables in the future. Conclusion For decades, the mass market food industry has tweaked their products to make them hyper-palatable and difficult to resist. They do this through marketing experiments and consumer behaviour research, schooling taste buds and brains to anticipate and relish specific cocktails of sweet fats (cakes, biscuits, chocolate, ice cream) and salty fats (chips, hamburgers, cheese, salted nuts). They add ingredients to make these products stimulate taste buds more effectively, while also producing cheaper items with longer life on the shelves, reducing spoilage and the complexity of storage for retailers. Consumers are trained to like the tastes of these foods. Bitter, sour, and umami receptors are comparatively under-stimulated, with sweet, salty, and fat-based tastes favoured in their place. Western societies pay the price for this learned preference in high blood pressure, high cholesterol, diabetes, and obesity. Public health advocate Bruce Neal and colleagues, working to reduce added salt in processed foods, note that the food and manufacturing industries can now provide most of the calories that the world needs to survive. “The challenge now”, they argue, “is to have these same industries provide foods that support long and healthy adult lives. And in this regard there remains a very considerable way to go”. If the public were to believe that their sense of taste is mutable and has been distorted for corporate and industrial gain, and if they were to demand greater access to natural foods in their unprocessed state, then that journey towards a healthier future might be far less protracted than these and many other researchers seem to believe. References Bernstein, Adam, and Walter Willett. “Trends in 24-Hr Sodium Excretion in the United States, 1957–2003: A Systematic Review.” American Journal of Clinical Nutrition 92 (2010): 1172–1180. Bhaktivedanta Book Trust. 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Metabolically healthy obesity (MHO) accounts for roughly 35% of all obese patients. There is no clear consensus that has been reached on whether MHO is a stable condition or merely a transitory period between metabolically healthy lean and metabolically unhealthy obesity (MUO). Additionally, the mechanisms underlying MHO and any transition to MUO are not clear. Macrophages are the most common immune cells in adipose tissues and have a significant presence in atherosclerosis. Fas (or CD95), which is highly expressed on macrophages, is classically recognized as a pro-apoptotic cell surface receptor. However, Fas also plays a significant role as a pro-inflammatory molecule. Previously, we established a mouse model (ApoE-/-/miR155-/-; DKO mouse) of MHO, based on the criteria of not having metabolic syndrome (MetS) and insulin resistance (IR). In our current study, we hypothesized that MHO is a transition phase toward MUO, and that inflammation driven by our newly classified CD95+CD86- macrophages is a novel mechanism for this transition. We found that, with extended (24 weeks) high-fat diet feeding (HFD), MHO mice became MUO, shown by increased atherosclerosis. Mechanistically, we found the following: 1) at the MHO stage, DKO mice exhibited increased pro-inflammatory markers in adipose tissue, including CD95, and serum; 2) total adipose tissue macrophages (ATMs) increased; 3) CD95+CD86- subset of ATMs also increased; and 4) human aortic endothelial cells (HAECs) were activated (as determined by upregulated ICAM1 expression) when incubated with conditioned media from CD95+-containing DKO ATMs and human peripheral blood mononuclear cells-derived macrophages in comparison to respective controls. These results suggest that extended HFD in MHO mice promotes vascular inflammation and atherosclerosis via increasing CD95+ pro-inflammatory ATMs. In conclusion, we have identified a novel molecular mechanism underlying MHO transition to MUO with HFD. We have also found a previously unappreciated role of CD95+ macrophages as a potentially novel subset that may be utilized to assess pro-inflammatory characteristics of macrophages, specifically in adipose tissue in the absence of pro-inflammatory miR-155. These findings have provided novel insights on MHO transition to MUO and new therapeutic targets for the future treatment of MUO, MetS, other obese diseases, and type II diabetes.

Longing on a large scale is what makes history.Don DeLillo, UnderworldIntroductionWhile the media industries have been rather thoroughly dissected for their capacity to generate enthusiasm through well-honed practices of marketing and patterns of consumerism, any analysis of the shift underway to capture and modulate the ‘enthusiastic’ and affective labour of media industry practitioners themselves may still have much to learn by reaching back to the long tradition in Western philosophy: a tradition, starting with the Greeks that has almost always contrasted enthusiasm with reason (Heyd). To quote Hume: “Hope, pride, presumption, a warm imagination, together with ignorance, are … the true sources of enthusiasm” (73). Hume’s remarks are contextualised in protestant theological debates of the 18th century, where enthusiasm was a term for a religious practice, in which God possesses the believer. Especially English preachers and theologians were putting considerable energy into demonising this far too ecstatic form of belief in god (Heyd). This ambivalent attitude towards enthusiasm time-travels from the Greeks and the Enlightenment period straight into the 20th century. In 1929, William Henry Schoenau, an early author of self-help literature for the white-collar worker, aimed to gain a wider audience with the title: “Charm, Enthusiasm and Originality - their Acquisition and Use”. According to him, enthusiasm is necessary for the success of the salesman, and has to be generated by techniques such as a rigorous special diet and physical exercises of his facial muscles. But it also has to be controlled:Enthusiasm, when controlled by subtle repression, results in either élan, originality, magnetism, charm or “IT”, depending on the manner of its use. Uncontrolled enthusiasm results in blaring jazz, fanaticism and recklessness. A complete lack of enthusiasm produces the obsequious waiter and the uneducated street car conductor. (7)Though William Henry Schoenau got rather lost in his somewhat esoteric take on enthusiasm – for him it was a result of magnetic and electric currents – we argue that Schoenau had a point: Enthusiasm is a necessary affect in many forms of work, and especially so in the creative industries. It has to be generated, it sometimes has to be enacted, and it has also to be controlled. However, we disagree with Schoenau in one important issue: For us, enthusiasm can only be controlled up to a certain degree. Enthusiasm in the Creative IndustriesSchoenau wrote for an audience of salesmen and ambitious managers. This was simultaneous with the rise of Fordism. Most labour in Fordism was routine labour with the assembly line as its iconic representation. In mass-production itself, enthusiasm was not needed, often not even wanted. Henry Ford himself noted dryly: “Why do I get a human being when all I want is a pair of hands” (Kane 128). It was reserved for few occupational groups situated around the core of the mass-produced economy, such as salesmen, inventors, and leaders like him. “Henry Ford had a burning enthusiasm for the motor car” (Pearle 196).In industrial capitalism enthusiasm on a larger scale was not for the masses. It could be found in political movements, but hardly in the realm of work. This was different in the first socialist state. In the 1920s and 1930s Soviet Union the leaders turned their experience in stimulating a revolutionary mindset into a formula for industrial development – famously documented in Dziga Vertov’s “Enthusiasm. Symphony of the Donbass”.In capitalist countries things changed with the crisis of Fordism. The end of mass production and its transformation to flexible specialisation (Piore/Sabel) prepared the ground for a revival of enthusiasm on a large scale. Post-industrial economies rely on permanent innovation. Now discourses in media, management, and academia emphasise the relevance of buzzwords such as flexibility, adaptability, change, youth, speed, fun, and creativity. In social science debates around topics such as the cultural economy (Ray/Sayers, Cook et al., du Gay/Pryke, Amin/Thrift), affective labour (Lazzarato, Hardt/Negri, Virno) and creative industries (Florida, Hartley) gained in momentum (for an interesting take on enthusiasm see Bröckling). Enthusiasm has become an imperative for most professions. Those who are not on fire are in danger of getting fired. Producing and Consuming EnthusiasmOur interest in enthusiasm as affective labour emerged in an ethnographic and experimental project that we conducted in 2003-2007 in London’s creative industries. The project brought together three industrial and one academic partner to produce a reality TV show tailor-made for IPTV (internet-protocol-based television). During this project we encountered enthusiasm in many forms. Initially, we were faced with the need to be enthusiastic, while we established the project coalition. To be convincing, we had to pitch the commercial potential of such a project enthusiastically to our potential partners, and often we had to cope with rejections and start the search and pitch again (Caldwell). When the project coalition was set up, we as academic partners managed the network. In the following two years we had to cope with our partner’s different directions, different rhythms and different styles of enthusiasm. The TV producer for example had different ways to express excitement than the new media firm. Such differences resulted in conflicts and blockades, and part of our task as project managers was to rebuild an enthusiastic spirit after periods of frustration. At the same time enthusiasm was one of the ingredients of the digital object that we produced: `Real’ emotions form the material of most reality TV shows (Grindstaff). Affects are for reality TV, what steel was for a Fordist factory. We needed an enthusiastic audience as part of the filmed material. There is thus a need to elicit, select, engineer and film such emotions. To this aim we engaged with the participants and the audience in complex ways, sometimes by distancing ourselves, other times by consciously manipulating them, and at even other times by sharing enthusiasm (similar processes in respect to other emotions are ethnographically described in Hesmondhalgh/Baker). Generating and managing enthusiasm is obviously a necessary part of affective labour in the creative industries. However, just as Hesmondhalgh/Baker indicate, this seemingly simple claim is problematic.Affective Labour as Practice‘Affective labour’ is a term that describes labour through its products: ‘A feeling of ease, well-being, satisfaction, excitement, or passion’ (Hardt/Negri 292-293). Thus, the term ‘affective labour’ usually describes a sector by the area of human endeavour, which it commodifies. But the concept looses its coherence, if it is used to describe labour by its practice (for an analogue argument see Dowling). The latter is what interests us. Such a usage will have to re-introduce the notion of the working subject. To see affective labour as a practice should enable us to describe in more detail, how enthusiasm shapes the becoming of a cultural object. Who employed affect when and what kinds of affects in which way? Analysing enthusiasm as social practice and affective labour usually brings about one of two contrasting perceptions. On the one hand one can celebrate enthusiasm – like Pekka Himanen – as one of the key characteristics for a new work ethic emerging alongside the Protestant Ethic. On the other hand we find critique of the need to display affects. Barbara Ehrenreich shows how a forced display of enthusiasm becomes a requirement for all office workers to survive in late capitalism. Judging from our experience these two approaches need to be synthesized: Much affective labour consists in the display of affects, in showing off, in pretending. On the other hand, enthusiasm can only realise its potential, if it is ‘real’ (as opposed to enacted).With Ehrenreich, Hochschild and many others we think that an analysis of affective labour as a practice needs to start with a notion of expression. Enthusiasm can be expressed through excited gestures, rapid movements, raised voices, eyes wide open, clapping hands, speech. For us it was often impossible to separate which expression was ‘genuine’ and which was enacted. Judging from introspection, it is probable that many actors had a similar experience to ours: They mixed some genuine enthusiasm with more or less enforced forms of re-enactment. Perhaps re-enactment turned to a ‘real’ feeling: We enacted ourselves into an authentic mood - an effect that is also described as “deep acting” (Grandey). What can happen inside us, can also happen in social situations. German philosopher Max Scheler went to substantial lengths to make a case for the contagiousness of affects, and enthusiasm is one of the most contagious affects. Mutual contagiousness of enthusiasm can lead to collective elation, with or without genuine enthusiasm of all members. The difference of real, authentic affects and enacted affects is thus not only theoretically, but also empirically rather problematic. It is impossible to make convincing claims about the degree of authenticity of an affect. However, it is also impossible to ignore this ambivalence. Both ‘authentic’ and ‘faked’ enthusiasm can be affective labour, but they differ hugely in terms of their productive capacities.Enthusiasm as Productive ForceWhy is enthusiasm so important in the first place? The answer is threefold. Firstly, an enthusiastic worker is more productive. He or she will work more intensively, put in more commitment, is likely to go the so-called extra mile. Enthusiasm can create a surplus of labour and a surplus of value, thus a surplus of productivity. Secondly enthusiasm is part of the creative act. It can unleash energies and overcome self-imposed limitations. Thirdly enthusiasm is future-oriented, a stimulus for investment, always risky. Enthusiasm can be the affective equivalent of venture capital – but it is not reified in capital, but remains incorporated in labour. Thus enthusiasm not only leads to an increase of productivity, it can be productive itself. This is what makes it to one of the most precious commodities in the creative industries. To make this argument in more detail we need to turn to one of the key philosophers of affect.Thinking Enthusiasm with SpinozaFor Spinoza, all affects are derivatives of a first basic drive or appetite. Desire/appetite is the direct equivalent of what Spinoza calls Conatus: Our striving to increase our power. From this starting point, Spinoza derives two basic affects: pleasure/joy and sadness/pain. Pleasure/joy is the result of an increase of our power, and sadness/pain is the result of its decrease. Spinoza explains all other affects through this basic framework. Even though enthusiasm is not one of the affects that Spinoza mentions, we want to suggest that Spinoza’s approach enables us to understand the productivity of enthusiasm. Enthusiasm is a hybrid between desire (the drive) and joy (the basic affect). Like hope or fear, it is future-oriented. It is a desire (to increase our power) combined with an anticipated outcome. Present and the future are tightly bound. Enthusiasm differs in this respect from its closest relatives: hope and optimism. Both hope and optimism believe in the desired outcome, but only against the odds and with a presumption of doubt. Enthusiasm is a form of ecstatic and hyper-confident hope. It already rewards us with joy in the present.With Spinoza we can understand the magical trick of future-oriented enthusiasm: To be enthusiastic means to anticipate an outcome of an increased power. This anticipation increases our power in the present. The increased power in the present can then be used to achieve the increased power in the future. If successful, it becomes a self-fulfilling prophecy. It is this future-orientedness, which can make enthusiasm productive. Actions and PassionsIn its Greek origin (‘enthousiasmos’) to be enthusiastic meant to be possessed or inspired by a god. An enthusiast was someone with an intense religious fervour and sometimes someone with an exaggerated belief in religious inspiration. Accordingly, enthusiasm is often connected to the devotion to an ideal, cause, study or pursuit. In late capitalism, we get possessed by different gods. We get possessed by the gods of opportunity – in our case the opportunities of a new technology like IPTV. Obsessions cannot easily be switched on and off. This is part of affective labour: The ability to open up and let the gods of future-oriented enthusiasm take hold of us. We believe in something not for the sake of believing, but for the sake of what we believe in. But at the same time we know that we need to believe. The management of this contradiction is a problem of control. As enthusiasm now constitutes a precious commodity, we cannot leave it to mere chance. Spinoza addresses exactly this point. He distinguishes two kinds of affects, actions and passions. Actions are what we control, passions are what controls us. Joy (= the experience of increased power of acting) can also weaken, if someone is not able to control the affection that triggered the joy. In such a case it becomes a passion: An increase of power that weakens in the long run. Enthusiasm is often exactly this. How can enthusiasm as a passion be turned into an action? One possible answer is to control what Spinoza calls the ‘ideas’ of the bodily affections. For Spinoza, affections (affectiones) ‘strike’ the body, but affect (affectus) is formed of both, of the bodily affectiones, but also of our ideas of these affectiones. Can such ideas become convictions, beliefs, persuasions? Our experience suggests that this is indeed possible. The excitement about the creative possibilities of IPTV, for example, was turned into a conviction. We had internalised the affect as part of our beliefs. But we had internalised it for a prize: The more it became an idea the more stable it got, but the less it was a full, bodily affect, something that touched our nervous system. We gained power over it for the price that it became less powerful in its drive.Managing the UnmanageableIn all institutions and organisations enthusiasm needs to be managed on a regular basis. In project networks however the orchestration of affects faces a different set of obstacles than in traditional organizations. Power structures are often shifting and not formally defined. Project partners are likely to have diverging interests, different expectations and different views on how to collaborate. What might be a disappointing result for one partner can be a successful result for another one. Differences of interest can be accompanied by differences of the expression of enthusiasm. This was clearly the case in our project network. The TV company entered a state of hype and frenzy while pitching the project. They were expressing their enthusiasm with talk about prominent TV channels that would buy the product, and celebrities who would take part in the show. The new media company showed its commitment through the development of beautifully designed time plans and prototypes – one of them included the idea to advertise the logo of the project on banners placed on airplanes. This sort of enthusiastic presentation led the TV producer to oppose the vision of the new media’s brand developer: She perceived this as an example of unrealistic pipe dreams. In turn the TV producer’s repeated name-dropping led other partners to mistrust them.Timing was another reason why it seemed to be impossible to integrate the affective cohorts of all partners into one well-oiled machine. Work in TV production requires periods of heightened enthusiasm while shooting the script. Not surprisingly, TV professionals save up their energy for this time. In contrast, new media practitioners create their products on the go: hype and energy are spread over the whole work process. Their labour becomes materialised in detailed plans, concepts, and prototypes. In short, the affective machine of a project network needs orchestration. This is a question of management.As this management failed so often in our project, we could discover another issue in the universe of enthusiasm: Disappointed high spirits can easily turn into bitterness and hostility. High expectations can lead to a lack of motivation and finally to a loss of loyalty towards the product and towards other project partners. Thus managing enthusiasm is not just about timing. It is also about managing disappointment and frustration. These are techniques, which have to be well developed on the level of the self-management as well as group management.Beyond the ProjectWe want to conclude this paper with a scene that happened at the very end of the project. In a final meeting, all partners agreed – much to our surprise – that the product was a big success. At that time we as academic partners found this irritating. There were many reasons why we disagreed: we did not produce a new format, we did not get positive user feedback, and we could not sell the show to further broadcasters (our original aims). However, all of this did not seem to have any impact on this final assessment. At the time of the meeting this looked for us like surreal theatre. Looking back now, this display of enthusiasm was indeed perhaps a ‘rational’ thing to do. Most projects and products in the creative industries are not successful on the market (Frith). 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