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Journal articles on the topic 'Lipid anabolism'
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1
Krycer, James R., Lake-Ee Quek, Deanne Francis, Armella Zadoorian, Fiona C. Weiss, Kristen C. Cooke, Marin E. Nelson, et al. "Insulin signaling requires glucose to promote lipid anabolism in adipocytes." Journal of Biological Chemistry 295, no. 38 (July 28, 2020): 13250–66. http://dx.doi.org/10.1074/jbc.ra120.014907.
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Adipose tissue is essential for metabolic homeostasis, balancing lipid storage and mobilization based on nutritional status. This is coordinated by insulin, which triggers kinase signaling cascades to modulate numerous metabolic proteins, leading to increased glucose uptake and anabolic processes like lipogenesis. Given recent evidence that glucose is dispensable for adipocyte respiration, we sought to test whether glucose is necessary for insulin-stimulated anabolism. Examining lipogenesis in cultured adipocytes, glucose was essential for insulin to stimulate the synthesis of fatty acids and glyceride–glycerol. Importantly, glucose was dispensable for lipogenesis in the absence of insulin, suggesting that distinct carbon sources are used with or without insulin. Metabolic tracing studies revealed that glucose was required for insulin to stimulate pathways providing carbon substrate, NADPH, and glycerol 3-phosphate for lipid synthesis and storage. Glucose also displaced leucine as a lipogenic substrate and was necessary to suppress fatty acid oxidation. Together, glucose provided substrates and metabolic control for insulin to promote lipogenesis in adipocytes. This contrasted with the suppression of lipolysis by insulin signaling, which occurred independently of glucose. Given previous observations that signal transduction acts primarily before glucose uptake in adipocytes, these data are consistent with a model whereby insulin initially utilizes protein phosphorylation to stimulate lipid anabolism, which is sustained by subsequent glucose metabolism. Consequently, lipid abundance was sensitive to glucose availability, both during adipogenesis and in Drosophila flies in vivo. Together, these data highlight the importance of glucose metabolism to support insulin action, providing a complementary regulatory mechanism to signal transduction to stimulate adipose anabolism.
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Sanchez-Alvarez, Miguel, Qifeng Zhang, Fabian Finger, Michael J. O. Wakelam, and Chris Bakal. "Cell cycle progression is an essential regulatory component of phospholipid metabolism and membrane homeostasis." Open Biology 5, no. 9 (September 2015): 150093. http://dx.doi.org/10.1098/rsob.150093.
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We show that phospholipid anabolism does not occur uniformly during the metazoan cell cycle. Transition to S-phase is required for optimal mobilization of lipid precursors, synthesis of specific phospholipid species and endoplasmic reticulum (ER) homeostasis. Average changes observed in whole-cell phospholipid composition, and total ER lipid content, upon stimulation of cell growth can be explained by the cell cycle distribution of the population. TORC1 promotes phospholipid anabolism by slowing S/G2 progression. The cell cycle stage-specific nature of lipid biogenesis is dependent on p53. We propose that coupling lipid metabolism to cell cycle progression is a means by which cells have evolved to coordinate proliferation with cell and organelle growth.
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Bensinger, Steven, Yoko Kidani, M. Benjamin Hock, Joseph Argus, Evangelia Komisopoulou, and Thomas Graeber. "An essential role for SREBP signaling in T cell blastogenesis (47.17)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 47.17. http://dx.doi.org/10.4049/jimmunol.188.supp.47.17.
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Abstract Accumulating evidence indicates that cellular metabolism is an important regulator of T cell immunity. We and others have shown that activation of T cell rapidly initiates a robust genetic and biochemical program that drives the biosynthesis of lipids. Surprisingly, inhibiting lipid synthesis markedly decreases DNA synthesis and lymphocyte proliferation, suggesting a fundamental link between lipid anabolism and cell cycle progression. To date, the molecular mechanisms underlying these intriguing observations are largely undefined. The Sterol Regulatory Element Binding Proteins (SREBP) are b-HLH transcription factors with a well-placed role in lipid homeostasis. The impact of SREBPs on T cell development and function has not been evaluated. Herein we demonstrate an essential role for SREBPs in CD8 T cell blastogenesis. Gene expression and ChIP studies coupled with metabolic flux analysis revealed an essential role for SREBP signaling in the acquisition of a lipid anabolic program by blasting T cells. In the absence of SREBP activity, mitogen-stimulated T cells do not efficiently enlarge and arrest in G0/G1 of cell cycle before undergoing apoptosis-independent cell death. Homeostatic proliferation and antigen-specific viral immunity is also compromised in the absence of SREBP activity. Taken together, these data delineate a critical role for SREBPs in T cell growth and provide a mechanistic understanding of how SREBPs regulate the acquisition of anabolic metabolism in T cells.
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Wang, Shuang, Rasool Kamal, Yue Zhang, Renhui Zhou, Liting Lv, Qitian Huang, Siriguleng Qian, Sufang Zhang, and Zongbao Kent Zhao. "Expression of VHb Improved Lipid Production in Rhodosporidium toruloides." Energies 13, no. 17 (August 27, 2020): 4446. http://dx.doi.org/10.3390/en13174446.
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The oleaginous yeast Rhodosporidium toruloides has emerged as a robust host for production of microbial lipids as alternative biofuel feedstocks. Oxygen supply is a limiting factor for microbial lipid production, as lipid biosynthesis is highly oxygen-demanding. Vitreoscilla hemoglobin (VHb) is a protein capable of promoting oxygen delivery for anabolism. In this study, we developed R. toruloides with VHb expression for improved lipid production. The VHb expression cassette was integrated into the R. toruloides chromosome via the Agrobacterium-mediated transformation. In shake flask cultures, the engineered strain 4#-13 produced 34% more lipids than the parental strain did. Results obtained under reduced aeration conditions in 3 L bioreactor showed that lipid titer and lipid yield of the engineered strain 4#-13 were 116% and 71%, respectively, higher than those of the parental strain. Under high cell density culture conditions, the engineered strain 4#-13 grew faster and produced 72% more lipids. Our results demonstrated that the VHb gene is functional in R. toruloides for promoting lipid production. The strains described here may be further engineered by integrating extra genetic parts to attain robust producers for more valuable products. This should improve the economics of microbial lipids to facilitate a sustainable production of biodiesel and other lipid-based biofuels.
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De Oliveira, Matheus Pinto, and Marc Liesa. "The Role of Mitochondrial Fat Oxidation in Cancer Cell Proliferation and Survival." Cells 9, no. 12 (December 4, 2020): 2600. http://dx.doi.org/10.3390/cells9122600.
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Tumors remodel their metabolism to support anabolic processes needed for replication, as well as to survive nutrient scarcity and oxidative stress imposed by their changing environment. In most healthy tissues, the shift from anabolism to catabolism results in decreased glycolysis and elevated fatty acid oxidation (FAO). This change in the nutrient selected for oxidation is regulated by the glucose-fatty acid cycle, also known as the Randle cycle. Briefly, this cycle consists of a decrease in glycolysis caused by increased mitochondrial FAO in muscle as a result of elevated extracellular fatty acid availability. Closing the cycle, increased glycolysis in response to elevated extracellular glucose availability causes a decrease in mitochondrial FAO. This competition between glycolysis and FAO and its relationship with anabolism and catabolism is conserved in some cancers. Accordingly, decreasing glycolysis to lactate, even by diverting pyruvate to mitochondria, can stop proliferation. Moreover, colorectal cancer cells can effectively shift to FAO to survive both glucose restriction and increases in oxidative stress at the expense of decreasing anabolism. However, a subset of B-cell lymphomas and other cancers require a concurrent increase in mitochondrial FAO and glycolysis to support anabolism and proliferation, thus escaping the competing nature of the Randle cycle. How mitochondria are remodeled in these FAO-dependent lymphomas to preferably oxidize fat, while concurrently sustaining high glycolysis and increasing de novo fatty acid synthesis is unclear. Here, we review studies focusing on the role of mitochondrial FAO and mitochondrial-driven lipid synthesis in cancer proliferation and survival, specifically in colorectal cancer and lymphomas. We conclude that a specific metabolic liability of these FAO-dependent cancers could be a unique remodeling of mitochondrial function that licenses elevated FAO concurrent to high glycolysis and fatty acid synthesis. In addition, blocking this mitochondrial remodeling could selectively stop growth of tumors that shifted to mitochondrial FAO to survive oxidative stress and nutrient scarcity.
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Song, Rui, Mengxiao Hu, Xiyu Qin, Lili Qiu, Pengjie Wang, Xiaoxu Zhang, Rong Liu, and Xiaoyu Wang. "The Roles of Lipid Metabolism in the Pathogenesis of Chronic Diseases in the Elderly." Nutrients 15, no. 15 (August 3, 2023): 3433. http://dx.doi.org/10.3390/nu15153433.
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Lipid metabolism plays crucial roles in cellular processes such as hormone synthesis, energy production, and fat storage. Older adults are at risk of the dysregulation of lipid metabolism, which is associated with progressive declines in the physiological function of various organs. With advancing age, digestion and absorption commonly change, thereby resulting in decreased nutrient uptake. However, in the elderly population, the accumulation of excess fat becomes more pronounced due to a decline in the body’s capacity to utilize lipids effectively. This is characterized by enhanced adipocyte synthesis and reduced breakdown, along with diminished peripheral tissue utilization capacity. Excessive lipid accumulation in the body, which manifests as hyperlipidemia and accumulated visceral fat, is linked to several chronic lipid-related diseases, including cardiovascular disease, type 2 diabetes, obesity, and nonalcoholic fatty liver disease. This review provides a summary of the altered lipid metabolism during aging, including lipid digestion, absorption, anabolism, and catabolism, as well as their associations with age-related chronic diseases, which aids in developing nutritional interventions for older adults to prevent or alleviate age-related chronic diseases.
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Stuani, Lucille, Fabien Riols, Pierre Millard, Marie Sabatier, Aurélie Batut, Estelle Saland, Fanny Viars, et al. "Stable Isotope Labeling Highlights Enhanced Fatty Acid and Lipid Metabolism in Human Acute Myeloid Leukemia." International Journal of Molecular Sciences 19, no. 11 (October 25, 2018): 3325. http://dx.doi.org/10.3390/ijms19113325.
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Background: In Acute Myeloid Leukemia (AML), a complete response to chemotherapy is usually obtained after conventional chemotherapy but overall patient survival is poor due to highly frequent relapses. As opposed to chronic myeloid leukemia, B lymphoma or multiple myeloma, AML is one of the rare malignant hemopathies the therapy of which has not significantly improved during the past 30 years despite intense research efforts. One promising approach is to determine metabolic dependencies in AML cells. Moreover, two key metabolic enzymes, isocitrate dehydrogenases (IDH1/2), are mutated in more than 15% of AML patient, reinforcing the interest in studying metabolic reprogramming, in particular in this subgroup of patients. Methods: Using a multi-omics approach combining proteomics, lipidomics, and isotopic profiling of [U-13C] glucose and [U-13C] glutamine cultures with more classical biochemical analyses, we studied the impact of the IDH1 R132H mutation in AML cells on lipid biosynthesis. Results: Global proteomic and lipidomic approaches showed a dysregulation of lipid metabolism, especially an increase of phosphatidylinositol, sphingolipids (especially few species of ceramide, sphingosine, and sphinganine), free cholesterol and monounsaturated fatty acids in IDH1 mutant cells. Isotopic profiling of fatty acids revealed that higher lipid anabolism in IDH1 mutant cells corroborated with an increase in lipogenesis fluxes. Conclusions: This integrative approach was efficient to gain insight into metabolism and dynamics of lipid species in leukemic cells. Therefore, we have determined that lipid anabolism is strongly reprogrammed in IDH1 mutant AML cells with a crucial dysregulation of fatty acid metabolism and fluxes, both being mediated by 2-HG (2-Hydroxyglutarate) production.
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MacKinnon, Barbara M., and D. L. Lee. "Age-related changes in Heligmosomoides polygyrus (Nematoda): neutral lipid content in developing oocytes." Canadian Journal of Zoology 66, no. 12 (December 1, 1988): 2791–96. http://dx.doi.org/10.1139/z88-407.
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Changes in neutral lipid content of developing female gametes in Heligmosomoides polygyrus at 8, 12, 20, 40, 80, and 140 days postinfection (p.i.) were investigated and correlated with egg production by the worms over the same period. Egg production increased to day 20 p.i. when the average egg output for one female reached approximately 700 eggs/day. A decline in egg production occurred from 80 days p.i. until the end of the experiment (140 days p.i.). Neutral lipid content was low in oogonia from worms of all ages. Developing oocytes contained the highest levels of neutral lipid. There was a significant loss of lipid just before fertilization of the oocytes. An increase in lipid occurred in all developmental stages of gametes from day 8 to day 40 p.i., and a significant decline occurred thereafter to day 140 p.i. Although egg production and lipid content of the female reproductive tract showed similar trends, there was not a precise correlation. It is felt that nuclear and cytoplasmic processes other than lipid anabolism or catabolism within the developing gametes play a more important role in influencing egg output.
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Liu, L., Y. Yang, F. Yang, Y. Lin, K. Liu, X. Wang, and Y. Zhang. "A mechanistic investigation about hepatoxic effects of borneol using zebrafish." Human & Experimental Toxicology 42 (January 2, 2023): 096032712211490. http://dx.doi.org/10.1177/09603271221149011.
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Except for clinical value, borneol is routinely used in food and cosmetics with seldom safety evaluation. To investigate its hepatoxicity, we exposed 3 dpf (days post fertilization) larval zebrafish to borneol at a gradient of concentrations (200–500 μM) for 3 days. Herein, our results revealed that high doses of borneol (300–500 μM) caused liver size decrease or lateral lobe absence. Borneol also seriously disturbed the hepatic protein metabolism presented with the increased activity of alanine aminotransferase (ALT) and lipid metabolism shown with the increased level of triglycerides (TG) and total cholesterol (TC). The lipid accumulation (oil red staining) was detected as well. Additionally, significant upregulation of genes was detected that related to oxidative stress, lipid anabolism, endoplasmic reticulum stress (ERS), and autophagy. Conversely, the lipid metabolism-related genes were markedly downregulated. Moreover, the changes in the superoxide dismutase activity and the level of glutathione and malondialdehyde raised the likelihood of lipid peroxidation. The outcomes indicated the involvement of oxidative stress, ERS, lipid metabolism, and autophagy in borneol-induced lipid metabolic disorder and hepatic injury. This study will provide a more comprehensive understanding of borneol hepatoxicity and the theoretical basis for the safe use of this compound.
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Altumairah, Mohammed A. H., and Ravindra P. Choudhary. "Overview on Diabetes Mellitus." Journal of Medical and Health Studies 2, no. 2 (September 21, 2021): 63–69. http://dx.doi.org/10.32996/jmhs.2021.2.2.7.
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Diabetes mellitus is a group of diverse illnesses that often show hyperglycemia and glucose intolerance via insulin shortage, insulin impairment or both (Sicree et al., 2006). These difficulties occur due to disruptions in regulation systems controlling the storage and movement of metabolic fuels, including carbohydrate, lipid and protein catabolism and anabolism, induced by poor insulin production, insulin activity or both (Shillitoe, 1988; Votey and Peters, 2004). With more than 62 million diabetics already diagnosed in India, the situation of a potential pandemic is approaching fast.
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Hu, Haitao, Lun Tan, Xiaojiao Li, Jingjing Li, Caiyun Fan, Feng Huang, Zhao Zhuo, et al. "Betaine Reduces Lipid Anabolism and Promotes Lipid Transport in Mice Fed a High-Fat Diet by Influencing Intestinal Protein Expression." Foods 11, no. 16 (August 12, 2022): 2421. http://dx.doi.org/10.3390/foods11162421.
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Betaine is more efficient than choline and methionine methyl donors, as it can increase nitrogen storage, promote fat mobilisation and fatty acid oxidation and change body fat content and distribution. Lipid is absorbed primarily in the small intestine after consumption, which is also the basis of lipid metabolism. This study was conducted to establish a mouse model of obesity in Kunming mice of the same age and similar body weight, and to assess the effect of betaine on the intestinal protein expression profile of mice using a proteomic approach. Analysis showed that betaine supplementation reversed the reduction in expression of proteins related to lipid metabolism and transport in the intestine of mice induced by a high-fat diet (HFD). For example, the addition of betaine resulted in a significant upregulation of microsomal triglyceride transfer protein (Mttp), apolipoprotein A-IV (Apoa4), fatty-acid-binding protein 1 (Fabp1) and fatty-acid-binding protein 2 (Fabp2) expression compared to the HFD group (p < 0.05), which exhibited accelerated lipid absorption and then translocation from the intestine into the body’s circulation, in addition to a significant increase in Acetyl-CoA acyltransferase (Acaa1a) protein expression, hastening lipid metabolism in the intestine (p < 0.05). Simultaneously, a significant reduction in protein expression of alpha-enolase 1 (Eno1) as the key enzyme for gluconeogenesis in mice in the betaine-supplemented group resulted in a reduction in lipid synthesis in the intestine (p < 0.05). These findings provide useful information for understanding the changes in the protein profile of the small intestine in response to betaine supplementation and the potential physiological regulation of diets’ nutrient absorption.
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Vlaardingerbroek, H., C. v. d. Akker, K. Dorst, H. Schierbeek, and J. v. Goudoever. "132 Early Lipid and High Dose Amino Acid Administration Increases Anabolism in Vlbw Infants." Archives of Disease in Childhood 97, Suppl 2 (October 1, 2012): A37. http://dx.doi.org/10.1136/archdischild-2012-302724.0132.
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Sun, Peng, Min Jin, Lefei Jiao, Óscar Monroig, Juan Carlos Navarro, Douglas R. Tocher, Mónica B. Betancor, Xuexi Wang, Ye Yuan, and Qicun Zhou. "Effects of dietary lipid level on growth, fatty acid profiles, antioxidant capacity and expression of genes involved in lipid metabolism in juvenile swimming crab, Portunus trituberculatus." British Journal of Nutrition 123, no. 2 (October 11, 2019): 149–60. http://dx.doi.org/10.1017/s0007114519002563.
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AbstractThe regulation of lipogenesis and lipolysis mechanisms related to consumption of lipid has not been studied in swimming crab. The aims of the present study were to evaluate the effects of dietary lipid levels on growth, enzymes activities and expression of genes of lipid metabolism in hepatopancreas of juvenile swimming crab. Three isonitrogenous diets were formulated to contain crude lipid levels at 5·8, 9·9 and 15·1 %. Crabs fed the diet containing 15·1 % lipid had significantly lower growth performance and feed utilisation than those fed the 5·8 and 9·9 % lipid diets. Crabs fed 5·8 % lipid had lower malondialdehyde concentrations in the haemolymph and hepatopancreas than those fed the other diets. Highest glutathione peroxidase in haemolymph and superoxide dismutase in hepatopancreas were observed in crabs fed 5·8 % lipid. The lowest fatty acid synthase and glucose 6-phosphate dehydrogenase activities in hepatopancreas were observed in crabs fed 15·1 % lipid, whereas crabs fed 5·8 % lipid had lower carnitine palmitoyltransferase-1 activity than those fed the other diets. Crabs fed 15·1 % lipid showed lower hepatopancreas expression of genes involved in long-chain-PUFA biosynthesis, lipoprotein clearance, fatty acid uptake, fatty acid oxidation, lipid anabolism and lipid catabolism than those fed the other diets, whereas expression of some genes of lipoprotein assembly and fatty acid oxidation was up-regulated compared with crabs fed 5·8 % lipid. Overall, high dietary lipid level can inhibit growth, reduce antioxidant enzyme activities and influence lipid metabolic pathways to regulate lipid deposition in crab.
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Savchenko, A. A., D. E. Zdzitovetsky, and N. A. Luzan. "COMMUNICATION OF NAD- AND NADP-DEPENDENT DEHYDROGENASE ACTIVITIES IN LYMPHOCYTES WITH OUTCOME OF PREVALENCE PURULENT PERITONITIS." Bulletin of Siberian Medicine 13, no. 5 (October 28, 2014): 79–86. http://dx.doi.org/10.20538/1682-0363-2014-5-79-86.
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Aim of this study was to investigate of NAD(P)-dependent dehydrogenases activity in lymphocytes at different outcomes widespread purulent peritonitis(WPP). Enzyme activity in blood lymphocytes was determined by bioluminescent method. Found that patients with a poor outcome of WPP in blood lymphocytes made more pronounced reaction of lipid anabolism and catabolism of xenobiotics. Regardless of the outcome of the disease in blood lymphocytes of WPP patients reduced levels of enzymes activity that determine the intensity of anaerobic and aerobic respiration and the level of plastic processes, but the activation reactions of lipid catabolism and transport products through glycerol-3-phosphate dehydrogenase on reactions of glycolysis. Based on the informativeness of the NAD(P)-dependent dehydrogenases activity in the classification neural network model for the disease outcome, metabolic coefficient is proposed, which has prognostic significance.
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Singh, Amit, David K. Crossman, Deborah Mai, Loni Guidry, Martin I. Voskuil, Matthew B. Renfrow, and Adrie J. C. Steyn. "Mycobacterium tuberculosis WhiB3 Maintains Redox Homeostasis by Regulating Virulence Lipid Anabolism to Modulate Macrophage Response." PLoS Pathogens 5, no. 8 (August 14, 2009): e1000545. http://dx.doi.org/10.1371/journal.ppat.1000545.
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Finlay, Liam A., Alex J. Michels, Judy A. Butler, Eric J. Smith, Jeffrey S. Monette, Régis F. Moreau, Shay Kate Petersen, Balz Frei, and Tory M. Hagen. "R-α-lipoic acid does not reverse hepatic inflammation of aging, but lowers lipid anabolism, while accentuating circadian rhythm transcript profiles." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 302, no. 5 (March 1, 2012): R587—R597. http://dx.doi.org/10.1152/ajpregu.00393.2011.
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To determine the effects of age and lipoic acid supplementation on hepatic gene expression, we fed young (3 mo) and old (24 mo) male Fischer 344 rats a diet with or without 0.2% (wt/wt) R-α-lipoic acid (LA) for 2 wk. Total RNA isolated from liver tissue was analyzed by Affymetrix microarray to examine changes in transcriptional profiles. Results showed elevated proinflammatory gene expression in the aging liver and evidence for increased immune cell activation and tissue remodeling, together representing 45% of the age-related transcriptome changes. In addition, age-related increases in transcripts of genes related to fatty acid, triglyceride, and cholesterol synthesis, including acetyl-CoA carboxylase-β (Acacb) and fatty acid synthase (Fasn), were observed. Supplementation of old animals with LA did not reverse the necroinflammatory phenotype but, intriguingly, altered the expression of genes governing circadian rhythm. Most notably, Arntl, Npas2, and Per changed in a coordinated manner with respect to rhythmic transcription. LA further caused a decrease in transcripts of several bile acid and lipid synthesis genes, including Acacb and Fasn, which are regulated by first-order clock transcription factors. Similar effects of LA supplementation on bile acid and lipid synthesis genes were observed in young animals. Transcript changes of lipid metabolism genes were corroborated by a decrease in FASN and ACC protein levels. We conclude that advanced age is associated with a necroinflammatory phenotype and increased lipid synthesis, while chronic LA supplementation influences hepatic genes associated with lipid and energy metabolism and circadian rhythm, regardless of age.
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Pelz, Katherine, Grace McCarthy, Heike Mendez, Samantha Z. Brown, Jonathan R. Brody, and Aaron J. Grossberg. "Abstract PO-023: Impaired adipose anabolism drives fat wasting in pancreatic cancer cachexia." Cancer Research 81, no. 22_Supplement (November 15, 2021): PO—023—PO—023. http://dx.doi.org/10.1158/1538-7445.panca21-po-023.
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Abstract Purpose/Objectives: The disease associated wasting condition, cachexia, is a common complication of pancreatic ductal adenocarcinoma (PDAC) that impacts quality of life and portends poor survival. Cachexia remains refractory to nutritional supplementation, but the mechanisms underlying this phenotype are unclear. By examining the adipose response to different nutritional contexts in cachectic mice, we sought to understand the relative contributions of enhanced catabolism and impaired anabolism on adipose tissue wasting. Materials/Methods: Adult C57BL/6J mice received orthotopic PDAC tumor injections (KrasG12D; p53R172H/+; Pdx1-cre) or sham injections. Mice were fasted 24 h or fasted and refed 24 h at mid-cachexia time point, and gross fat pads were weighed to assess anabolic potential. 3T3-L1 cells were treated with PDAC cell conditioned media during or after differentiation to model cachexia in vitro. Lipolytic rate was quantified as normalized quantity of glycerol released from inguinal (iWAT) and gonadal (gWAT) fat pads ex vivo or differentiated 3T3-L1 cells in vitro. Lipogenesis was measured in vitro using Oil-red-O staining. Adipose tissue mRNA levels were measured using bulk RNAseq and confirmed with qPCR. Malabsorption was assessed via fecal protease activity and total fecal protein and lipid content. Results: Adipose tissue in PDAC and control mice were equally sensitive to fasting/food restriction. Both iWAT and gWAT fat pads from PDAC mice showed decreased lipolysis ex vivo, associated with decreased lipase (Atgl & Lipe) mRNA expression. In the fast/refeed paradigm, PDAC mice were unable to restore both iWAT and gWAT mass after refeed, in contrast to control mice. We found no evidence of malabsorption at this timepoint by any measure. RNAseq on gWAT revealed 614 differentially expressed genes between PDAC and control mice. Downregulated (n=111) genes were most closely associated with adipogenesis (adj p<.05), and expression of adipogenesis master regulators Pparg and Cebpa reduced in WAT from PDAC mice. Upregulated genes were associated with increased RELA and NFkB activity (adj p<5 × 10−22) and inflammatory response hallmarks. Treatment of 3T3-L1 cells with PDAC conditioned media phenocopied in vivo model, showing impaired lipolysis and lipogenesis, associated with decreased expression of lipolytic, adipogenic, and lipogenic genes. Conclusions: Adipose tissue wasting in PDAC cachexia can result from impaired anabolism in the absence of enhanced lipolysis or malabsorption. This deficit in adipogenesis is mediated by a cancer cell secreted product and is associated with increased inflammatory signaling in adipocytes, most likely via RELA and NFkB activity. Restoring adipose anabolic potential may provide a novel approach to cachexia treatment in PDAC. Citation Format: Katherine Pelz, Grace McCarthy, Heike Mendez, Samantha Z. Brown, Jonathan R. Brody, Aaron J. Grossberg. Impaired adipose anabolism drives fat wasting in pancreatic cancer cachexia [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-023.
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Mylonis, Ilias, George Simos, and Efrosyni Paraskeva. "Hypoxia-Inducible Factors and the Regulation of Lipid Metabolism." Cells 8, no. 3 (March 3, 2019): 214. http://dx.doi.org/10.3390/cells8030214.
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Oxygen deprivation or hypoxia characterizes a number of serious pathological conditions and elicits a number of adaptive changes that are mainly mediated at the transcriptional level by the family of hypoxia-inducible factors (HIFs). The HIF target gene repertoire includes genes responsible for the regulation of metabolism, oxygen delivery and cell survival. Although the involvement of HIFs in the regulation of carbohydrate metabolism and the switch to anaerobic glycolysis under hypoxia is well established, their role in the control of lipid anabolism and catabolism remains still relatively obscure. Recent evidence indicates that many aspects of lipid metabolism are modified during hypoxia or in tumor cells in a HIF-dependent manner, contributing significantly to the pathogenesis and/or progression of cancer and metabolic disorders. However, direct transcriptional regulation by HIFs has been only demonstrated in relatively few cases, leaving open the exact and isoform-specific mechanisms that underlie HIF-dependency. This review summarizes the evidence for both direct and indirect roles of HIFs in the regulation of genes involved in lipid metabolism as well as the involvement of HIFs in various diseases as demonstrated by studies with transgenic animal models.
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Liu, Mingyang, Xiaochuan Zheng, Cunxin Sun, Qunlan Zhou, Bo Liu, and Pao Xu. "Tea Tree Oil Mediates Antioxidant Factors Relish and Nrf2-Autophagy Axis Regulating the Lipid Metabolism of Macrobrachium rosenbergii." Antioxidants 11, no. 11 (November 16, 2022): 2260. http://dx.doi.org/10.3390/antiox11112260.
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Both oxidative stress and autophagy refer to regulating fat metabolism, and the former affects autophagy, but the role and mechanism of the antioxidant–autophagy axis in regulating lipid metabolism remains unclear. As an antioxidant, tea tree oil (TTO) has little research on the regulatory mechanism of lipid metabolism in crustaceans. This study investigated whether TTO could alter hepatopancreatic lipid metabolism by affecting the antioxidant–autophagy axis. Feed Macrobrachium rosenbergii with three different levels of TTO diets for 8 weeks: CT (0 mg/kg TTO), 100TTO (100 mg/kg TTO), and 1000TTO (1000 mg/kg TTO). The results showed that 100TTO treatment reduced the hemolymph lipids level and hepatopancreatic lipid deposition compared to CT. In contrast, 1000TTO treatment increased hepatopancreatic lipid deposition, damaging both morphology and function in the hepatopancreas. The 100TTO treatment promoted lipolysis and reduced liposynthesis at the transcriptional level compared to the CT group. Meanwhile, it improved the hepatopancreas antioxidant capacity and maintained mitochondrial structural and ROS homeostasis. In addition, it simultaneously activated the expression of transcription factors Keap1-Nrf2 and Imd-Relish. By contrast, the 1000TTO group significantly enhanced the ROS level, which considerably activated the Keap1-Nrf2 signaling expression but had no significant effects on the expression of Imd-Relish. The 100TTO group supplementation significantly enhanced lipid droplet breakdown and autophagy-related genes and protein expression. On the contrary, the 1000TTO group significantly inhibited the expression of genes and proteins related to autophagy. Pearson analysis revealed that Nrf2 has a positive correlation to lipid anabolism-related genes (Fasn, Srebp1, Pparγ) and autophagy regulators (mtor, akt, p62), and were negatively correlated with lipolysis-related genes (Cpt1, Hsl, Ampkα) and autophagy markers (Ulk1, Lc3). Relish was positively correlated with Atgl, Cpt1, Ampkα, Ulk1, and Lc3, and negatively correlated with Pparγ and p62. Moreover, Keap1 and Imd were negatively correlated with p62 and mtor, respectively. In sum, 100 mg/kg TTO enhanced antioxidant activity and increased autophagy intensity through the Relish-Imd pathway to enhance lipid droplet breakdown, while 1000 mg/kg TTO overexpressed Nrf2, thus inhibiting autophagy and ultimately causing excessive lipid deposition and peroxidation. Our study gives a fresh perspective for deciphering the bidirectional regulation mechanism of lipid metabolism by different doses of TTO based on the antioxidant–autophagy axis.
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Tan, Jiaorong, Jiahong Xu, Guohua Wei, Lijuan Zhang, Long’e Sun, Guangyu Wang, Fei Li, and Fengxiang Jiang. "HNF1α Controls Liver Lipid Metabolism and Insulin Resistance via Negatively Regulating the SOCS-3-STAT3 Signaling Pathway." Journal of Diabetes Research 2019 (May 15, 2019): 1–15. http://dx.doi.org/10.1155/2019/5483946.
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This study is aimed at evaluating the effects, functions, and mechanism of HNF1α on hepatic glycolipid metabolism. In this study, free fatty acid- (FFA-) induced steatosis of hepatocyte liver cell LO2 was used as an in vitro model. The methods of Oil Red O staining, RT-qPCR, western blot, and immunofluorescence staining were used to detect LO2-regulated HNF1α expression and its effects on FFA-induced LO2 cell steatosis, the insulin signaling and SOCS-3-STAT3 signaling pathways, the expression of lipid metabolism-related regulators, and phosphorylation. With increased FFA induction time, the expression of HNF1α in the LO2 fatty degeneration hepatic cells gradually decreased. Downregulation of HNF1α expression aggravated FFA-induced steatosis of LO2 hepatocytes. HNF1α promotes activation of the insulin pathway and oxidative breakdown of fat and inhibits lipid anabolism. Inhibitors of STAT3 can reverse the regulation of decreased HNF1α expression on the insulin signaling pathway and fat metabolism. We also confirmed this pathway using HNF1α-/- mice combining treatment with STAT3 inhibitor NSC 74859 in vivo. HNF1α regulates hepatic lipid metabolism by promoting the expression of SOCS-3 and negatively regulating the STAT3 signaling pathway.
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Yang, Woojung, Jae-woo Lee, Yonghwan Kim, Jong Hun Lee, and Hee-Taik Kang. "Increased Omega-3 Fatty Acid Intake is Inversely Associated with Sarcopenic Obesity in Women but not in Men, Based on the 2014–2018 Korean National Health and Nutrition Examination Survey." Journal of Clinical Medicine 9, no. 12 (November 27, 2020): 3856. http://dx.doi.org/10.3390/jcm9123856.
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(1) Background: Omega-3 fatty acids (ω3FAs) are known to improve protein anabolism, increase the sensitivity to anabolic stimuli, decrease lipogenesis, and stimulate lipid oxidation. We aim to investigate whether ω3FAs are associated with the prevalence of sarcopenic obesity (SO). (2) Methods: Data were obtained from the 2014–2018 Korean National Health and Nutrition Examination Survey. The ratio of daily ω3FA intake to energy intake (ω3FA ratio) was categorized into four quartile groups. (3) Results: The prevalence of SO from Q1 to Q4 was 8.9%, 11.3%, 11.0%, and 9.8% respectively, in men and 17.4%, 14.0%, 13.9%, and 10.1% respectively, in women. The ω3FA ratio in individuals with and without SO were 1.0% and 0.9% in men (p-value = 0.271) respectively, and 0.8% and 1.0% in women (p-value = 0.017), respectively. Compared with Q1, odds ratios (95% confidence intervals) of Q2, Q3, and Q4 of ω3FA ratios were 1.563 (0.802–3.047), 1.246 (0.611–2.542), and 0.924 (0.458–1.864) respectively, in men and 0.663 (0.379–1.160), 0.640 (0.372–1.102), and 0.246 (0.113–0.534) respectively, in women, after fully adjusting for confounding factors. (4) Conclusions: The ω3FA ratio was significantly higher in older females without SO than in older females with SO. The ω3FA ratio was associated with the prevalence of SO in elderly females.
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Zhang, Wenge, Yu Qiao, Fulei Qi, Qingyi Shen, Ruqian Zhao, and Xiaojing Yang. "Zinc-α2-Glycoprotein Knockout Influenced Genes Expression Profile in Adipose Tissue and Decreased the Lipid Mobilizing After Dexamethasone Treatment in Mice." Hormone and Metabolic Research 52, no. 10 (June 15, 2020): 755–63. http://dx.doi.org/10.1055/a-1186-0649.
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AbstractZinc-α2-glycoprotein (ZAG), as an adipokine, plays an important role in lipid metabolism. However, its influence on whole gene expression profile in adipose tissue is not known. Under stress condition, how ZAG affects the lipid metabolism is also unclear. Therefore, in this study ZAG systemic knockout (KO) mice were used as a model to reveal the genes expression profile in visceral fat tissues of ZAG KO mice and wild-type mice by genome-wide microarray screening. Then dexamethasone (DEX) was used to explore the effect of ZAG deletion on body fat metabolism under stress. Our results showed that 179 genes were differentially expressed more than 1.5 times between ZAG KO mice and wild type mice, of which 26 genes were upregulated dramatically and 153 genes were significantly downregulated. Under DEX simulated stress, ZAG systemic knockout in vivo resulted in a markedly decrease of triglycerides (TG) and nonesterified fatty acid (NEFA) content in in plasma. Similarly, for lipid catabolism, ZAG KO led to a significant increase of phosphorylated HSL (p-HSL) protein and a rising tendency of adipose triglyceride lipase (ATGL) protein relative to those of the DEX group. For lipid anabolism, fatty acid synthase (FAS) and adiponectin protein expression in visceral fat rose notably in ZAG KO mice after DEX treatment. In conclusion, ZAG knockout can affect the gene expression profile of adipose tissue, reduce elevated TG and NEFA levels in plasma, and alter lipid metabolism under DEX treatment. These findings provide new insights into the mechanism of lipid metabolic disorders in response to stress.
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Hong-Brown, Ly Q., Anne M. Pruznak, Robert A. Frost, Thomas C. Vary, and Charles H. Lang. "Indinavir alters regulators of protein anabolism and catabolism in skeletal muscle." American Journal of Physiology-Endocrinology and Metabolism 289, no. 3 (September 2005): E382—E390. http://dx.doi.org/10.1152/ajpendo.00591.2004.
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The HIV protease inhibitor indinavir adversely impairs carbohydrate and lipid metabolism, whereas its influence on protein metabolism under in vivo conditions remains unknown. The present study tested the hypothesis that indinavir also decreases basal protein synthesis and impairs the anabolic response to insulin in skeletal muscle. Indinavir was infused intravenously for 4 h into conscious rats, at which time the homeostasis model assessment of insulin resistance was increased. Indinavir decreased muscle protein synthesis by 30%, and this reduction was due to impaired translational efficiency. To identify potential mechanisms responsible for regulating mRNA translation, several eukaryotic initiation factors (eIFs) were examined. Under basal fasted conditions, there was a redistribution of eIF4E from the active eIF4E·eIF4G complex to the inactive eIF4E·4E-BP1 complex, and this change was associated with a marked decrease in the phosphorylation of 4E-BP1 in muscle. Likewise, indinavir decreased constitutive phosphorylation of eIF4G and mTOR in muscle, but not S6K1 or the ribosomal protein S6. In contrast, the ability of a maximally stimulating dose of insulin to increase the phosphorylation of PKB, 4E-BP1, S6K1, or mTOR was not altered 20 min after intravenous injection. Indinavir increased mRNA expression of the ubiquitin ligase MuRF1, but the plasma concentration of 3-methylhistidine remained unaltered. These indinavir-induced changes were associated with a marked reduction in the plasma testosterone concentration but were independent of changes in plasma levels of IGF-I, corticosterone, TNF-α, or IL-6. In conclusion, indinavir acutely impairs basal protein synthesis and translation initiation in skeletal muscle but, in contrast to muscle glucose uptake, does not impair insulin-stimulated signaling of protein synthetic pathways.
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Vinaixa, María, Sandra Canelles, África González-Murillo, Vítor Ferreira, Diana Grajales, Santiago Guerra-Cantera, Ana Campillo-Calatayud, et al. "Increased Hypothalamic Anti-Inflammatory Mediators in Non-Diabetic Insulin Receptor Substrate 2-Deficient Mice." Cells 10, no. 8 (August 13, 2021): 2085. http://dx.doi.org/10.3390/cells10082085.
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Insulin receptor substrate (IRS) 2 is a key mediator of insulin signaling and IRS-2 knockout (IRS2−/−) mice are a preclinical model to study the development of diabetes, as they develop peripheral insulin resistance and beta-cell failure. The differential inflammatory profile and insulin signaling in the hypothalamus of non-diabetic (ND) and diabetic (D) IRS2−/− mice might be implicated in the onset of diabetes. Because the lipid profile is related to changes in inflammation and insulin sensitivity, we analyzed whether ND IRS2−/− mice presented a different hypothalamic fatty acid metabolism and lipid pattern than D IRS2−/− mice and the relationship with inflammation and markers of insulin sensitivity. ND IRS2−/− mice showed elevated hypothalamic anti-inflammatory cytokines, while D IRS2−/− mice displayed a proinflammatory profile. The increased activity of enzymes related to the pentose-phosphate route and lipid anabolism and elevated polyunsaturated fatty acid levels were found in the hypothalamus of ND IRS2−/− mice. Conversely, D IRS2−/− mice have no changes in fatty acid composition, but hypothalamic energy balance and markers related to anti-inflammatory and insulin-sensitizing properties were reduced. The data suggest that the concurrence of an anti-inflammatory profile, increased insulin sensitivity and polyunsaturated fatty acids content in the hypothalamus may slow down or delay the onset of diabetes.
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Hayirli, A., and R. R. Grummer. "Factors affecting dry matter intake prepartum in relationship to etiology of peripartum lipid-related metabolic disorders: A review." Canadian Journal of Animal Science 84, no. 3 (September 1, 2004): 337–47. http://dx.doi.org/10.4141/a03-122.
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Transition from gestation to lactation is a tremendous challenge for dairy cattle and requires metabolic and hormonal adjustments. The periparturient period, particularly the last week of gestation, is characterized by a dramatic decline (20 to 40%) in dry matter intake (DMI) prior to parturition and a slow rate of increase in DMI after parturition. As a result of negative energy balance during the periparturient period, excessive fat mobilization in adipose tissue and inability of disposing fatty acids (F A) via β-oxidation and exporting triglyceride (TG) as very low density lipoproteins (VLDL) in the liver cause hepatic lipidosis. Controlling hepatic lipidosis, therefore, depends on either limiting non-esterified fatty acids (NEFA) uptake by the liver or increasing oxidation of FA and export of TG by the liver, or both. Results of studies regarding lipid metabolism in the liver to minimize lipidosis are controversial. Thus, until factor(s) limiting hepatic VLDL-TG export are identified, limiting fat mobilization from adipose tissue will play a key role in prevention of hepatic lipidosis and ketosis. Depression in DMI prior to parturition shifts metabolism from anabolism to catabolism. Animal factors such as parity and body condition score and dietary factors such as density of organic nutrients influence DMI. Particularly, increasing energy density of the transition cow diet, without causing acidosis, by supplemental nonstructural carbohydrate (NFC) increases DMI and serum insulin concentration, which suppress lipolysis in adipose tissue and favors anabolic status. In summary, level of DMI and magnitude of DMI depression prior to parturition are linked to the etiology of postpartum lipid-related metabolic disorders. Thus, easing transition from gestation to lactation by offering high dietary NFC in consideration with other factors allows cows to produce more milk, become healthier, and be rebred sooner during postpartum. Key words: Periparturient dairy cattle, dry matter intake, hepatic lipidosis, ketosis
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Hoehn, Kyle L., Susan F. Hudachek, Scott A. Summers, and Gregory L. Florant. "Seasonal, tissue-specific regulation of Akt/protein kinase B and glycogen synthase in hibernators." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 286, no. 3 (March 2004): R498—R504. http://dx.doi.org/10.1152/ajpregu.00509.2003.
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Yellow-bellied marmots ( Marmota flaviventris) exhibit a circannual cycle of hyperphagia and nutrient storage in the summer followed by hibernation in the winter. This annual cycle of body mass gain and loss is primarily due to large-scale accumulation of lipid in the summer, which is then mobilized and oxidized for energy during winter. The rapid and predictable change in body mass makes these animals ideal for studies investigating the molecular basis for body weight regulation. In the study described herein, we monitored seasonal changes in the protein levels and activity of a central regulator of anabolic metabolism, the serine-threonine kinase Akt-protein kinase B (Akt/PKB), during the months accompanying maximal weight gain and entry into hibernation (June-November). Interestingly, under fasting conditions, Akt/PKB demonstrated a tissue-specific seasonal activation. Specifically, although Akt/PKB levels did not change, the activity of Akt/PKB (isoforms 1/α and 2/β) in white adipose tissue (WAT) increased significantly in July. Moreover, glycogen synthase, which lies downstream of Akt/PKB on a linear pathway linking the enzyme to the stimulation of glycogen synthesis, demonstrated a similar pattern of seasonal activation. By contrast, Akt/PKB activity in skeletal muscle peaked much later (i.e., September). These data suggest the existence of a novel, tissue-specific mechanism regulating Akt/PKB activation during periods of marked anabolism.
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Kidani, Yoko, Heidi Elsaesser, M. Hock, Laurent Vergnes, Kevin Williams, Joseph Argus, Beth Marbois, et al. "Towards understanding the influence of lipid metabolism on CD8 T cell biology (P1136)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 64.15. http://dx.doi.org/10.4049/jimmunol.190.supp.64.15.
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Abstract A hallmark of the adaptive immune system is the ability of CD8 T cells to undergo rapid clonal expansion in response to antigenic stimulation. To meet the biosynthetic requirements of rapid growth and proliferation, effector T cells must reprogram their metabolism to provide essential macromolecules. We have previously shown that mitogen signaling induces a gene expression program that drives de novo cholesterol and fatty acid biosynthesis, however the molecular events linking antigen receptor signaling with lipid anabolism remain poorly understood. Herein, we demonstrate an essential role for sterol regulatory element binding proteins (SREBPs) in the acquisition of effector cell metabolism. Without SREBP signaling, CD8 T cells are unable to grow and acquire the effector cell metabolism program, resulting in attenuated clonal expansion during viral infection. In contrast, SREBPs are dispensable for homeostatic proliferation, demonstrating a context-specific requirement for SREBP signaling during effector T cell blastogenesis. Mechanistic studies indicate that SREBP activity is required to maintain a level of cellular cholesterol sufficient to permit rapid ER and cellular growth. Taken together, these studies provide novel insights into the molecular signals underlying the metabolic reprogramming of CD8 T cell during the transition from quiescence to activation, and demonstrate the importance of SREBPs in regulating a cholesterol metabolic checkpoint during blastogenesis.
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Rennie, M. J. "Exercise- and nutrient-controlled mechanisms involved in maintenance of the musculoskeletal mass." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 1302–5. http://dx.doi.org/10.1042/bst0351302.
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The mechanisms of maintenance of the protein mass of muscle and associated connective tissue and bone are becoming more accessible as a result of the use of a combination of well-established techniques for measurement of protein turnover and measurement of protein expression and phosphorylation state of signalling molecules involved in anabolic and catabolic responses. Amino acids, hormones and physical activity appear to be the major short-term physiological regulators of muscle mass, mainly through their actions on protein synthesis and breakdown, on a time scale of minutes to hours, with duration of changes in gene expression up to weeks. Amino acids are the main components in the diet regulating protein turnover, having marked effects in stimulating muscle protein synthesis and with almost no effect on muscle protein breakdown. Branched-chain amino acids, and in particular leucine, simulate protein synthesis via signalling pathways involving mTOR (mammalian target of rapamycin) in a dose–response manner. Insulin has little effect on protein synthesis in human muscle, but it has a marked inhibitory effect on protein breakdown. The amino acid simulation of anabolism is not dependent on the presence of insulin, IGF-1 (insulin-like growth factor-1) or growth hormone. Exercise not only stimulates protein synthesis in muscle, but also in tendon; and disuse atrophy is accompanied by marked decreases of both muscle and tendon collagen protein synthesis. Bone collagen synthesis appears to be nutritionally regulated by the availability of amino acids, but not lipid or glucose.
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Snarski, Patricia, Sergiy Sukhanov, Tadashi Yoshida, Yusuke Higashi, Svitlana Danchuk, Bysani Chandrasekar, Di Tian, Vikara Rivera-Lopez, and Patrick Delafontaine. "Macrophage-Specific IGF-1 Overexpression Reduces CXCL12 Chemokine Levels and Suppresses Atherosclerotic Burden in Apoe-Deficient Mice." Arteriosclerosis, Thrombosis, and Vascular Biology 42, no. 2 (February 2022): 113–26. http://dx.doi.org/10.1161/atvbaha.121.316090.
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Objective: IGF-1 (insulin-like growth factor 1) exerts pleiotropic effects including promotion of cellular growth, differentiation, survival, and anabolism. We have shown that systemic IGF-1 administration reduced atherosclerosis in Apoe −/ − (apolipoprotein E deficient) mice, and this effect was associated with a reduction in lesional macrophages and a decreased number of foam cells in the plaque. Almost all cell types secrete IGF-1, but the effect of macrophage-derived IGF-1 on the pathogenesis of atherosclerosis is poorly understood. We hypothesized that macrophage-derived IGF-1 will reduce atherosclerosis. Approach and Results: We created macrophage-specific IGF-1 overexpressing mice on an Apoe − / − background. Macrophage-specific IGF-1 overexpression reduced plaque macrophages, foam cells, and atherosclerotic burden and promoted features of stable atherosclerotic plaque. Macrophage-specific IGF1 mice had a reduction in monocyte infiltration into plaque, decreased expression of CXCL12 (CXC chemokine ligand 12), and upregulation of ABCA1 (ATP-binding cassette transporter 1), a cholesterol efflux regulator, in atherosclerotic plaque and in peritoneal macrophages. IGF-1 prevented oxidized lipid-induced CXCL12 upregulation and foam cell formation in cultured THP-1 macrophages and increased lipid efflux. We also found an increase in cholesterol efflux in macrophage-specific IGF1–derived peritoneal macrophages. Conclusions: Macrophage IGF-1 overexpression reduced atherosclerotic burden and increased features of plaque stability, likely via a reduction in CXCL12-mediated monocyte recruitment and an increase in ABCA1-dependent macrophage lipid efflux.
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Kim, Na-Yeon, Shalom Sara Thomas, Dae-Il Hwang, Ji-Hye Lee, Kyung-Ah Kim, and Youn-Soo Cha. "Anti-Obesity Effects of Morus alba L. and Aronia melanocarpa in a High-Fat Diet-Induced Obese C57BL/6J Mouse Model." Foods 10, no. 8 (August 18, 2021): 1914. http://dx.doi.org/10.3390/foods10081914.
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The present study investigated the synergic effect of extracts of Morus alba (MA) and Aronia melanocarpa (Michx.) (AR) against high-fat diet induced obesity. Four-week-old male C57BL/6J mice were randomly divided into five groups that were fed for 14 weeks with a normal diet (ND), high-fat diet (HD), HD with M. alba 400 mg/kg body weight (MA), HD with A. melanocarpa 400 mg/kg body weight (AR), or HD with a mixture (1:1, v/v) of M. alba and A. melanocarpa (400 mg/kg) (MA + AR). Treatment with MA, AR, and MA + AR for 14 weeks reduced high fat diet-induced weight gain and improved serum lipid levels, and histological analysis revealed that MA and AR treatment markedly decreased lipid accumulation in the liver and adipocyte size in epididymal fat. Furthermore, micro-CT images showed MA + AR significantly reduced abdominal fat volume. Expression levels of genes involved in lipid anabolism, such as SREBP-1c, PPAR-γ, CEBPα, FAS, and CD36 were decreased by MA + AR treatment whereas PPAR-α, ACOX1, and CPT-1a levels were increased by MA + AR treatment. Protein expression of p-AMPK and p-ACC were increased in the MA + AR group, indicating that MA + AR ameliorated obesity by upregulating AMPK signaling. Together, our findings indicate that MA and AR exert a synergistic effect against diet-induced obesity and are promising agents for managing obesity.
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Judelson, Daniel A., Carl M. Maresh, Linda M. Yamamoto, Mark J. Farrell, Lawrence E. Armstrong, William J. Kraemer, Jeff S. Volek, Barry A. Spiering, Douglas J. Casa, and Jeffrey M. Anderson. "Effect of hydration state on resistance exercise-induced endocrine markers of anabolism, catabolism, and metabolism." Journal of Applied Physiology 105, no. 3 (September 2008): 816–24. http://dx.doi.org/10.1152/japplphysiol.01010.2007.
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Hypohydration (decreased total body water) exacerbates the catabolic hormonal response to endurance exercise with unclear effects on anabolic hormones. Limited research exists that evaluates the effect of hypohydration on endocrine responses to resistance exercise; this work merits attention as the acute postexercise hormonal environment potently modulates resistance training adaptations. The purpose of this study was to examine the effect of hydration state on the endocrine and metabolic responses to resistance exercise. Seven healthy resistance-trained men (age = 23 ± 4 yr, body mass = 87.8 ± 6.8 kg, body fat = 11.5 ± 5.2%) completed three identical resistance exercise bouts in different hydration states: euhydrated (EU), hypohydrated by ∼2.5% body mass (HY25), and hypohydrated by ∼5.0% body mass (HY50). Investigators manipulated hydration status via controlled water deprivation and exercise-heat stress. Cortisol, epinephrine, norepinephrine, testosterone, growth hormone, insulin-like growth factor-I, insulin, glucose, lactate, glycerol, and free fatty acids were measured during euhydrated rest, immediately preceding resistance exercise, immediately postexercise, and during 60 min of recovery. Body mass decreased 0.2 ± 0.4, 2.4 ± 0.4, and 4.8 ± 0.4% during EU, HY25, and HY50, respectively, supported by humoral and urinary changes that clearly indicated subjects achieved three distinct hydration states. Hypohydration significantly 1) increased circulating concentrations of cortisol and norepinephrine, 2) attenuated the testosterone response to exercise, and 3) altered carbohydrate and lipid metabolism. These results suggest that hypohydration can modify the hormonal and metabolic response to resistance exercise, influencing the postexercise circulatory milieu.
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Corrigan, Michele A., Siobhan Coyle, Kian F. Eichholz, Mathieu Riffault, Brian Lenehan, and David A. Hoey. "Aged Osteoporotic Bone Marrow Stromal Cells Demonstrate Defective Recruitment, Mechanosensitivity, and Matrix Deposition." Cells Tissues Organs 207, no. 2 (2019): 83–96. http://dx.doi.org/10.1159/000503444.
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Bone formation requires the replenishment of the osteoblast from a progenitor or stem cell population, which must be recruited, expanded, and differentiated to ensure continued anabolism. How this occurs and whether it is altered in the osteoporotic environment is poorly understood. Furthermore, given that emerging treatments for osteoporosis are targeting this progenitor population, it is critical to determine the regenerative capacity of this cell type in the setting of osteoporosis. Human bone marrow stromal cells (hMSCs) from a cohort of aged osteoporotic patients were compared to MSCs isolated from healthy donors in terms of the ability to undergo recruitment and proliferation, and also respond to both the biophysical and biochemical cues that drive osteogenic matrix deposition. hMSCs isolated from healthy donors demonstrate good recruitment, mechanosensitivity, proliferation, and differentiation capacity. Contrastingly, hMSCs isolated from aged osteoporotic patients had significantly diminished regenerative potential. Interestingly, we demonstrated that osteoporotic hMSCs no longer responded to chemokine-directing recruitment and became desensitised to mechanical stimulation. The osteoporotic MSCs had a reduced proliferative potential and, importantly, they demonstrated an attenuated differentiation capability with reduced mineral and lipid formation. Moreover, during osteogenesis, despite minimal differences in the quantity of deposited collagen, the distribution of collagen was dramatically altered in osteoporosis, suggesting a potential defect in matrix quality. Taken together, this study has demonstrated that hMSCs isolated from aged osteoporotic patients demonstrate defective cell behaviour on multiple fronts, resulting in a significantly reduced regenerative potential, which must be considered during the development of new anabolic therapies that target this cell population.
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Liu, S. M., N. R. Adams, J. B. Briegel, T. L. Smith, and G. B. Martin. "Effect of genetic resistance to gastrointestinal nematodes on plasma concentrations of insulin-like growth factor-1 and leptin in Merino sheep." Australian Journal of Experimental Agriculture 47, no. 8 (2007): 905. http://dx.doi.org/10.1071/ea06253.
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Gastrointestinal nematode infection in sheep changes the nutritional economy of the host, but little is known about the effects of infection on the hormonal systems that regulate the metabolism of the animal. This study examined two key hormones, insulin-like growth factor-1 (IGF-1) and leptin, in genetically resistant and random bred control Merino sheep in the presence or absence of nematode infection. Sixty-four 10-month-old Rylington Merino wethers, half from the parasite-resistant line and half from unselected control line, were initially maintained at two body conditions (body condition scores averaged 1.7 and 2.5) in individual pens in an animal house. The animals were kept parasite-free for 9 weeks, then ‘trickle-infected’ with Trichostrongylus colubriformis and Teladorsagia circumcincta larvae, each at a rate of 10 000 per week, for 13 weeks. Each body condition score group was subdivided into two groups at the beginning of the infection procedure and feed supply was controlled at 1× or 1.5× the maintenance metabolisable energy requirement. Plasma IGF-1 concentrations decreased marginally by day 21 of infection, then markedly by day 49, and then remained low until day 84. Plasma leptin concentrations tended to increase during the infection period. Both body condition and feed intake had significant effects on IGF-1 and leptin concentrations, and the higher concentrations were related to the good body condition or high feed intake. The parasite-resistant sheep had consistently higher concentrations of IGF-1 compared with the controls, whereas the concentrations of leptin were similar. The significant changes in IGF-1 but not leptin suggest that infection may have a more significant impact on protein anabolism, and least impact on lipid metabolism. Selection for parasite resistance appears to result in enhanced protein anabolism.
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Dattilo, Rosanna, Carla Mottini, Emanuela Camera, Alessia Lamolinara, Noam Auslander, Ginevra Doglioni, Michela Muscolini, et al. "Pyrvinium Pamoate Induces Death of Triple-Negative Breast Cancer Stem–Like Cells and Reduces Metastases through Effects on Lipid Anabolism." Cancer Research 80, no. 19 (July 23, 2020): 4087–102. http://dx.doi.org/10.1158/0008-5472.can-19-1184.
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Liu, Yingying, Fengna Li, Lingyun He, Bie Tan, Jinping Deng, Xiangfeng Kong, Yinghui Li, Meimei Geng, Yulong Yin, and Guoyao Wu. "Dietary protein intake affects expression of genes for lipid metabolism in porcine skeletal muscle in a genotype-dependent manner." British Journal of Nutrition 113, no. 7 (March 16, 2015): 1069–77. http://dx.doi.org/10.1017/s0007114514004310.
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Skeletal muscle is a major site for the oxidation of fatty acids (FA) in mammals, including humans. Using a swine model, we tested the hypothesis that dietary protein intake regulates the expression of key genes for lipid metabolism in skeletal muscle. A total of ninety-six barrows (forty-eight pure-bred Bama mini-pigs (fatty genotype) and forty-eight Landrace pigs (lean genotype)) were fed from 5 weeks of age to market weight. Pigs of fatty or lean genotype were randomly assigned to one of two dietary treatments (low- or adequate-protein diet), with twenty-four individually fed pigs per treatment. Our data showed that dietary protein levels affected the expression of genes involved in the anabolism and catabolism of lipids in the longissimus dorsi and biceps femoris muscles in a genotype-dependent manner. Specifically, Bama mini-pigs had more intramuscular fat, SFA and MUFA, as well as elevated mRNA expression levels of lipogenic genes, compared with Landrace pigs. In contrast, Bama mini-pigs had lower mRNA expression levels of lipolytic genes than Landrace pigs fed an adequate-protein diet in the growing phase. These data are consistent with higher white-fat deposition in Bama mini-pigs than in Landrace pigs. In conclusion, adequate provision of dietary protein (amino acids) plays an important role in regulating the expression of key lipogenic genes, and the growth of white adipose tissue, in a genotype- and tissue-specific manner. These findings have important implications for developing novel dietary strategies in pig production.
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Rial, Sabri, Gaetan Ravaut, Tommy Malaret, Karl-F. Bergeron, and Catherine Mounier. "Hexanoic, Octanoic and Decanoic Acids Promote Basal and Insulin-Induced Phosphorylation of the Akt-mTOR Axis and a Balanced Lipid Metabolism in the HepG2 Hepatoma Cell Line." Molecules 23, no. 9 (September 11, 2018): 2315. http://dx.doi.org/10.3390/molecules23092315.
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Metabolic illnesses such as non-alcoholic fatty liver disease (NAFLD) are in constant increase worldwide. Highly consumed long chain fatty acids (LCFA) are among the most obesogenic and steatogenic nutrients. Hepatic steatosis is associated with several complications such as insulin resistance. Growing evidence points to medium chain fatty acids (MCFA), more efficiently oxidized than LCFA, as a promising dietary alternative against NAFLD. However, reports on the hepatic effects of MCFA are sometimes conflicting. In this study we exposed HepG2 cells, a human hepatocellular model, to 0.25 mM of hexanoic (C6), or octanoic (C8), and decanoic (C10) acids separately or in a C8 + C10 equimolar mix reflecting commercially available MCFA-rich oils. We found that C6, a poorly studied MCFA, as well as C8 and C10 did not provoke the deleterious lipid anabolism runaway typically induced by LCFA palmitate. MCFA tended, instead, to promote a balanced metabolic profile and were generally non-cytotoxic. Accordingly, mitochondrial integrity was mostly preserved following MCFA treatment. However, treatments with C8 induced a mitochondrial membrane potential decrease, suggesting prolonged exposure to this lipid could be problematic. Finally, MCFA treatments maintained optimal insulin sensitivity and even fostered basal and insulin-dependent phosphorylation of the Akt-mTOR pathway. Overall, MCFA could constitute an effective nutritional tool to manage liver steatosis and hepatic insulin resistance.
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Rivas Serna, Irma Magaly, Ilaria Romito, Andrea Maugeri, Oriana Lo Re, Sebastiano Giallongo, Gianluigi Mazzoccoli, Jude A. Oben, et al. "A Lipidomic Signature Complements Stemness Features Acquisition in Liver Cancer Cells." International Journal of Molecular Sciences 21, no. 22 (November 10, 2020): 8452. http://dx.doi.org/10.3390/ijms21228452.
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Lipid catabolism and anabolism changes play a role in stemness acquisition by cancer cells, and cancer stem cells (CSCs) are particularly dependent on the activity of the enzymes involved in these processes. Lipidomic changes could play a role in CSCs’ ability to cause disease relapse and chemoresistance. The exploration of lipid composition and metabolism changes in CSCs in the context of hepatocellular cancer (HCC) is still incomplete and their lipidomic scenario continues to be elusive. We aimed to evaluate through high-throughput mass spectrometry (MS)-based lipidomics the levels of the members of the six major classes of sphingolipids and phospholipids in two HCC cell lines (HepG2 and Huh-7) silenced for the expression of histone variant macroH2A1 (favoring stemness acquisition), or silenced for the expression of focal adhesion tyrosine kinase (FAK) (hindering aggressiveness and stemness). Transcriptomic changes were evaluated by RNA sequencing as well. We found definite lipidomic and transcriptomic changes in the HCC lines upon knockdown (KD) of macroH2A1 or FAK, in line with the acquisition or loss of stemness features. In particular, macroH2A1 KD increased total sphingomyelin (SM) levels and decreased total lysophosphatidylcholine (LPC) levels, while FAK KD decreased total phosphatidylcholine (PC) levels. In conclusion, in HCC cell lines knocked down for specific signaling/epigenetic processes driving opposite stemness potential, we defined a lipidomic signature that hallmarks hepatic CSCs to be exploited for therapeutic strategies.
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Ding, Lu, Yingjie Liu, Meng Kang, Xiaofeng Wei, Chuanye Geng, Wenzhi Liu, Lin Han, et al. "UPLC-QTOF/MS Metabolomics and Biochemical Assays Reveal Changes in Hepatic Nutrition and Energy Metabolism during Sexual Maturation in Female Rainbow Trout (Oncorhynchus mykiss)." Biology 11, no. 11 (November 18, 2022): 1679. http://dx.doi.org/10.3390/biology11111679.
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Mobilization and repartition of nutrients and energy are prerequisites for the normal sexual maturity of broodstock. However, there are few studies on the mechanisms of hepatic nutrients and energy metabolism during sexual maturation in female rainbow trout (Oncorhynchus mykiss). This study investigated hepatic metabolite changes and explored the potential nutritional regulation mechanism between mature and immature female rainbow trout by combining UPLC-QTOF/MS metabolomics and biochemical assays. It was observed that hepatic biochemical assays differed considerably between the two groups, such as glucose, triglycerides, hexokinase, lipase, and aspartate aminotransferase. Liver metabolomics showed that various differential metabolites involved in amino acid and lipid metabolism markedly increased, suggesting the enhancement of lipid metabolism and amino acid anabolism in the liver provides the necessary material basis for ovarian development. Meanwhile, glycogen catabolism and glycolysis hold the key to maintaining organismal energy homeostasis with normal sexual maturation of female rainbow trout. Overall, the results from this study suggested that the liver undergoes drastic reprogramming of the metabolic profile in response to mobilization and repartition of nutrients and energy during the sexual maturation of female rainbow trout. This study further deepened the understanding of the reproductive biology of rainbow trout, and provided the theoretical basis and practical ramifications for nutritional requirements of breeding high-quality broodstock in the artificial propagation of rainbow trout.
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Hu, Xiaoying, Bo Shi, Min Jin, Xuexi Wang, Ye Yuan, Jiaxiang Luo, and Qicun Zhou. "Molecular cloning, tissue distribution and gene expression in response to nutritional regulation of sterol regulatory element binding protein-1 from the swimming crab Portunus trituberculatus (Miers, 1876) (Decapoda, Portunidae)." Crustaceana 94, no. 2 (February 15, 2021): 235–50. http://dx.doi.org/10.1163/15685403-bja10095.
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Abstract The sterol regulatory element-binding proteins (SREBPs) are a family of transcription factors known to activate the transcription of genes encoding key lipogenic enzymes. The present study reports on the molecular cloning, tissue expression and nutritional regulation of SREBP-1 from the swimming crab Portunus trituberculatus (Miers, 1876). The SREBP-1 full-length cDNA was 3785 bp, encoding a polypeptide of 1039 amino acids. Quantitative PCR analysis revealed that SREBP-1 expression was detected in various tissues, and the significantly higher expression levels were found in eyestalk and hepatopancreas compared with other tested tissues. Additionally, the effects of dietary iron on expression of SREBP-1 were investigated, and the results indicated that SREBP-1 expressions were down-regulated by crabs fed diets containing 218.9 and 373.9 mg/kg iron compared with that fed the basal diet (55.2 mg/kg). Suggesting that the relative expression level of SREBP-1 can be suppressed by dietary iron supplementation. These findings provide further insight into the regulatory capacity of SREBP-1 in the lipid anabolism of P. trituberculatus.
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Včelařová, Ludmila, Vladimír Skalický, Ivo Chamrád, René Lenobel, Martin F. Kubeš, Aleš Pěnčík, and Ondřej Novák. "Auxin Metabolome Profiling in the Arabidopsis Endoplasmic Reticulum Using an Optimised Organelle Isolation Protocol." International Journal of Molecular Sciences 22, no. 17 (August 29, 2021): 9370. http://dx.doi.org/10.3390/ijms22179370.
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The endoplasmic reticulum (ER) is an extensive network of intracellular membranes. Its major functions include proteosynthesis, protein folding, post-transcriptional modification and sorting of proteins within the cell, and lipid anabolism. Moreover, several studies have suggested that it may be involved in regulating intracellular auxin homeostasis in plants by modulating its metabolism. Therefore, to study auxin metabolome in the ER, it is necessary to obtain a highly enriched (ideally, pure) ER fraction. Isolation of the ER is challenging because its biochemical properties are very similar to those of other cellular endomembranes. Most published protocols for ER isolation use density gradient ultracentrifugation, despite its suboptimal resolving power. Here we present an optimised protocol for ER isolation from Arabidopsis thaliana seedlings for the subsequent mass spectrometric determination of ER-specific auxin metabolite profiles. Auxin metabolite analysis revealed highly elevated levels of active auxin form (IAA) within the ER compared to whole plants. Moreover, samples prepared using our optimised isolation ER protocol are amenable to analysis using various “omics” technologies including analyses of both macromolecular and low molecular weight compounds from the same sample.
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Mushawwir, Andi, N. Suwarno, and H. N. Aritonang. "Impact of Glutathione Administration on Antioxidant Levels and Ileum Histologic of Growth Phase of Cihateup Duck in Extensively Maintained." Jurnal Sain Peternakan Indonesia 17, no. 3 (September 29, 2022): 142–48. http://dx.doi.org/10.31186/jspi.id.17.3.142-148.
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This research has been carried out for a month using eighty three-month-old female Cihateup ducks and has been used to study the influence of glutathione on the endogen antioxidant response and histological illeum. The separation of glutathione was carried out using the distillation technique. Each experimental group consisted of 20 ducks, each treated with G0 = without glutathione; G1= Administration of glutathione 150 µL/head; G2 = Administration of glutathione 175 µL/head; G3= Administration of glutathione 175 µL/head. Tissue and blood sampling was collected at the end of the study by EDTA tube and a fixative solution, and tissue preparations were made using the Mallory-Asan technique and analyzed using a binocular microscope. Antioxidant levels were measured using a spectrophotometer technique based on the instructions of the Randox Kit. The results showed that glutathione affected (P<0.05) morphometric ileum (villi, Peyeri's plaque and goblet cells) and increased with increasing glutathione level and endogenous antioxidant response. It was concluded that glutathione is able to stimulate protein and lipid anabolism, as well as hormonal signals related to ileal tissue growth and antioxidants.
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Yabut, Julian M., Justin D. Crane, Alexander E. Green, Damien J. Keating, Waliul I. Khan, and Gregory R. Steinberg. "Emerging Roles for Serotonin in Regulating Metabolism: New Implications for an Ancient Molecule." Endocrine Reviews 40, no. 4 (March 22, 2019): 1092–107. http://dx.doi.org/10.1210/er.2018-00283.
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Abstract Serotonin is a phylogenetically ancient biogenic amine that has played an integral role in maintaining energy homeostasis for billions of years. In mammals, serotonin produced within the central nervous system regulates behavior, suppresses appetite, and promotes energy expenditure by increasing sympathetic drive to brown adipose tissue. In addition to these central circuits, emerging evidence also suggests an important role for peripheral serotonin as a factor that enhances nutrient absorption and storage. Specifically, glucose and fatty acids stimulate the release of serotonin from the duodenum, promoting gut peristalsis and nutrient absorption. Serotonin also enters the bloodstream and interacts with multiple organs, priming the body for energy storage by promoting insulin secretion and de novo lipogenesis in the liver and white adipose tissue, while reducing lipolysis and the metabolic activity of brown and beige adipose tissue. Collectively, peripheral serotonin acts as an endocrine factor to promote the efficient storage of energy by upregulating lipid anabolism. Pharmacological inhibition of serotonin synthesis or signaling in key metabolic tissues are potential drug targets for obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD).
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Alao, John-Patrick, Luc Legon, Aleksandra Dabrowska, Anne-Marie Tricolici, Juhi Kumar, and Charalampos Rallis. "Interplays of AMPK and TOR in Autophagy Regulation in Yeast." Cells 12, no. 4 (February 4, 2023): 519. http://dx.doi.org/10.3390/cells12040519.
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Cells survey their environment and need to balance growth and anabolism with stress programmes and catabolism towards maximum cellular bioenergetics economy and survival. Nutrient-responsive pathways, such as the mechanistic target of rapamycin (mTOR) interact and cross-talk, continuously, with stress-responsive hubs such as the AMP-activated protein kinase (AMPK) to regulate fundamental cellular processes such as transcription, protein translation, lipid and carbohydrate homeostasis. Especially in nutrient stresses or deprivations, cells tune their metabolism accordingly and, crucially, recycle materials through autophagy mechanisms. It has now become apparent that autophagy is pivotal in lifespan, health and cell survival as it is a gatekeeper of clearing damaged macromolecules and organelles and serving as quality assurance mechanism within cells. Autophagy is hard-wired with energy and nutrient levels as well as with damage-response, and yeasts have been instrumental in elucidating such connectivities. In this review, we briefly outline cross-talks and feedback loops that link growth and stress, mainly, in the fission yeast Schizosaccharomyces pombe, a favourite model in cell and molecular biology.
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Kee, Anthony J., Robert C. Baxter, Anthony R. Carlsson, and Ross C. Smith. "Parenteral amino acid intake alters the anabolic actions of insulin-like growth factor I in rats." American Journal of Physiology-Endocrinology and Metabolism 277, no. 1 (July 1, 1999): E63—E72. http://dx.doi.org/10.1152/ajpendo.1999.277.1.e63.
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The anabolic properties of insulin-like growth factor (IGF) I are attenuated by oral diets that are low in protein. However, it is not known whether parenteral nutrition (PN) providing a low amino acid (AA) input will influence IGF-I action. With the use of a rat model, this study examined the interaction between AA input (1.27 and 0.62 g N ⋅ kg body wt−1⋅ 24 h−1, AA and ½AA groups, respectively) and recombinant human IGF-I (rhIGF-I, 2.5 mg ⋅ kg body wt−1⋅ 24 h−1) infusion on the composition of the carcass and organs and on plasma insulin, IGF-I, IGF-binding protein 1 (IGFBP-1), and acid-labile subunit (ALS) concentrations. Carcass protein deposition only occurred in the AA groups ( P < 0.003) and was not influenced by administration of rhIGF-I. However, visceral protein loss persisted in the AA group but was prevented by rhIGF-I infusion. The changes in water content of the carcass and the organs were generally in the expected proportion of normal lean tissue. The accumulation of lipid that follows the infusion of the AA-deficient PN was prevented by rhIGF-I infusion, which may indicate an improved energy utilization. Neither serum insulin nor ALS concentrations were influenced by the level of AA infusion but were reduced by rhIGF-I administration. However, plasma IGF-I levels were elevated by higher AA infusion and by IGF-I administration. Also, IGFBP-1 concentrations were reduced by the higher AA infusion and increased with rhIGF-I administration. Interestingly, there was a significant interaction effect between both of these influences. It is concluded that free IGF-I concentration, which may be regulated by IGFBP-1 through a direct effect of AAs on the liver, may have an important role in regulating anabolism in visceral and possibly skeletal tissue during PN.
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Sarr, Ousseynou, Florence Gondret, Agnès Jamin, Isabelle Le Huërou-Luron, and Isabelle Louveau. "A high-protein neonatal formula induces a temporary reduction of adiposity and changes later adipocyte physiology." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 300, no. 2 (February 2011): R387—R397. http://dx.doi.org/10.1152/ajpregu.00459.2010.
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The high-protein content of formula offered to low-birth weight babies is suspected to increase the risk of obesity later in life. This study assesses the immediate and subsequent effects of a protein intake in excess during suckling on hormonal and metabolic status and adipose tissue features in a porcine model of intrauterine growth restriction. Piglets were fed milk replacers formulated to provide an adequate (AP) or a high (HP) protein supply from day 2 to day 28. A subset of piglets was killed at day 28. After weaning, the remaining piglets had free access to the same solid high-fat diet until day 160. From day 2 to day 28, HP piglets had a greater daily weight gain ( P < 0.05). Relative weight of perirenal adipose tissue (PAT), adipocyte mean diameters, activities of lipogenic enzymes in PAT and subcutaneous adipose tissue (SCAT), and leptinemia were lower ( P < 0.05) in HP piglets than in AP piglets. Genes related to glucose utilization and lipid anabolism in PAT and SCAT were ( P < 0.05) or tended ( P < 0.1) to be downregulated in HP piglets. At day 160, adipocytes were enlarged, whereas lipogenic rates in adipocytes were reduced ( P < 0.05) in SCAT of HP compared with AP pigs. Percent body fat, mRNA levels of genes controlling lipid metabolism, and plasma concentrations of hormones and metabolites were similar in HP and AP pigs. In conclusion, a HP neonatal formula induced a temporary reduction of adiposity and changed adipocyte physiology at peripubertal age.
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Okoro, T., C. Stewart, N. Al-Shanti, A. Lemmey, P. Maddison, and J. G. Andrew. "OBJECTIVE FUNCTION, LEAN MASS, AND ASSOCIATED GENETIC ADAPTATIONS OF THE OPERATED LEG FOLLOWING TOTAL HIP ARTHROPLASTY." Journal of Musculoskeletal Research 18, no. 02 (June 2015): 1550007. http://dx.doi.org/10.1142/s0218957715500074.
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Purpose: To characterize muscle recovery following total hip arthroplasty (THA) combining genetic adaptations in the affected leg with objective function and body composition assessment. Methods: Preoperatively and at six weeks postoperatively, objective function was assessed by: maximal voluntary contraction of the operated leg quadriceps (MVCOLQ) in Newtons (N), 30[Formula: see text]s chair sit-to-stand (ST), and six-minute walk test (6MWT), with lean mass of the operated leg estimated by dual energy X-ray absorptiometry (DEXA). Genetic adaptations were assessed from vastus lateralis (VL) biopsies by quantitative polymerase chain reaction (qPCR) analysis of markers of hypertrophy (FOS, calpain2 (CAPN2)), atrophy (20[Formula: see text]s proteasome alpha subunit 7 (PSMA7), cathepsin L2 (CTSL2), inflammation (Tumour necrosis factor alpha (TNF-[Formula: see text]), Interleukin-6 (IL-6)) and lipid metabolism (lipoprotein lipase, LPL and peroxisome proliferated activated receptor gamma (PPARAG). Results: 14 patients were recruited. At six weeks, no significant differences, relative to preoperative values, were noted in either objective function or leg lean mass. Markers for hypertrophy were increased (FOS [Formula: see text]1463%, [Formula: see text]), with atrophy (PSMA7 [Formula: see text]44.8%, [Formula: see text]; CTSL2 [Formula: see text]42.5%, [Formula: see text]), inflammation (TNF [Formula: see text]29.6%, [Formula: see text]) and lipid metabolism markers showing a decreasing trend (LPL [Formula: see text]42.45%, [Formula: see text]). Conclusion: The initial post-THA intramuscular environment appears supportive of anabolism. However, this is not reflected in objective function or lean mass measures at six weeks, suggesting longer duration may be required for physiological adaptation to occur.
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Ikonomov, Ognian C., Diego Sbrissa, Khortnal Delvecchio, Han-Zhong Feng, Gregory D. Cartee, Jian-Ping Jin, and Assia Shisheva. "Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber-type switching." American Journal of Physiology-Endocrinology and Metabolism 305, no. 1 (July 1, 2013): E119—E131. http://dx.doi.org/10.1152/ajpendo.00030.2013.
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The evolutionarily conserved kinase PIKfyve that synthesizes PtdIns5P and PtdIns(3,5)P2 has been implicated in insulin-regulated GLUT4 translocation/glucose entry in 3T3-L1 adipocytes. To decipher PIKfyve's role in muscle and systemic glucose metabolism, here we have developed a novel mouse model with Pikfyve gene disruption in striated muscle (MPIfKO). These mice exhibited systemic glucose intolerance and insulin resistance at an early age but had unaltered muscle mass or proportion of slow/fast-twitch muscle fibers. Insulin stimulation of in vivo or ex vivo glucose uptake and GLUT4 surface translocation was severely blunted in skeletal muscle. These changes were associated with premature attenuation of Akt phosphorylation in response to in vivo insulin, as tested in young mice. Starting at 10–11 wk of age, MPIfKO mice progressively accumulated greater body weight and fat mass. Despite increased adiposity, serum free fatty acid and triglyceride levels were normal until adulthood. Together with the undetectable lipid accumulation in liver, these data suggest that lipotoxicity and muscle fiber switching do not contribute to muscle insulin resistance in MPIfKO mice. Furthermore, the 80% increase in total fat mass resulted from increased fat cell size rather than altered fat cell number. The observed profound hyperinsulinemia combined with the documented increases in constitutive Akt activation, in vivo glucose uptake, and gene expression of key enzymes for fatty acid biosynthesis in MPIfKO fat tissue suggest that the latter is being sensitized for de novo lipid anabolism. Our data provide the first in vivo evidence that PIKfyve is essential for systemic glucose homeostasis and insulin-regulated glucose uptake/GLUT4 translocation in skeletal muscle.
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Barrios, Vicente, Santiago Guerra-Cantera, Álvaro Martín-Rivada, Sandra Canelles, Ana Campillo-Calatayud, Eduardo Arilla-Ferreiro, Laura M. Frago, Julie A. Chowen, and Jesús Argente. "Chronic Central Leptin Infusion Promotes an Anti-Inflammatory Cytokine Profile Related to the Activation of Insulin Signaling in the Gastrocnemius of Male Rats." Biomedicines 10, no. 7 (June 21, 2022): 1465. http://dx.doi.org/10.3390/biomedicines10071465.
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Leptin is involved in the modulation of insulin signaling in peripheral tissues, being closely associated with changes in lipid metabolism. This adipokine modifies inflammatory pathways that can interact with insulin targets in peripheral organs; however, the mechanisms remain unclear. Inflammatory and insulin signaling targets, cytokines, adiponectin, irisin and non-esterified fatty acid (NEFA) levels and enzymes of fatty acid anabolism were studied in the gastrocnemius of chronic centrally infused leptin (L), pair-fed and control rats. The phosphorylation of signal transducer and activator of transcription 3 (STAT3) and c-Jun N-terminal kinase (JNK) was reduced in L rats (59% and 58%, respectively). The phosphorylation of the insulin receptor and Akt and adiponectin and irisin content was increased in L rats (154%, 157%, 308% and 329%, respectively). The levels of glucose-6-phosphate dehydrogenase, the mRNA content of acetyl Co-A carboxylase and NEFA concentrations were diminished in the muscles of L rats (59%, 50% and 61%, respectively). The activation of JNK correlated positively with STAT3 phosphorylation, tumoral necrosis factor-α and NEFA and negatively with irisin and Akt phosphorylation. These data suggest that the activation of insulin signaling targets and a decrease in NEFA content are associated with a reduction in muscle inflammation parameters, suggesting that leptin may integrate these pathways.
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Zhou, Ming, Chenjun Zhai, Kai Shen, Gang Liu, Lei Liu, Jian He, Jun Chen, and Yaozeng Xu. "miR-1 Inhibits the Ferroptosis of Chondrocyte by Targeting CX43 and Alleviates Osteoarthritis Progression." Journal of Immunology Research 2023 (June 30, 2023): 1–14. http://dx.doi.org/10.1155/2023/2061071.
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Dysregulation of miRNAs in chondrocytes has been confirmed to participate in osteoarthritis (OA) progression. Previous study has screen out several key miRNAs may play crucial role in OA based on bioinformatic analysis. Herein, we identified the downregulation of miR-1 in OA samples and inflamed chondrocytes. The further experiments revealed that miR-1 played an essential role in maintaining chondrocytes proliferation, migration, antiapoptosis, and anabolism. Connexin 43 (CX43) was further predicted and confirmed to be the target of miR-1, and mediated the promotion effects of miR-1 in regulating chondrocyte functions. Mechanistically, miR-1 maintained the expression of GPX4 and SLC7A11 by targeting CX43, attenuated the accumulation of intracellular ROS, lipid ROS, MDA, and Fe2+ in chondrocytes, thereby inhibiting the ferroptosis of chondrocytes. Finally, experimental OA model was constructed by anterior cruciate ligament transection surgery, and Agomir-1 was injected into the joint cavity of mice to assess the protective effect of miR-1 in OA progression. Histological staining, immunofluorescence staining and Osteoarthritis Research Society International score revealed that miR-1 could alleviate the OA progression. Therefore, our study elucidated the mechanism of miR-1 in OA in detail and provided a new insight for the treatment of OA.
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Davis, Teresa A., Agus Suryawan, Jane Naberhuis, Marko Rudar, and Marta Fiorotto. "PSVII-7 Prematurity alters the regulation of Akt signaling in skeletal muscle of piglets." Journal of Animal Science 99, Supplement_3 (October 8, 2021): 408–9. http://dx.doi.org/10.1093/jas/skab235.735.
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Abstract Objectives: Postnatal growth faltering is common after preterm birth. Recently we showed that premature birth in piglets impairs normal postnatal weight gain and skeletal muscle protein synthesis compared to piglets born at term. This response is associated with a reduction in the feeding-induced activation of Akt and subsequent downstream signaling, despite no change in insulin receptor activation. The aim of this study was to identify key regulators of Akt responsible for the blunted anabolic response in preterm muscle. Methods: Piglets delivered by cesarean section 11 d (preterm/PT) or 2 d (term/T) before term birth were fed by total parenteral nutrition. On day 3, after 4 h fasting, piglets were fasted one additional h or fed orally a sow milk replacer (per kg body weight: 31.5 kcal, 1.3 g carbohydrate, 2.7 g amino acids BW, 1.6 g lipid). Positive and negative regulators of Akt activity in longissimus dorsi muscle were determined by Western blot. Results: Phosphorylation of Akt1 and Akt2, but not Akt3, was lower in PT than in T pigs (P < 0.05). Phosphorylation of Akt activators, PDK1 and mTORC2, and the abundance of Ubl4A, a positive regulator of Akt, were lower in PT than in T (P < 0.05). Abundance of Akt inhibitors, PHLPP and SHIP2, but not PTEN, was higher in PT than in T (P < 0.05). Activation of the Akt phosphatase, PP2A, was unaffected by feeding in PT but inhibited by feeding in T pigs (P < 0.05). Conclusions: These results show that the feeding-induced activation of positive regulators of Akt is reduced by preterm birth, whereas the activation of negative regulators is enhanced. Our findings suggest that premature birth impairs the activation of Akt that is essential for channeling dietary nutrients for anabolism and likely contributes to the postnatal growth faltering of prematurity. Research Support: NIH and USDA.