Journal articles on the topic 'Transcription; gene regulation; obesity'
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1
He, Qing, Zhanguo Gao, Jun Yin, Jin Zhang, Zhong Yun, and Jianping Ye. "Regulation of HIF-1α activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia." American Journal of Physiology-Endocrinology and Metabolism 300, no. 5 (May 2011): E877—E885. http://dx.doi.org/10.1152/ajpendo.00626.2010.
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The transcription factor HIF-1α activity is increased in adipose tissue to contribute to chronic inflammation in obesity. However, its upstream and downstream events remain to be characterized in adipose tissue in obesity. We addressed this issue by investigating adipocyte HIF-1α activity in response to obesity-associated factors, such as adipogenesis, insulin, and hypoxia. In adipose tissue, both HIF-1α mRNA and protein were increased by obesity. The underlying mechanism was investigated in 3T3-L1 adipocytes. HIF-1α mRNA and protein were augmented by adipocyte differentiation. In differentiated adipocytes, insulin further enhanced HIF-1α in both levels. Hypoxia enhanced only HIF-1α protein, not mRNA. PI3K and mTOR activities are required for the HIF-1α expression. Function of HIF-1α protein was investigated in the regulation of VEGF gene transcription. ChIP assay shows that HIF-1α binds to the proximal hypoxia response element in the VEGF gene promoter, and its function is inhibited by a corepressor composed of HDAC3 and SMRT. These observations suggest that of the three obesity-associated factors, all of them are able to augment HIF-1α protein levels, but only two (adipogenesis and insulin) are able to enhance HIF-1α mRNA activity. Adipose tissue HIF-1α activity is influenced by multiple signals, including adipogenesis, insulin, and hypoxia in obesity. The transcriptional activity of HIF-1α is inhibited by HDAC3-SMRT corepressor in the VEGF gene promoter.
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Ren, Wei, Jianjin Guo, Feng Jiang, Jun Lu, Ying Ding, Aimei Li, Xiubin Liang, and Weiping Jia. "CCAAT/Enhancer-Binding ProteinαIs a Crucial Regulator of Human Fat Mass and Obesity Associated Gene Transcription and Expression." BioMed Research International 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/406909.
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Several susceptibility loci have been reported associated with obesity and T2DM in GWAS. Fat mass and obesity associated gene (FTO) is the first gene associated with body mass index (BMI) and risk for diabetes in diverse patient populations. FTO is highly expressed in the brain and pancreas, and is involved in regulating dietary intake and energy expenditure. While much is known about the epigenetic mutations contributing to obesity and T2DM, less is certain with the expression regulation of FTO gene. In this study, a highly conserved canonical C/EBPαbinding site was located around position −45~−54 bp relative to the human FTO gene transcriptional start site. Site-directed mutagenesis of the putative C/EBPαbinding sites decreased FTO promoter activity. Overexpression and RNAi studies also indicated that C/EBPαwas required for the expression of FTO. Chromatin immunoprecipitation (ChIP) experiment was carried out and the result shows direct binding of C/EBPαto the putative binding regions in the FTO promoter. Collectively, our data suggest that C/EBPαmay act as a positive regulator binding to FTO promoter and consequently, activates the gene transcription.
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Martínez-Hernández, Alfredo, Luís Enríquez, María Jesús Moreno-Moreno, and Amelia Martí. "Genetics of obesity." Public Health Nutrition 10, no. 10A (October 2007): 1138–44. http://dx.doi.org/10.1017/s1368980007000626.
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AbstractObjectiveThe aim was to review and update advances in genetics of obesity.DesignAnalysis and interpretation of recent investigations about regulating the energy balance as well as about gene-nutrient interactions and current nutrigenomic research methods.Background and main statementsObesity results from a long-term positive energy balance. However, its rising prevalence in developed and developing societies must reflect lifestyle changes, since genetic susceptibility remains stable over many generations. Like most complex diseases, obesity derives from a failure of adequate homoeostasis within the physiological system controlling body weight. The identification of genes that are involved in syndromic, monogenic and polygenic obesity has seriously improved our knowledge of body weight regulation. This disorder may arise from a deregulation at the genetic level (e.g. gene transcription or altered protein function) or environmental exposure (e.g. diet, physical activity, etc.).ConclusionsIn practice, obesity involves the interaction between genetic and environmental factors.
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Liu, Meilian, and Feng Liu. "Transcriptional and post-translational regulation of adiponectin." Biochemical Journal 425, no. 1 (December 14, 2009): 41–52. http://dx.doi.org/10.1042/bj20091045.
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Adiponectin is an adipose-tissue-derived hormone with anti-diabetic, anti-atherogenic and anti-inflammatory functions. Adiponectin circulates in the bloodstream in trimeric, hexameric and high-molecular-mass species, and different forms of adiponectin have been found to play distinct roles in the regulation of energy homoeostasis. The serum levels of adiponectin are negatively correlated with obesity and insulin resistance, yet the underlying mechanisms remain elusive. In the present review, we summarize recent progress made on the mechanisms regulating adiponectin gene transcription, multimerization and secretion. We also discuss the potential relevance of these studies to the development of new clinical therapy for insulin resistance, Type 2 diabetes and other obesity-related metabolic disorders.
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Miroshnikova, V. V., A. A. Panteleeva, E. A. Bazhenova, E. P. Demina, T. S. Usenko, M. A. Nikolaev, I. A. Semenova, et al. "Regulation of ABCA1 and ABCG1 gene expression in the intraabdominal adipose tissue." Biomeditsinskaya Khimiya 62, no. 3 (2016): 283–89. http://dx.doi.org/10.18097/pbmc20166203283.
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Tissue specific expression of genes encoding cholesterol transporters ABCA1 and ABCG1 as well as genes encoding the most important transcriptional regulators of adipogenesis – LXRa, LXRb, PPARg and RORa has been investigated in intraabdominal adipose tissue (IAT) samples.A direct correlation between the content of ABCA1 and ABCG1 proteins with RORa protein level (r=0.480, p<0.05; r=0.435, p<0.05, respectively) suggests the role of the transcription factor RORa in the regulation of IAT ABCA1 and ABCG1 protein levels. ABCA1 and ABCG1 gene expression positively correlated with obesity indicators such as body mass index (BMI) (r=0.522, p=0.004; r=0.594, p=0.001, respectively) and waist circumference (r=0.403, p=0.033; r=0.474, p=0.013, respectively). The development of obesity is associated with decreased IAT levels of RORa and LXRb mRNA (p=0.016 and p=0.002, respectively). These data suggest that the nuclear factor RORa can play a significant role in the regulation of cholesterol metabolism and control IAT expression of ABCA1 and ABCG1, while the level of IAT LXRb gene expression may be an important factor associated with the development of obesity.
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Yuxin, Liu, Lin Chen, Luo Xiaoxia, Luo Yue, Lai Junjie, Li Youzhu, Zhou Huiliang, and Liu Qicai. "Research Progress on the Relationship between Obesity-Inflammation-Aromatase Axis and Male Infertility." Oxidative Medicine and Cellular Longevity 2021 (February 8, 2021): 1–7. http://dx.doi.org/10.1155/2021/6612796.
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Aromatase is a key enzyme in the transformation of androgen into estrogen. Its high expression will destroy the hormonal balance in the male body, and the excessive transformation of androgen into estrogen in the body will further damage the spermatogenic function of the testis, affect the normal development of the sperm, and cause spermatogenic disturbance. Adipose tissue has a high expression of aromatase and shows high enzymatic activity and ability to convert estrogen. Adipose tissue is the most estrogen-producing nongonadal tissue in the body because of its large size, accounting for about 20% of the body mass in healthy adults. PPARγ is recognized as the key adipose differentiation in the transcriptional regulation of the transcription factor. In the process of adipocyte differentiation, PPARγ regulate the expression of aromatase. The increase of aromatase is associated with the inflammatory response in adipose tissue caused by obesity. After obesity, the increase of proinflammatory factors in adipocytes will lead to enhanced transcription of the CYP19 gene encoding aromatase in adipocytes, which in turn will lead to increased expression of aromatase in adipocytes. This article reviews the regulation of male sterility from the angle of the “obesity-inflammation-aromatase” axis.
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Fan, Ji-lin, Ting-ting Zhu, Xiao-ling Tian, Zhen-yu Xue, Jing-qi Guo, Wen-qing Ren, and Shi-liang Zhang. "Relationship Between Obesity and Hypertension From Bioinformatics Analysis." American Journal of Hypertension 36, no. 1 (January 1, 2023): 72. http://dx.doi.org/10.1093/ajh/hpac090.
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Abstract Background To explore the relationship between obesity and hypertension using bioinformatics analyses. Methods Disease databases (GeneCards, OMIM, CTD, TTD, DisGeNET, and Drugbank) were used to obtain hypertension and obesity-related targets. The intersection targets of obesity and hypertension were constructed using Venn diagrams. STRING online platform was used to obtain protein–protein interaction networks of common targets, and Cytohubba plug-in was used to screen the core targets. Gene ontology (GO) analysis and the enrichment analysis of Kyoto encyclopedia of genes and genomes (KEGG) were carried out using DAVID database. Results A total of 459 and 551 targets were obtained for obesity and hypertension, respectively. Among them, 135 were targets for both obesity and hypertension in which tumor necrosis factor (TNF), cell tumor antigen p53 (TP53), chemokine 2 (CCL2), Toll-like receptor 4 (TLR4), interleukin (IL) 1B, nitric oxide synthase 3 (NOS3), IL-6, and serine/threonine protein kinase 1 (AKT1) were key targets for regulating obesity and hypertension. Enrichment analysis yielded 306 GO entries [P < 0.05, false discovery rate (FDR) <0.05], which were involved in positive regulation of mitogen-activated protein kinase (MAPK) cascade, positive regulation of nitric oxide biosynthetic process, cilium basal body, hormone activity, and RNA polymerase II repeating transcription factor binding. The 86 enriched KEGG entries (P < 0.05, FDR <0.05) included adipocytokine signaling pathway, regulation of lipolysis in adipocytes, PI3K–Akt signaling pathway and forkhead transcription factor O (FoxO) signaling pathway. Conclusions TNF, TP53, CCL2, TLR4, IL-1B, NOS3, IL-6, AKT1, and the key pathways including adipocytokine signaling pathway, regulation of adipocyte lipolysis, PI3K–Akt and FoxO signaling pathway play a regulatory role in interactions between obesity and hypertension. These findings provide new insights into the complex interactions between obesity and hypertension.
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CLAYCOMBE, KATE J., YANXIN WANG, BRYNN H. JONES, SUYEON KIM, WILLIAM O. WILKISON, MICHAEL B. ZEMEL, JOSEPH CHUN, and NAIMA MOUSTAID-MOUSSA. "Transcriptional regulation of the adipocyte fatty acid synthase gene by agouti: interaction with insulin." Physiological Genomics 3, no. 3 (September 8, 2000): 157–62. http://dx.doi.org/10.1152/physiolgenomics.2000.3.3.157.
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Claycombe, Kate J., Yanxin Wang, Brynn H. Jones, Suyeon Kim, William O. Wilkison, Michael B. Zemel, Joseph Chun, and Naima Moustaid-Moussa. Transcriptional regulation of the adipocyte fatty acid synthase gene by agouti: interaction with insulin. Physiol Genomics 3: 157–162, 2000.—Mice carrying dominant mutations at the agouti locus exhibit ectopic expression of agouti gene transcripts, obesity, and type II diabetes through unknown mechanisms. To gain insight into the role of agouti protein in modulating adiposity, we investigated regulation of a key lipogenic gene, fatty acid synthase (FAS) by agouti alone and in combination with insulin. Both agouti and insulin increase FAS activity in 3T3-L1 and in human adipocytes. Agouti and insulin independently and additively increase FAS activity in 3T3-L1 adipocytes. We further investigated the mechanism responsible for the agouti-induced FAS expression in these cells and demonstrated that both insulin (3-fold increase) and agouti (2-fold) increased FAS gene expression at the transcriptional level. Furthermore, insulin and agouti together exerted additive effects (5-fold increase) on FAS gene transcription. Transfection assays of FAS promoter-luciferase fusion gene constructs into 3T3-L1 adipocytes indicated that the agouti response element(s) is (are) located in the −435 to −415 region (−435/−415) of the FAS promoter. Nuclear proteins binding to this novel sequence are adipocyte specific. Thus the agouti response sequences mapped to a region upstream of the insulin-responsive element (which we previously reported to be located at −67/−52), consistent with additive effects of these two factors on FAS gene transcription.
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Crispim, Daisy, Felipe Mateus Pellenz, and Tais Silveira Assmann. "Identification of Key Genes and Pathways for Childhood Obesity Using System Biology Approach Based on Comprehensive Gene Information." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A49—A50. http://dx.doi.org/10.1210/jendso/bvab048.098.
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Abstract Introduction: Childhood obesity is one of the most important public health issues of the 21st century. Epidemiological studies have suggested that obesity during childhood increases the risk of developing comorbidities, such as type 2 diabetes, later in life. Childhood obesity is a complex disease whose molecular mechanisms are not completely elucidated. In this context, a system biology approach could contribute to the scientific knowledge regarding genetic factors related to childhood obesity onset. Aim: To identify molecular mechanisms involved in childhood obesity by implementing a system biology approach. Methods: Experimentally validated and computationally predicted genes related to Pediatric Obesity (C2362324) were downloaded from the DisGeNET v7.0 database. The protein-protein interaction (PPI) network was constructed using the STRING v11.0 database and analyzed using NetworkAnalyst v3.0 and Cytoscape v3.8.1. The relevance of each node for the network structure and functionality was assessed using the degree method to define hub genes. Functional and pathway enrichment analyses were performed based on Gene Ontology (GO) terms and KEGG Pathways. Results: The search on the DisGeNET database retrieved 191 childhood obesity-related genes. The PPI network of these genes showed 19 hub genes (STAT3, SIRT1, BCL2, IRS1, PPARG, SOCS3, TGFB1, HDAC4, DNMT1, ADCY3, PPARA, NEDD4L, ACACB, NR0B2, VEGFA, APOA1, GHR, CALR, and MKKS). These hub genes were involved in biological processes of lipid storage / kinase activity, regulation of fatty-acid metabolic processes, regulation of pri-miRNA transcription by RNA polymerase II, and negative regulation of small molecules and carbohydrate metabolic processes. In terms of molecular functions, repressing of transcription factors biding was found enriched. Regarding KEGG Pathways, the hub genes are involved with adipocytokine signaling, insulin resistance, longevity regulation, and cytokine signaling pathways. Conclusion: Our approach identified 19 hub genes, which are highly connected and probably have a key role in childhood obesity. Moreover, functional enrichment analyses demonstrated they are enriched in several biological processes and pathways related to the underlying molecular mechanisms of obesity. These findings provide a more comprehensive information regarding genetic and molecular factors behind childhood obesity pathogenesis. Further experimental investigation of our findings may shed light on the pathophysiology of this disease and contribute to the identification of new therapeutic targets.
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Karnieli, Eddy, and Michal Armoni. "Transcriptional regulation of the insulin-responsive glucose transporter GLUT4 gene: from physiology to pathology." American Journal of Physiology-Endocrinology and Metabolism 295, no. 1 (July 2008): E38—E45. http://dx.doi.org/10.1152/ajpendo.90306.2008.
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The insulin-responsive glucose transporter 4 (GLUT4) plays a key role in glucose uptake and metabolism in insulin target tissues. Being a rate-limiting step in glucose metabolism, the expression and function of the GLUT4 isoform has been extensively studied and found to be tightly regulated at both mRNA and protein levels. Adaptation to states of enhanced metabolic demand is associated with increased glucose metabolism and GLUT4 gene expression, whereas states of insulin resistance such as type 2 diabetes mellitus (DM2), obesity, and aging are associated with impaired regulation of GLUT4 gene expression and function. The present review focuses on the interplay among hormonal, nutritional, and transcription factors in the regulation of GLUT4 transcription in health and sickness.
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Zhang, Xiao, Tian-Ying Li, Hong-Mei Xiao, Kenneth C. Ehrlich, Hui Shen, Hong-Wen Deng, and Melanie Ehrlich. "Epigenomic and Transcriptomic Prioritization of Candidate Obesity-Risk Regulatory GWAS SNPs." International Journal of Molecular Sciences 23, no. 3 (January 23, 2022): 1271. http://dx.doi.org/10.3390/ijms23031271.
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Concern about rising rates of obesity has prompted searches for obesity-related single nucleotide polymorphisms (SNPs) in genome-wide association studies (GWAS). Identifying plausible regulatory SNPs is very difficult partially because of linkage disequilibrium. We used an unusual epigenomic and transcriptomic analysis of obesity GWAS-derived SNPs in adipose versus heterologous tissues. From 50 GWAS and 121,064 expanded SNPs, we prioritized 47 potential causal regulatory SNPs (Tier-1 SNPs) for 14 gene loci. A detailed examination of seven loci revealed that four (CABLES1, PC, PEMT, and FAM13A) had Tier-1 SNPs positioned so that they could regulate use of alternative transcription start sites, resulting in different polypeptides being generated or different amounts of an intronic microRNA gene being expressed. HOXA11 and long noncoding RNA gene RP11-392O17.1 had Tier-1 SNPs in their 3′ or promoter region, respectively, and strong preferences for expression in subcutaneous versus visceral adipose tissue. ZBED3-AS1 had two intragenic Tier-1 SNPs, each of which could contribute to mediating obesity risk through modulating long-distance chromatin interactions. Our approach not only revealed especially credible novel regulatory SNPs, but also helped evaluate previously highlighted obesity GWAS SNPs that were candidates for transcription regulation.
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Li, Zhihui, and Hongbing Wang. "Molecular Mechanisms of the SLC13A5 Gene Transcription." Metabolites 11, no. 10 (October 15, 2021): 706. http://dx.doi.org/10.3390/metabo11100706.
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Citrate is a crucial energy sensor that plays a central role in cellular metabolic homeostasis. The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter highly expressed in the mammalian liver with relatively low levels in the testis and brain, imports citrate from extracellular spaces into the cells. The perturbation of SLC13A5 expression and/or activity is associated with non-alcoholic fatty liver disease, obesity, insulin resistance, cell proliferation, and early infantile epileptic encephalopathy. SLC13A5 has been proposed as a promising therapeutic target for the treatment of these metabolic disorders. In the liver, the inductive expression of SLC13A5 has been linked to several xenobiotic receptors such as the pregnane X receptor and the aryl hydrocarbon receptor as well as certain hormonal and nutritional stimuli. Nevertheless, in comparison to the heightened interest in understanding the biological function and clinical relevance of SLC13A5, studies focusing on the regulatory mechanisms of SLC13A5 expression are relatively limited. In this review, we discuss the current advances in our understanding of the molecular mechanisms by which the expression of SLC13A5 is regulated. We expect this review will provide greater insights into the regulation of the SLC13A5 gene transcription and the signaling pathways involved therein.
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Parker, M. G., M. Christian, and R. White. "The nuclear receptor co-repressor RIP140 controls the expression of metabolic gene networks." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1103–6. http://dx.doi.org/10.1042/bst0341103.
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NRs (nuclear receptors) regulate the expression of specific gene networks in target cells by recruiting cofactor complexes involved in chromatin remodelling and in the assembly of transcription complexes. The importance of activating gene expression, in metabolic tissues, is well established, but the contribution of transcriptional inhibition is less well defined. In this review, we highlight a crucial role for RIP140 (receptor-interacting protein 140), a transcriptional co-repressor for NR, in the regulation of metabolic gene expression. Many genes involved in lipid and carbohydrate metabolism are repressed by RIP140 in adipose and muscle. The repressive function of RIP140 results from its ability to bridge NRs to repressive enzyme complexes that modify DNA and histones. In the absence of RIP140, expression from many metabolic genes is increased so that mice exhibit a lean phenotype and resistance to high-fat-diet-induced obesity and display increased glucose tolerance and insulin sensitivity. We propose that a functional interplay between transcriptional activators and the co-repressor RIP140 is an essential process in metabolic regulation.
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Ye, Yu-Xuan, Peng-Lu Pan, Ji-Yu Xu, Zhang-Fei Shen, Dong Kang, Jia-Bao Lu, Qing-Lin Hu, et al. "Forkhead box transcription factor L2 activates Fcp3C to regulate insect chorion formation." Open Biology 7, no. 6 (June 2017): 170061. http://dx.doi.org/10.1098/rsob.170061.
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Most animals are oviparous. However, the genes regulating egg shell formation remain not very clear. In this study, we found that Nilaparvata lugens Forkhead box transcription factor L2 ( Nl FoxL2) directly activated follicle cell protein 3C ( NlFcp3C ) to regulate chorion formation. NlFoxL2 and NlFcp3C had a similar expression pattern, both highly expressed in the follicular cells of female adults. Knockdown of NlFoxL2 or NlFcp3C also resulted in the same phenotypes: obesity and female infertility. RNA interference (RNAi) results suggested that NlFcp3C is a downstream gene of NlFoxL2 . Furthermore, transient expression showed that Nl FoxL2 could directly activate the NlFcp3C promoter. These results suggest that NlFcp3C is a direct target gene of Nl FoxL2. Depletion of NlFoxL2 or NlFcp3C prevented normal chorion formation. Our results first revealed the functions of Fcp3C and FoxL2 in regulation of oocyte maturation in an oviparous animal.
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Chen, Kun, Ji-Dan Zhou, Feng Zhang, Fang Zhang, Rui-Rui Zhang, Meng-Si Zhan, Xiao-Yin Tang, Bing Deng, Ming-Gang Lei, and Yuan-Zhu Xiong. "Transcription factor C/EBPβ promotes the transcription of the porcine GPR120 gene." Journal of Molecular Endocrinology 56, no. 2 (November 17, 2015): 91–100. http://dx.doi.org/10.1530/jme-15-0200.
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G protein-coupled receptor 120 (GPR120), an adipogenic receptor critical for the differentiation and maturation of adipocytes, plays an important role in controlling obesity in both humans and rodents and, thus, is an attractive target of obesity treatment studies. However, the mechanisms that regulate the expression of porcine GPR120 remain unclear. In this study, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) techniques were used to analyze and identify the binding of C/EBPβ (transcription factor CCAAT/enhancer binding protein beta) to the GPR120 promoter. C/EBPβ overexpression and RNA interference studies showed that C/EBPβ regulated GPR120 promoter activity and endogenous GPR120 expression. The binding site of C/EBPβ in the GPR120 promoter region from −101 to −87 was identified by promoter deletion analysis and site-directed mutagenesis. Overexpression of C/EBPβ increased endogenous GPR120 expression in pig kidney cells (PK). Furthermore, when endogenous C/EBPβ was knocked down, GPR120 mRNA and protein levels were decreased. The stimulatory effect of C/EBPβ on GPR120 transcription and its ability to bind the transcription factor-binding site were confirmed by luciferase, ChIP, and EMSA. Moreover, the mRNA and protein expression levels of C/EBPβ were induced by high fat diet feeding. Taken together, it can be concluded that C/EBPβ plays a vital role in regulating GPR120 transcription and suggests HFD-feeding induces GPR120 transcription by influencing C/EBPβ expression.
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Clarke, Steven D. "Polyunsaturated fatty acid regulation of gene transcription: a mechanism to improve energy balance and insulin resistance." British Journal of Nutrition 83, S1 (June 2000): S59—S66. http://dx.doi.org/10.1017/s0007114500000969.
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This review addresses the hypothesis that polyunsaturated fatty acids (PUFA), particularly those of the n-3 family, play essential roles in the maintenance of energy balance and glucose metabolism. The data discussed indicate that dietary PUFA function as fuel partitioners in that they direct glucose toward glycogen storage, and direct fatty acids away from triglyceride synthesis and assimilation and toward fatty acid oxidation. In addition, the n-3 family of PUFA appear to have the unique ability to enhance thermogenesis and thereby reduce the efficiency of body fat deposition. PUFA exert their effects on lipid metabolism and thermogenesis by up-regulating the transcription of the mitochondrial uncoupling protein-3, and inducing genes encoding proteins involved in fatty acid oxidation (e.g. carnitine palmitoyltransferase and acyl-CoA oxidase) while simultaneously down-regulating the transcription of genes encoding proteins involved in lipid synthesis (e.g. fatty acid synthase). The potential transcriptional mechanism and the transcription factors affected by PUFA are discussed. Moreover, the data are interpreted in the context of the role that PUFA may play as dietary factors in the development of obesity and insulin resistance. Collectively the results of these studies suggest that the metabolic functions governed by PUFA should be considered as part of the criteria utilized in defining the dietary needs for n-6 and n-3 PUFA, and in establishing the optimum dietary ratio for n-6 : n-3 fatty acids.
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Khan, Raza, Junjvlieke, Xiaoyu, Garcia, Elnour, Hongbao, and Linsen. "Function and Transcriptional Regulation of Bovine TORC2 Gene in Adipocytes: Roles of C/EBP, XBP1, INSM1 and ZNF263." International Journal of Molecular Sciences 20, no. 18 (September 4, 2019): 4338. http://dx.doi.org/10.3390/ijms20184338.
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The TORC2 gene is a member of the transducer of the regulated cyclic adenosine monophosphate (cAMP) response element binding protein gene family, which plays a key role in metabolism and adipogenesis. In the present study, we confirmed the role of TORC2 in bovine preadipocyte proliferation through cell cycle staining flow cytometry, cell counting assay, 5-ethynyl-2′-deoxyuridine staining (EdU), and mRNA and protein expression analysis of proliferation-related marker genes. In addition, Oil red O staining analysis, immunofluorescence of adiponectin, mRNA and protein level expression of lipid related marker genes confirmed the role of TORC2 in the regulation of bovine adipocyte differentiation. Furthermore, the transcription start site and sub-cellular localization of the TORC2 gene was identified in bovine adipocytes. To investigate the underlying regulatory mechanism of the bovine TORC2, we cloned a 1990 bp of the 5' untranslated region (5′UTR) promoter region into a luciferase reporter vector and seven vector fragments were constructed through serial deletion of the 5′UTR flanking region. The core promoter region of the TORC2 gene was identified at location −314 to −69 bp upstream of the transcription start site. Based on the results of the transcriptional activities of the promoter vector fragments, luciferase activities of mutated fragments and siRNAs interference, four transcription factors (CCAAT/enhancer-binding protein C/BEP, X-box binding protein 1 XBP1, Insulinoma-associated 1 INSM1, and Zinc finger protein 263 ZNF263) were identified as the transcriptional regulators of TORC2 gene. These findings were further confirmed through Electrophoretic Mobility Shift Assay (EMSA) within nuclear extracts of bovine adipocytes. Furthermore, we also identified that C/EBP, XBP1, INSM1 and ZNF263 regulate TORC2 gene as activators in the promoter region. We can conclude that TORC2 gene is potentially a positive regulator of adipogenesis. These findings will not only provide an insight for the improvement of intramuscular fat in cattle, but will enhance our understanding regarding therapeutic intervention of metabolic syndrome and obesity in public health as well.
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Chahal, Jaspreet, Ching-Chu Chen, Madhavi J. Rane, Joseph P. Moore, Michelle T. Barati, Ying Song, and Betty C. Villafuerte. "Regulation of Insulin-Response Element Binding Protein-1 in Obesity and Diabetes: Potential Role in Impaired Insulin-Induced Gene Transcription." Endocrinology 149, no. 10 (June 19, 2008): 4829–36. http://dx.doi.org/10.1210/en.2007-1693.
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One of the major mechanisms by which insulin modulates glucose homeostasis is through regulation of gene expression. Therefore, reduced expression of transcription factors that are required for insulin-regulated gene expression may contribute to insulin resistance. We recently identified insulin response element-binding protein-1 (IRE-BP1) as a transcription factor that binds and transactivates multiple insulin-responsive genes, but the regulation of IRE-BP1 in vivo is largely unknown. In this study, we show that IRE-BP1 interacts with the insulin response sequence of the IGF-I, IGFBP-1, and IGFBP-3 genes using chromatin immunoprecipitation assay. Furthermore, activation by IRE-BP1 is sequence specific and mimics that of the insulin effect on gene transcription. Tissue expression of IRE-BP1 is 50- to 200-fold higher in classical insulin target compared with nontarget tissues in lean animals, with a significantly reduced level of expression in the skeletal muscle and adipose tissue in obese and diabetic animals. In the liver, IRE-BP1 is localized to the nucleus in lean rats but is sequestered to the cytoplasm in obese and diabetic animals. Cytoplasmic sequestration appears to be related to inhibition of insulin-mediated phosphatidylinositol-3 kinase signaling. Therefore, in diabetes and obesity, the mechanisms involved in reducing the transactivation of the insulin response sequence by IRE-BP1 include decreased gene transcription and nuclear exclusion to prevent DNA binding. Our study supports the notion that IRE-BP1 may be relevant to the action of insulin in vivo and may play a role in the development of insulin resistance and diabetes.
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Ihara, Hayato, David J. Loskutoff, and Tetsumei Urano. "A Role for Adipocyte-Enriched Transcription Factor, PPAR-γ, in Up-Regulation of PAI-1 Gene Expression during Adipogenesis." Blood 104, no. 11 (November 16, 2004): 1940. http://dx.doi.org/10.1182/blood.v104.11.1940.1940.
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Abstract Obese patients are at risk for development of cardiovascular disease, which can in part be explained by disturbances in the haemostatic and fibrinolytic systems. Recently, it has been demonstrated that the adipocyte itself is able to produce a primary fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAI-1), possibly explaining the high levels found in obesity. We have previously shown that pioglitazone, a selective ligand for peroxisome proliferator-activated receptor (PPAR)-γ, and insulin not only enhances adipocyte differentiation, but also up-regulates PAI-1 gene transcription in 3T3-L1 adipocytes (Ihara et al. FASEB J., 2001). These results suggest that PAI-1 gene expression during adipogenesis can be regulated by a direct action of PPAR-γ. In the present study, we investigate a role of an adipocyte-enriched transcription factor, PPAR-γ, in up-regulation of PAI-1 gene expression in adipose tissues. To identify cis-acting genetic elements required for induction of PAI-1 gene transcription, we constructed the plasmids containing a 5′ deletion series of the PAI-1 promoter. When sequences between -762 and -723 were deleted, the level of induction significantly fell. By sequence homology search in this region, we found an atypical PPAR-responsive element (aPPRE) at positions −752 to −733. Gel mobility shift and supershift assays using oligonucleotides of the aPPRE overlapping C/EBP binding site indicated that the aPPRE is important for PPAR-γ binding. Chromatin immunoprecipitation assay demonstrated that PPAR-γ is physically associated with PAI-1 gene promoter region including the aPPRE in vivo. Furthermore, mutation of the aPPRE abrogated the increase in transcriptional activities of PAI-1 promoter. Functional assay revealed that besides PPAR-γ/RXR-α expression vectors, co-transfection of CREB-binding protein expression vector increased the luciferase activity to 7.5 fold and 11 fold of control value in COS-1 cells and 3T3-L1 preadipocytes, respectively. These data indicate that the transcriptional induction of PAI-1 gene during adipogenesis is mediated through the binding of PPAR-γ/RXR-α to the functional aPPRE in the PAI-1 gene promoters.
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Wang, Hong, and Robert H. Eckel. "Lipoprotein lipase: from gene to obesity." American Journal of Physiology-Endocrinology and Metabolism 297, no. 2 (August 2009): E271—E288. http://dx.doi.org/10.1152/ajpendo.90920.2008.
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Lipoprotein lipase (LPL) is a multifunctional enzyme produced by many tissues, including adipose tissue, cardiac and skeletal muscle, islets, and macrophages. LPL is the rate-limiting enzyme for the hydrolysis of the triglyceride (TG) core of circulating TG-rich lipoproteins, chylomicrons, and very low-density lipoproteins (VLDL). LPL-catalyzed reaction products, fatty acids, and monoacylglycerol are in part taken up by the tissues locally and processed differentially; e.g., they are stored as neutral lipids in adipose tissue, oxidized, or stored in skeletal and cardiac muscle or as cholesteryl ester and TG in macrophages. LPL is regulated at transcriptional, posttranscriptional, and posttranslational levels in a tissue-specific manner. Nutrient states and hormonal levels all have divergent effects on the regulation of LPL, and a variety of proteins that interact with LPL to regulate its tissue-specific activity have also been identified. To examine this divergent regulation further, transgenic and knockout murine models of tissue-specific LPL expression have been developed. Mice with overexpression of LPL in skeletal muscle accumulate TG in muscle, develop insulin resistance, are protected from excessive weight gain, and increase their metabolic rate in the cold. Mice with LPL deletion in skeletal muscle have reduced TG accumulation and increased insulin action on glucose transport in muscle. Ultimately, this leads to increased lipid partitioning to other tissues, insulin resistance, and obesity. Mice with LPL deletion in the heart develop hypertriglyceridemia and cardiac dysfunction. The fact that the heart depends increasingly on glucose implies that free fatty acids are not a sufficient fuel for optimal cardiac function. Overall, LPL is a fascinating enzyme that contributes in a pronounced way to normal lipoprotein metabolism, tissue-specific substrate delivery and utilization, and the many aspects of obesity and other metabolic disorders that relate to energy balance, insulin action, and body weight regulation.
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Cao, Weina, Yatao Xu, Dan Luo, Muhammad Saeed, and Chao Sun. "Hoxa5 Promotes Adipose Differentiation via Increasing DNA Methylation Level and Inhibiting PKA/HSL Signal Pathway in Mice." Cellular Physiology and Biochemistry 45, no. 3 (2018): 1023–33. http://dx.doi.org/10.1159/000487343.
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Background/Aims: Impaired adipogenesis may be the underlying cause in the development of obesity and type II diabetes. Mechanistically, the family of Homeobox transcription factors is implicated in the regulation of adipocyte fate. Hoxa5 is highly expressed in adipocytes, and its mRNA expression is decreased during differentiation. However, the function of Hoxa5 in adipose tissue has been poorly understood. The aim of this study is to unveil the role of Hoxa5 on adipocyte differentiation and its underlying mechanisms. Methods: Quantitative real-time PCR (qPCR) and western blot were performed to determine Hoxa5 expression in primary adipocytes and in adipose tissues from mice. Lipid accumulation was evaluated by bodipy staining. Dual luciferase assay was applied to explore the transcription factor of Hoxa5 and the transcriptional target gene modulated by Hoxa5. All measurements were performed at least for three times at least. Results: A significant reduction of Hoxa5 expression was observed in adipose tissue of High Fat Diet (HFD) induced obesity mice. We determined Hoxa5 increased adipocytes differentiation and mitochondrial biogenesis in adipocytes in vitro. CEBPβ was determined a transcription factor of Hoxa5 and inhibited methylation level of Hoxa5 by combining on the promoter of Hoxa5. Importantly, we found Fabp4, a known positive regulator of adipocytes differentiation, was transcriptional activation by Hoxa5. In addition, Hoxa5 promotes adipocytes differentiation by inhibiting PKA/HSL pathway. Conclusion: Our study demonstrated the promoting role of Hoxa5 in adipocytes differentiation and therefore bringing a new therapeutic mean to the treatment of obesity and type II diabetes.
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Chen, Shuqin, Huating Li, Jing Zhang, Shan Jiang, Mingliang Zhang, Yilan Xu, Kun Dong, Ying Yang, Qichen Fang, and Weiping Jia. "Identification of Sp1 as a Transcription Activator to Regulate Fibroblast Growth Factor 21 Gene Expression." BioMed Research International 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/8402035.
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Fibroblast growth factor 21 (FGF21) is a metabolic hormone with multiple beneficial effects on lipid and glucose homeostasis. Previous study demonstrated that FGF21 might be one of the Sp1 target genes. However, the transcriptional role of Sp1 on FGF21 in adipose tissue and liver has not been reported. In this study, we found that the proximal promoter of mouse FGF21 is located between −63 and −20 containing two putative Sp1-binding sites. Sp1 is a mammalian transcription factor involved in the regulation of many genes during physiological and pathological processes. Our study showed that overexpression of Sp1 or suppressing Sp1 expression resulted in increased or reduced FGF21 promoter activity, respectively. Mutation analysis demonstrated that the Sp1-binding site located between −46 and −38 plays a primary role in transcription of FGF21. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis indicated that Sp1 specifically bound to this region. Furthermore, the binding activity of Sp1 was significantly increased in adipose tissues of HFD-induced obese mouse and liver of DEN-treated mouse. Thus, our results demonstrate that Sp1 positively regulates the basal transcription of FGF21 in the liver and adipose tissue and contributes to the obesity-induced FGF21 upregulation in mouse adipose tissue and hepatic FGF21 upregulation in hepatocarcinogenesis.
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Maples, Jill M., Jeffrey J. Brault, Carol A. Witczak, Sanghee Park, Monica J. Hubal, Todd M. Weber, Joseph A. Houmard, and Brian M. Shewchuk. "Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity." American Journal of Physiology-Endocrinology and Metabolism 309, no. 4 (August 15, 2015): E345—E356. http://dx.doi.org/10.1152/ajpendo.00505.2014.
Full textAbstract:
The ability to increase fatty acid oxidation (FAO) in response to dietary lipid is impaired in the skeletal muscle of obese individuals, which is associated with a failure to coordinately upregulate genes involved with FAO. While the molecular mechanisms contributing to this metabolic inflexibility are not evident, a possible candidate is carnitine palmitoyltransferase-1B (CPT1B), which is a rate-limiting step in FAO. The present study was undertaken to determine if the differential response of skeletal muscle CPT1B gene transcription to lipid between lean and severely obese subjects is linked to epigenetic modifications (DNA methylation and histone acetylation) that impact transcriptional activation. In primary human skeletal muscle cultures the expression of CPT1B was blunted in severely obese women compared with their lean counterparts in response to lipid, which was accompanied by changes in CpG methylation, H3/H4 histone acetylation, and peroxisome proliferator-activated receptor-δ and hepatocyte nuclear factor 4α transcription factor occupancy at the CPT1B promoter. Methylation of specific CpG sites in the CPT1B promoter that correlated with CPT1B transcript level blocked the binding of the transcription factor upstream stimulatory factor, suggesting a potential causal mechanism. These findings indicate that epigenetic modifications may play important roles in the regulation of CPT1B in response to a physiologically relevant lipid mixture in human skeletal muscle, a major site of fatty acid catabolism, and that differential DNA methylation may underlie the depressed expression of CPT1B in response to lipid, contributing to the metabolic inflexibility associated with severe obesity.
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Zhang, Xiang, and Xiaoyu Hu. "MicroRNAs of the miR-17~92 family inhibit macrophage activation and inflammation." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 152.27. http://dx.doi.org/10.4049/jimmunol.204.supp.152.27.
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Abstract Production of pro- and anti-inflammatory cytokines by macrophages is tightly controlled by multiple layers of mechanisms including those involving miRNA-mediated regulation of post-transcriptional events. By genetically deleting all three individual miRNA clusters in the miR-17~92 family, we found that this family of miRNAs inhibit macrophage activation by promoting expression of a key anti-inflammatory cytokine IL-10 and thus suppress production of pro-inflammatory mediators such as TNF. Consistent with the heightened inflammatory responses in vitro, myeloid-specific ablation of miR-17~92 family miRNAs in vivo led to exacerbated obesity under the condition of a high-fat diet and poor survival in the DSS-induced colitis model. Moreover, miRNA-deficient adipose tissue macrophages and intestinal macrophages exhibited enhanced levels of TNF and reduced levels of IL-10. Mechanistically, miR-17~92 family miRNAs sustained IL-10 production in macrophages by promoting transcription of the Fos gene encoding a key transcription factor driving Il10 expression. The positive effects of miR-17~92 family miRNAs on Fos expression are secondary to negative regulation of Fos by transcription factor YY1 that is a direct target of miR-17~92 family miRNAs. Taken together, these results identified miR-17~92 family miRNAs as crucial regulators of the balance between pro- and anti-inflammatory cytokines and illustrated key roles for three clusters of the miR-17~92 family in cooperatively regulating macrophage activation and inflammatory responses.
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Minchenko, Dmytro O. "Insulin resistance in obese adolescents affects the expression of genes associated with immune response." Endocrine Regulations 53, no. 2 (April 1, 2019): 71–82. http://dx.doi.org/10.2478/enr-2019-0009.
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AbstractObjective. The development of obesity and its metabolic complications is associated with dysregulation of various intrinsic mechanisms, which control basic metabolic processes through changes in the expression of numerous regulatory genes.Methods. The expression level of HLA-DRA, HLA-DRB1, HLA-G, HLA-F, and NFX1 genes as well as miR-190b was measured in the blood of obese adolescents without signs of resistance to insulin and with insulin resistance in comparison with the group of relative healthy control individuals without signs of obesity.Results. It was shown that obesity without signs of insulin resistance is associated with upregulation of the expression level of HLA-DRA and HLA-DRB1 genes, but with down-regulation of HLA-G gene expression in the blood as compared to control group of relative healthy adolescents. At the same time, no significant changes were observed in the expression level of HLA-F and NFX1 genes in the blood of this group of obese adolescents. Development of insulin resistance in obese individuals leads to significant down-regulation of HLA-DRA, HLA-DRB1, HLA-G, and HLA-F gene expressions as well as to up-regulation of NFX1 gene as well as microRNA miR-190b in the blood as compared to obese patients without signs of insulin resistance.Conclusions. Results of this study provide evidence that obesity affects the expression of the subset of genes related to immune response in the blood and that development of insulin resistance in obese adolescents is associated with strong down-regulation of the expressions of HLA-DRA, HLA-DRB1, HLA-F, and HLA-G genes, which may be contribute to the development of obesity complications. It is possible that transcription factor NFX1 and miR-190b participate in downregulation of HLA-DRA gene expression in the blood of obese adolescents with insulin resistance.
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Kondo, Hidehiko, Yoshihiko Minegishi, Yumiko Komine, Takuya Mori, Ichiro Matsumoto, Keiko Abe, Ichiro Tokimitsu, Tadashi Hase, and Takatoshi Murase. "Differential regulation of intestinal lipid metabolism-related genes in obesity-resistant A/J vs. obesity-prone C57BL/6J mice." American Journal of Physiology-Endocrinology and Metabolism 291, no. 5 (November 2006): E1092—E1099. http://dx.doi.org/10.1152/ajpendo.00583.2005.
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The effects of high-fat (HF) feeding on gene expression in the small intestine were examined using obesity-resistant A/J mice and obesity-prone C57BL/6J (B6) mice. Both strains of mice were maintained on low-fat (LF; 5% fat) or HF (30% fat) diets for 2 wk. Quantitative reverse transcription-PCR analysis revealed that lipid metabolism-related genes, including carnitine palmitoyltransferase (CPT) I, liver fatty acid binding protein, pyruvate dehydrogenase kinase-4, and NADP+-dependent cytosolic malic enzyme, were upregulated by HF feeding in both strains of mice. The upregulated gene expression levels were higher in A/J mice than in B6 mice, suggesting more active lipid metabolism in the small intestine of A/J mice. The prominent upregulation of the lipid metabolism-related genes were specific to the small intestine; the expression levels were little or unchanged in the liver, muscle, and white adipose tissue. The increase by HF feeding and predominant expression of the intestinal lipid metabolism-related genes in A/J mice were reflected in the enzyme activities; malic enzyme, CPT, and β-oxidation activities were increased by HF feeding, and the upregulated malic enzyme and CPT activities were significantly higher in obesity-resistant A/J mice compared with those in obesity-prone B6 mice. These findings suggest that intestinal lipid metabolism is associated with susceptibility to obesity.
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Serazin-Leroy, Valérie, Mireille Morot, Philippe de Mazancourt, and Yves Giudicelli. "Androgen regulation and site specificity of angiotensinogen gene expression and secretion in rat adipocytes." American Journal of Physiology-Endocrinology and Metabolism 279, no. 6 (December 1, 2000): E1398—E1405. http://dx.doi.org/10.1152/ajpendo.2000.279.6.e1398.
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Adipose tissue is an important source of angiotensinogen (ATG), and hypertension is commonly associated with android obesity. Therefore, we tested the hypothesis that androgens may control ATG gene expression and secretion in rat fat cells. In intact male rats, ATG mRNA expression (Northern blot and co-reverse transcription-polymerase chain reaction analysis) and protein secretion were significantly higher in deep intra-abdominal (perirenal and epididymal) than in subcutaneous adipocytes. After castration, ATG mRNA was reduced almost 50% in the three fat deposits, with parallel changes in ATG protein secretion. Conversely, testosterone treatment fully restored the ATG mRNA decrease after castration, whatever the anatomical origin of the adipocytes. Finally, a 24-h in vitro exposure of perirenal fat cells or differentiated preadipocytes from castrated rats to testosterone or dihydrotestosterone (10 nM free hormone concentration) increased ATG mRNA expression by 50–100%, an effect that was prevented by the anti-androgen cyproterone acetate. These data, demonstrating both in vivo and in vitro androgen induction of ATG mRNA expression in rat adipocytes, add further weight to the hypothesis of a link between adipose tissue ATG production, androgens, and android obesity-related hypertension.
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Joshi, Amrita, Ronald Allen, Danielle Kroetz, Matthew Schaller, Jennifer Dalton, Steven Kunkel, and Katherine Gallagher. "Histone methyltransferase, Setdb2, regulates wound healing in a diet-induced obesity model of diabetes (IRM9P.601)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 130.10. http://dx.doi.org/10.4049/jimmunol.194.supp.130.10.
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Abstract Impaired wound healing in Type 2 diabetes (T2D) is associated with a chronic inflammatory response mediated by accumulation of macrophages producing pro-inflammatory cytokines. While recent work has shown that epigenetic regulation plays a key role in influencing macrophage function, the specific alterations that occur in T2D macrophages and their effects on gene transcription have not been elucidated. Work in our laboratory has shown that Histone H3 Lys9 methylation that results in transcriptional silencing is mediated by Setdb2 (SET domain, bifurcated2) and plays a critical role in lung inflammation. Thus, we examined the role of Setdb2 in wound healing and macrophage activation in a murine model of T2D. Superficial wounding resulted in increased transcript levels of Setdb2 in wound macrophages of control mice compared with diabetic mice. Specific deletion of Setdb2 in macrophages (Setdb2lyz2) using cre recombinase resulted in delayed wound healing. Furthermore, bone marrow derived macrophages from Setdb2lyz2 cre+ mice show reduced expression of key regulatory mediators such as IFN-β. In summary, our data indicate that Setdb2 may play a protective role in wound healing by regulating inflammation.
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Pritchard, LE, AV Turnbull, and A. White. "Pro-opiomelanocortin processing in the hypothalamus: impact on melanocortin signalling and obesity." Journal of Endocrinology 172, no. 3 (March 1, 2002): 411–21. http://dx.doi.org/10.1677/joe.0.1720411.
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Bioactive peptides derived from the prohormone, pro-opiomelanocortin (POMC), are generated in neurons of the hypothalamus and act as endogenous ligands for the melanocortin-4 receptor (MC4R), a key molecule underlying appetite control and energy homeostasis. It is therefore important to understand many aspects of POMC gene regulation in the brain, as pharmacological manipulation of POMC expression/processing could be a potential strategy to combat obesity. Most studies that have analysed POMC gene expression in the hypothalamus have focused on gene transcription experiments. Ultimately, however, factors that regulate post-translational processing and secretion of peptides will have most bearing on melanocortin signalling. This article focuses on (a) current evidence that POMC is involved in obesity, (b) how POMC transcription is regulated in the hypothalamus, (c) the mechanism by which proteolytic processing of POMC is controlled in the hypothalamus and what peptides are produced and (d) which POMC-derived peptides are the most potent ligands at the melanocortin receptor in vitro and in vivo. It seems that post-translational cleavage of POMC in the hypothalamus may be regulated with respect to energy requirement. We predict that further research into hypothalamic POMC processing, and the proteolytic enzymes involved, may yield important new clues on how flux through the MC4R pathway is regulated.
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Pearen, Michael A., and George E. O. Muscat. "Orphan Nuclear Receptors and the Regulation of Nutrient Metabolism: Understanding Obesity." Physiology 27, no. 3 (June 2012): 156–66. http://dx.doi.org/10.1152/physiol.00007.2012.
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Nuclear hormone receptors (NRs) are a superfamily of eukaryotic ligand-dependent transcription factors that translate endocrine, metabolic, nutritional, developmental, and pathophysiological signals into gene regulation. Members of the NR superfamily (on the basis of sequence homology) that lack identified natural and/or synthetic ligands are/were classified as “orphan” NRs. These members of the NR superfamily are abundantly expressed in tissues associated with major metabolic activity, such as skeletal muscle, adipose, and liver. Subsequently, in vivo genetic studies on these orphan NRs and exploitation of novel natural and synthetic agonists has revealed that orphan NRs regulate 1) carbohydrate, lipid, and energy homeostasis in a tissue-specific manner, and 2) the pathophysiology of dyslipidemia, obesity, Type 2 diabetes, and cardiovascular disease. This review discusses key studies that have implicated the orphan NRs as organ-specific regulators of metabolism and mediators of adverse pathophysiological effects. The emerging discovery of novel endogenous orphan NR ligands and synthetic agonists has provided the foundation for therapeutic exploitation of the orphans in the treatment of metabolic disease.
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Patankar, Jay V., Prakash G. Chandak, Sascha Obrowsky, Thomas Pfeifer, Clemens Diwoky, Andreas Uellen, Wolfgang Sattler, et al. "Loss of intestinal GATA4 prevents diet-induced obesity and promotes insulin sensitivity in mice." American Journal of Physiology-Endocrinology and Metabolism 300, no. 3 (March 2011): E478—E488. http://dx.doi.org/10.1152/ajpendo.00457.2010.
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Transcriptional regulation of small intestinal gene expression controls plasma total cholesterol (TC) and triglyceride (TG) levels, which are major determinants of metabolic diseases. GATA4, a zinc finger domain transcription factor, is critical for jejunal identity, and intestinal GATA4 deficiency leads to a jejunoileal transition. Although intestinal GATA4 ablation is known to misregulate jejunal gene expression, its pathophysiological impact on various components of metabolic syndrome remains unknown. Here, we used intestine-specific GATA4 knockout (GATA4iKO) mice to dissect the contribution of GATA4 on obesity development. We challenged adult GATA4iKO mice and control littermates with a Western-type diet (WTD) for 20 wk. Our findings show that WTD-fed GATA4iKO mice are resistant to diet-induced obesity. Accordingly, plasma TG and TC levels are markedly decreased. Intestinal lipid absorption in GATA4iKO mice was strongly reduced, whereas luminal lipolysis was unaffected. GATA4iKO mice displayed a greater glucagon-like peptide-1 (GLP-1) release on normal chow and even after long-term challenge with WTD remained glucose sensitive. In summary, our findings show that the absence of intestinal GATA4 has a beneficial effect on decreasing intestinal lipid absorption causing resistance to hyperlipidemia and obesity. In addition, we show that increased GLP-1 release in GATA4iKO mice decreases the risk for development of insulin resistance.
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Haro, Diego, Pedro Marrero, and Joana Relat. "Nutritional Regulation of Gene Expression: Carbohydrate-, Fat- and Amino Acid-Dependent Modulation of Transcriptional Activity." International Journal of Molecular Sciences 20, no. 6 (March 19, 2019): 1386. http://dx.doi.org/10.3390/ijms20061386.
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The ability to detect changes in nutrient levels and generate an adequate response to these changes is essential for the proper functioning of living organisms. Adaptation to the high degree of variability in nutrient intake requires precise control of metabolic pathways. Mammals have developed different mechanisms to detect the abundance of nutrients such as sugars, lipids and amino acids and provide an integrated response. These mechanisms include the control of gene expression (from transcription to translation). This review reports the main molecular mechanisms that connect nutrients’ levels, gene expression and metabolism in health. The manuscript is focused on sugars’ signaling through the carbohydrate-responsive element binding protein (ChREBP), the role of peroxisome proliferator-activated receptors (PPARs) in the response to fat and GCN2/activating transcription factor 4 (ATF4) and mTORC1 pathways that sense amino acid concentrations. Frequently, alterations in these pathways underlie the onset of several metabolic pathologies such as obesity, insulin resistance, type 2 diabetes, cardiovascular diseases or cancer. In this context, the complete understanding of these mechanisms may improve our knowledge of metabolic diseases and may offer new therapeutic approaches based on nutritional interventions and individual genetic makeup.
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Peng, Shiming, Wen Xiao, Dapeng Ju, Baofa Sun, Nannan Hou, Qianlan Liu, Yanli Wang, et al. "Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1." Science Translational Medicine 11, no. 488 (April 17, 2019): eaau7116. http://dx.doi.org/10.1126/scitranslmed.aau7116.
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Recent studies have established the involvement of the fat mass and obesity-associated gene (FTO) in metabolic disorders such as obesity and diabetes. However, the precise molecular mechanism by which FTO regulates metabolism remains unknown. Here, we used a structure-based virtual screening of U.S. Food and Drug Administration–approved drugs to identify entacapone as a potential FTO inhibitor. Using structural and biochemical studies, we showed that entacapone directly bound to FTO and inhibited FTO activity in vitro. Furthermore, entacapone administration reduced body weight and lowered fasting blood glucose concentrations in diet-induced obese mice. We identified the transcription factor forkhead box protein O1 (FOXO1) mRNA as a direct substrate of FTO, and demonstrated that entacapone elicited its effects on gluconeogenesis in the liver and thermogenesis in adipose tissues in mice by acting on an FTO-FOXO1 regulatory axis.
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Maples, Jill M., Jeffrey J. Brault, Brian M. Shewchuk, Carol A. Witczak, Kai Zou, Naomi Rowland, Monica J. Hubal, Todd M. Weber, and Joseph A. Houmard. "Lipid exposure elicits differential responses in gene expression and DNA methylation in primary human skeletal muscle cells from severely obese women." Physiological Genomics 47, no. 5 (May 2015): 139–46. http://dx.doi.org/10.1152/physiolgenomics.00065.2014.
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The skeletal muscle of obese individuals exhibits an impaired ability to increase the expression of genes linked with fatty acid oxidation (FAO) upon lipid exposure. The present study determined if this response could be attributed to differential DNA methylation signatures. RNA and DNA were isolated from primary human skeletal muscle cells (HSkMC) from lean and severely obese women following lipid incubation. mRNA expression and DNA methylation were quantified for genes that globally regulate FAO [PPARγ coactivator ( PGC-1α), peroxisome proliferator-activated receptors ( PPARs), nuclear respiratory factors ( NRFs)]. With lipid oversupply, increases in NRF-1, NRF-2, PPARα, and PPARδ expression were dampened in skeletal muscle from severely obese compared with lean women. The expression of genes downstream of the PPARs and NRFs also exhibited a pattern of not increasing as robustly upon lipid exposure with obesity. Increases in CpG methylation near the transcription start site with lipid oversupply were positively related to PPARδ expression; increases in methylation with lipid were depressed in HSkMC from severely obese women. With severe obesity, there is an impaired ability to upregulate global transcriptional regulators of FAO in response to lipid exposure. Transient changes in DNA methylation patterns and differences in the methylation signature with severe obesity may play a role in the transcriptional regulation of PPARδ in response to lipid. The persistence of differential responses to lipid in HSkMC derived from lean and obese subjects supports the possibility of stable epigenetic programming of skeletal muscle cells by the respective environments.
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Chartoumpekis, Dionysios V., Panos G. Ziros, Apostolos Zaravinos, Ralitsa P. Iskrenova, Agathoklis I. Psyrogiannis, Venetsana E. Kyriazopoulou, Gerasimos P. Sykiotis, and Ioannis G. Habeos. "Hepatic Gene Expression Profiling in Nrf2 Knockout Mice after Long-Term High-Fat Diet-Induced Obesity." Oxidative Medicine and Cellular Longevity 2013 (2013): 1–17. http://dx.doi.org/10.1155/2013/340731.
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Introduction. The transcription factor NFE2-related factor 2 (Nrf2) is a central regulator of antioxidant and detoxification gene expression in response to electrophilic or oxidative stress. Nrf2 has recently been shown to cross-talk with metabolic pathways, and its gene deletion protected mice from high-fat-diet-(HFD-) induced obesity and insulin resistance. This study aimed to identify potential Nrf2-regulated genes of metabolic interest by comparing gene expression profiles of livers of wild-type (WT) versus Nrf2 knockout (Nrf2-KO) mice after a long-term HFD.Methods. WT and Nrf2-KO mice were fed an HFD for 180 days; total RNA was prepared from liver and used for microarray analysis and quantitative real-time RT-PCR (qRT-PCR).Results. The microarray analysis identified 601 genes that were differentially expressed between WT and Nrf2-KO mice after long-term HFD. Selected genes, including ones known to be involved in metabolic regulation, were prioritized for verification by qRT-PCR:Cyp7a1andFabp5were significantly overexpressed in Nrf2-KO mice; in contrast,Car,Cyp2b10,Lipocalin 13,Aquaporin 8,Cbr3,Me1, andNqo1were significantly underexpressed in Nrf2-KO mice.Conclusion. Transcriptome profiling after HFD-induced obesity confirms thatNrf2is implicated in liver metabolic gene networks. The specific genes identified here may provide insights into Nrf2-dependent mechanisms of metabolic regulation.
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Portius, Dorothea, Cyril Sobolewski, and Michelangelo Foti. "MicroRNAs-Dependent Regulation of PPARs in Metabolic Diseases and Cancers." PPAR Research 2017 (2017): 1–19. http://dx.doi.org/10.1155/2017/7058424.
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Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-dependent nuclear receptors, which control the transcription of genes involved in energy homeostasis and inflammation and cell proliferation/differentiation. Alterations of PPARs’ expression and/or activity are commonly associated with metabolic disorders occurring with obesity, type 2 diabetes, and fatty liver disease, as well as with inflammation and cancer. Emerging evidence now indicates that microRNAs (miRNAs), a family of small noncoding RNAs, which fine-tune gene expression, play a significant role in the pathophysiological mechanisms regulating the expression and activity of PPARs. Herein, the regulation of PPARs by miRNAs is reviewed in the context of metabolic disorders, inflammation, and cancer. The reciprocal control of miRNAs expression by PPARs, as well as the therapeutic potential of modulating PPAR expression/activity by pharmacological compounds targeting miRNA, is also discussed.
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Bravo-Ruiz, Inés, Miguel Ángel Medina, and Beatriz Martínez-Poveda. "From Food to Genes: Transcriptional Regulation of Metabolism by Lipids and Carbohydrates." Nutrients 13, no. 5 (April 30, 2021): 1513. http://dx.doi.org/10.3390/nu13051513.
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Lipids and carbohydrates regulate gene expression by means of molecules that sense these macronutrients and act as transcription factors. The peroxisome proliferator-activated receptor (PPAR), activated by some fatty acids or their derivatives, and the carbohydrate response element binding protein (ChREBP), activated by glucose-derived metabolites, play a key role in metabolic homeostasis, especially in glucose and lipid metabolism. Furthermore, the action of both factors in obesity, diabetes and fatty liver, as well as the pharmacological development in the treatment of these pathologies are indeed of high relevance. In this review we present an overview of the discovery, mechanism of activation and metabolic functions of these nutrient-dependent transcription factors in different tissues contexts, from the nutritional genomics perspective. The possibility of targeting these factors in pharmacological approaches is also discussed. Lipid and carbohydrate-dependent transcription factors are key players in the complex metabolic homeostasis, but these factors also drive an adaptive response to non-physiological situations, such as overeating. Possibly the decisive role of ChREBP and PPAR in metabolic regulation points to them as ideal therapeutic targets, but their pleiotropic functions in different tissues makes it difficult to “hit the mark”.
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S., Udhaya Kumar, Bithia Rajan, Thirumal Kumar D., Anu Preethi V., Taghreed Abunada, Salma Younes, Sarah Okashah, Selvarajan Ethiraj, George Priya Doss C., and Hatem Zayed. "Involvement of Essential Signaling Cascades and Analysis of Gene Networks in Diabesity." Genes 11, no. 11 (October 25, 2020): 1256. http://dx.doi.org/10.3390/genes11111256.
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(1) Aims: Diabesity, defined as diabetes occurring in the context of obesity, is a serious health problem that is associated with an increased risk of premature heart attack, stroke, and death. To date, a key challenge has been to understand the molecular pathways that play significant roles in diabesity. In this study, we aimed to investigate the genetic links between diabetes and obesity in diabetic individuals and highlight the role(s) of shared genes in individuals with diabesity. (2) Methods: The interactions between the genes were analyzed using the Search Tool for the Retrieval of Interacting Genes (STRING) tool after the compilation of obesity genes associated with type 1 diabetes (T1D), type 2 diabetes (T2D), and maturity-onset diabetes of the young (MODY). Cytoscape plugins were utilized for enrichment analysis. (3) Results: We identified 546 obesity genes that are associated with T1D, T2D, and MODY. The network backbone of the identified genes comprised 514 nodes and 4126 edges with an estimated clustering coefficient of 0.242. The Molecular Complex Detection (MCODE) generated three clusters with a score of 33.61, 16.788, and 6.783, each. The highest-scoring nodes of the clusters were AGT, FGB, and LDLR genes. The genes from cluster 1 were enriched in FOXO-mediated transcription of oxidative stress, renin secretion, and regulation of lipolysis in adipocytes. The cluster 2 genes enriched in Src homology 2 domain-containing (SHC)-related events triggered by IGF1R, regulation of lipolysis in adipocytes, and GRB2: SOS produce a link to mitogen-activated protein kinase (MAPK) signaling for integrins. The cluster 3 genes ere enriched in IGF1R signaling cascade and insulin signaling pathway. (4) Conclusion: This study presents a platform to discover potential targets for diabesity treatment and helps in understanding the molecular mechanism.
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Yue, Lili, John W. Christman, and Theodore Mazzone. "Tumor Necrosis Factor-α-Mediated Suppression of Adipocyte Apolipoprotein E Gene Transcription: Primary Role for the Nuclear Factor (NF)-κB Pathway and NFκB p50." Endocrinology 149, no. 8 (May 8, 2008): 4051–58. http://dx.doi.org/10.1210/en.2008-0340.
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The adipose tissue inflammation accompanying obesity has important consequences for adipocyte lipid metabolism, and increased adipose tissue TNFα plays an important role for mediating the effect of inflammation on adipocyte function. Recent studies have shown that apolipoprotein E (apoE) is highly expressed in adipose tissue where it plays an important role in modulating adipocyte triglyceride metabolism, triglyceride mass, and adipocyte size. We have previously reported that TNFα reduces adipocyte apoE, and the current studies were undertaken to evaluate the molecular mechanism for this regulation. TNFα repression of adipocyte apoE gene expression required an intact nuclear factor (NF)-κB binding site at −43 in the apoE promoter. Site-directed mutagenesis at this site completely eliminated TNFα regulation of an apoE gene reporter. TNFα treatment activated binding of NFκB p50, isolated from adipocyte nuclei, to the apoE promoter. Two structurally distinct inhibitors of NFκB complex activation or translocation abrogated the TNFα effect on the apoE gene. Using chromatin immunoprecipitation assays, we demonstrated that treatment of adipocytes with TNFα led to increased binding of NFκB p50, and decreased binding of p65 and Sp1, to this region of the apoE promoter in living cells. The key role played by increased p50 binding was confirmed by p50 knockdown experiments. Reduction of p50 expression using small interference RNA completely eliminated TNFα-mediated reduction of endogenous adipocyte apoE gene expression. These results establish the molecular link between adipose tissue inflammation and apoE gene expression in adipocytes. The suppression of adipocyte apoE by the proinflammatory adipose tissue milieu associated with obesity will have important downstream effects on adipocyte triglyceride turnover and content.
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Nakagawa, Yoshimi, Aoi Satoh, Sachiko Yabe, Mika Furusawa, Naoko Tokushige, Hitomi Tezuka, Motoki Mikami, et al. "Hepatic CREB3L3 Controls Whole-Body Energy Homeostasis and Improves Obesity and Diabetes." Endocrinology 155, no. 12 (December 1, 2014): 4706–19. http://dx.doi.org/10.1210/en.2014-1113.
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Transcriptional regulation of metabolic genes in the liver is the key to maintaining systemic energy homeostasis during starvation. The membrane-bound transcription factor cAMP-responsive element-binding protein 3-like 3 (CREB3L3) has been reported to be activated during fasting and to regulate triglyceride metabolism. Here, we show that CREB3L3 confers a wide spectrum of metabolic responses to starvation in vivo. Adenoviral and transgenic overexpression of nuclear CREB3L3 induced systemic lipolysis, hepatic ketogenesis, and insulin sensitivity with increased energy expenditure, leading to marked reduction in body weight, plasma lipid levels, and glucose levels. CREB3L3 overexpression activated gene expression levels and plasma levels of antidiabetic hormones, including fibroblast growth factor 21 and IGF-binding protein 2. Amelioration of diabetes by hepatic activation of CREB3L3 was also observed in several types of diabetic obese mice. Nuclear CREB3L3 mutually activates the peroxisome proliferator-activated receptor (PPAR) α promoter in an autoloop fashion and is crucial for the ligand transactivation of PPARα by interacting with its transcriptional regulator, peroxisome proliferator-activated receptor gamma coactivator-1α. CREB3L3 directly and indirectly controls fibroblast growth factor 21 expression and its plasma level, which contributes at least partially to the catabolic effects of CREB3L3 on systemic energy homeostasis in the entire body. Therefore, CREB3L3 is a therapeutic target for obesity and diabetes.
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Gmoshinski, I. V., S. A. Apryatin, Kh Kh Sharafetdinov, D. B. Nikitjuk, and V. A. Tutelyan. "TRANSCRIPTOMICS RESEARCH IN THE CLINICAL AND EXPERIMENTAL INVESTIGATION OF PATHOGENETIC MECHANISMS OF ALIMENTARY OBESITY." Annals of the Russian academy of medical sciences 73, no. 3 (June 14, 2018): 172–80. http://dx.doi.org/10.15690/vramn973.
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The review considers the significant role of changes in the transcriptome of organs and tissues for studying the molecular mechanisms of obesity development. Modern methods of transcriptomics including technologies for quantitative RT-PCR and DNA microarrays provided a new approach to the search for sensitive molecular markers as obesity predictors Differential gene expression profiles are mostly organo- and tissue-specific for adipose tissue, liver, brain, and other organs and tissues; can significantly differ in animal in vivo models with genetically determined and dietary induced obesity. At the same time, coordinated regulation is registered in the organs and tissues of expression of extensive groups of genes associated with lipid, cholesterol, and carbohydrate metabolism, the synthesis and circulation of neurotransmitters of dopamine and serotonin, peptide hormones, cytokines which induce systemic inflammation. For systemic regulation mechanisms causing a concerted change in the transcription of tens and hundreds of genes in obesity, the adipokines effects should be pointed out, primarily leptin, as well as pro-inflammatory cytokines, the micro-RNA (miRs) system and central effects developing at NPY/AgRP+ and POMC/CART+ neurons of the arcuate nucleus of the hypothalamus. Results of transcriptomic studies can be used in preclinical trials of new drugs and methods of dietary correction of obesity in animal’s in vivo models, as well as in the search for clinical predictors and markers of metabolic abnormalities in patients with obesity receiving personalized therapy. The main problem of transcriptomic studies in in vivo models is incomplete consistency between the data obtained with full-transcriptional profiling and the results of quantitative RT-PCR expression of individual candidate genes, as well as metabolic and proteomic studies. The identification and elimination of the causes of such discrepancies can be one of the promising areas for improving transcriptomical research.
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Wu, Yueh-Lin, Heng Lin, Hsiao-Fen Li, Ming-Jaw Don, Pei-Chih King, and Hsi-Hsien Chen. "Salvia miltiorrhiza Extract and Individual Synthesized Component Derivatives Induce Activating-Transcription-Factor-3-Mediated Anti-Obesity Effects and Attenuate Obesity-Induced Metabolic Disorder by Suppressing C/EBPα in High-Fat-Induced Obese Mice." Cells 11, no. 6 (March 17, 2022): 1022. http://dx.doi.org/10.3390/cells11061022.
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Pharmacological studies indicate that Salvia miltiorrhiza extract (SME) can improve cardiac and blood vessel function. However, there is limited knowledge regarding the effects (exerted through epigenetic regulation) of SME and newly derived single compounds, with the exception of tanshinone IIA and IB, on obesity-induced metabolic disorders. In this study, we administered SME or dimethyl sulfoxide (DMSO) as controls to male C57BL/J6 mice after they were fed a high-fat diet (HFD) for 4 weeks. SME treatment significantly reduced body weight, fasting plasma glucose, triglyceride levels, insulin resistance, and adipogenesis/lipogenesis gene expression in treated mice compared with controls. Transcriptome array analysis revealed that the expression of numerous transcriptional factors, including activating transcription factor 3 (ATF3) and C/EBPα homologous protein (CHOP), was significantly higher in the SME group. ST32db, a novel synthetic derivative similar in structure to compounds from S. miltiorrhiza extract, ameliorates obesity and obesity-induced metabolic syndrome in HFD-fed wild-type mice but not ATF3−/− mice. ST32db treatment of 3T3-L1 adipocytes suppresses lipogenesis/adipogenesis through the ATF3 pathway to directly inhibit C/EBPα expression and indirectly inhibit the CHOP pathway. Overall, ST32db, a single compound modified from S. miltiorrhiza extract, has anti-obesity effects through ATF3-mediated C/EBPα downregulation and the CHOP pathway. Thus, SME and ST32db may reduce obesity and diabetes in mice, indicating the potential of both SME and ST32db as therapeutic drugs for the treatment of obesity-induced metabolic syndrome.
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Zietz, B., W. Drobnik, H. Herfarth, C. Buechler, J. Scholmerich, and A. Schaffler. "Plasminogen activator inhibitor-1 promoter activity in adipocytes is not influenced by the 4 G/5 G promoter polymorphism and is regulated by a USF-1/2 binding site immediately preceding the polymorphic region." Journal of Molecular Endocrinology 32, no. 1 (February 1, 2004): 155–63. http://dx.doi.org/10.1677/jme.0.0320155.
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Plasminogen activator inhibitor-1 (PAI-1) levels were found to be associated with obesity indicating that adipocytes influence PAI-1 plasma levels. In addition, the 4 G/5 G promoter polymorphism of the PAI-1 gene may modulate PAI-1 transcription. We investigated the transcriptional regulation of the human PAI-1 gene in adipocytes and analyzed the genetic contribution of the 4 G/5 G polymorphism. The PAI-1 promoter was analyzed using electrophoretic mobility shift assays (EMSAs) and luciferase reporter gene assays. A putative binding site for the upstream stimulatory factor-1/2 (USF-1/2) at the polymorphic region of the PAI-1 promoter was identified. The binding of USF-1/2 was studied using nuclear extracts prepared from adipocytes and was similar in all the promoter variants as analyzed by EMSA. A 257 bp PAI-1 promoter fragment including the 4 G/5 G site was transcriptionally active in adipocytes and was not influenced by the polymorphism. The present data indicate for the first time that USF-1/2 is transcriptionally active in differentiated adipocytes. However, USF-1/2 binding activity and PAI-1 transcription are not influenced by the 4 G/5 G-allele. These data possibly explain the observation that PAI-1 secretion from adipose tissue is not influenced by the PAI-1 promoter polymorphism.
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Kokaji, Toshiya, Atsushi Hatano, Yuki Ito, Katsuyuki Yugi, Miki Eto, Keigo Morita, Satoshi Ohno, et al. "Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity." Science Signaling 13, no. 660 (December 1, 2020): eaaz1236. http://dx.doi.org/10.1126/scisignal.aaz1236.
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Impaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in healthy and obese states, we constructed and analyzed transomics glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, and insulin signaling proteins from the livers of healthy and obese mice. We integrated multiomics time course data from wild-type and leptin-deficient obese (ob/ob) mice after orally administered glucose. In wild-type mice, metabolic reactions were rapidly regulated within 10 min of oral glucose administration by glucose-responsive metabolites, which functioned as allosteric regulators and substrates of metabolic enzymes, and by Akt-induced changes in the expression of glucose-responsive genes encoding metabolic enzymes. In ob/ob mice, the majority of rapid regulation by glucose-responsive metabolites was absent. Instead, glucose administration produced slow changes in the expression of carbohydrate, lipid, and amino acid metabolic enzyme–encoding genes to alter metabolic reactions on a time scale of hours. Few regulatory events occurred in both healthy and obese mice. Thus, our transomics network analysis revealed that regulation of glucose-responsive liver metabolism is mediated through different mechanisms in healthy and obese states. Rapid changes in allosteric regulators and substrates and in gene expression dominate the healthy state, whereas slow changes in gene expression dominate the obese state.
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Horie, Tetsuhiro, Kazuya Fukasawa, Takashi Iezaki, Gyujin Park, Yuki Onishi, Kakeru Ozaki, Takashi Kanayama, et al. "Hypoxic Stress Upregulates the Expression of Slc38a1 in Brown Adipocytes via Hypoxia-Inducible Factor-1α." Pharmacology 101, no. 1-2 (October 25, 2017): 64–71. http://dx.doi.org/10.1159/000480405.
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The availability of amino acid in the brown adipose tissue (BAT) has been shown to be altered under various conditions; however, little is known about the possible expression and pivotal role of amino acid transporters in BAT under physiological and pathological conditions. The present study comprehensively investigated whether amino acid transporters are regulated by obesogenic conditions in BAT in vivo. Moreover, we investigated the mechanism underlying the regulation of the expression of amino acid transporters by various stressors in brown adipocytes in vitro. The expression of solute carrier family 38 member 1 (Slc38a1; gene encoding sodium-coupled neutral amino acid transporter 1) was preferentially upregulated in the BAT of both genetic and acquired obesity mice in vivo. Moreover, the expression of Slc38a1 was induced by hypoxic stress through hypoxia-inducible factor-1α, which is a master transcription factor of the adaptive response to hypoxic stress, in brown adipocytes in vitro. These results indicate that Slc38a1 is an obesity-associated gene in BAT and a hypoxia-responsive gene in brown adipocytes.
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De Giorgio, Maria Rita, Mayumi Yoshioka, and Jonny St-Amand. "Feeding Regulates the Expression of Pancreatic Genes in Gastric Mucosa." Journal of Obesity 2010 (2010): 1–10. http://dx.doi.org/10.1155/2010/371950.
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The ineffective short-term control of feeding behavior compromises energy homeostasis and can lead to obesity. The gastrointestinal tract secretes several regulatory peptides. However, little is known about the stomach peptide contribution to the acute regulation of intake. In an attempt to identify new gastric signals, the serial analysis of gene expression (SAGE) method was used for the transcription profiling of stomach mucosa in 7 groups of mice: fasting and sacrificed 30 minutes, 1 hour, 3 hours after a low-fat (LF) or high-fat (HF)ad libitummeal. In total, 35 genes were differentially modulated by LF and HF meals compared to fasting, including 15 mRNAs coding for digestive enzymes/secretory proteins, and 10 novel transcripts. Although the basic expression profile did not undergo substantial variations, both LF and HF meals influenced the transcription. This study represents the first global analysis of stomach transcriptome as induced by different nutritional stimuli. Further studies including the characterization of novel genes may help to identify new targets for the therapy and prevention of obesity.
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Kuang, Zheng, Yuhao Wang, Yun Li, Cunqi Ye, Kelly A. Ruhn, Cassie L. Behrendt, Eric N. Olson, and Lora V. Hooper. "The intestinal microbiota programs diurnal rhythms in host metabolism through histone deacetylase 3." Science 365, no. 6460 (September 26, 2019): 1428–34. http://dx.doi.org/10.1126/science.aaw3134.
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Circadian rhythmicity is a defining feature of mammalian metabolism that synchronizes metabolic processes to day-night light cycles. Here, we show that the intestinal microbiota programs diurnal metabolic rhythms in the mouse small intestine through histone deacetylase 3 (HDAC3). The microbiota induced expression of intestinal epithelial HDAC3, which was recruited rhythmically to chromatin, and produced synchronized diurnal oscillations in histone acetylation, metabolic gene expression, and nutrient uptake. HDAC3 also functioned noncanonically to coactivate estrogen-related receptor α, inducing microbiota-dependent rhythmic transcription of the lipid transporter gene Cd36 and promoting lipid absorption and diet-induced obesity. Our findings reveal that HDAC3 integrates microbial and circadian cues for regulation of diurnal metabolic rhythms and pinpoint a key mechanism by which the microbiota controls host metabolism.
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Carrer, Michele, Ning Liu, Chad E. Grueter, Andrew H. Williams, Madlyn I. Frisard, Matthew W. Hulver, Rhonda Bassel-Duby, and Eric N. Olson. "Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*." Proceedings of the National Academy of Sciences 109, no. 38 (September 4, 2012): 15330–35. http://dx.doi.org/10.1073/pnas.1207605109.
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Obesity and metabolic syndrome are associated with mitochondrial dysfunction and deranged regulation of metabolic genes. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional coactivator that regulates metabolism and mitochondrial biogenesis through stimulation of nuclear hormone receptors and other transcription factors. We report that the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 and miR-378*, which counterbalance the metabolic actions of PGC-1β. Mice genetically lacking miR-378 and miR-378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Among the many targets of these miRNAs, carnitine O-acetyltransferase, a mitochondrial enzyme involved in fatty acid metabolism, and MED13, a component of the Mediator complex that controls nuclear hormone receptor activity, are repressed by miR-378 and miR-378*, respectively, and are elevated in the livers of miR-378/378* KO mice. Consistent with these targets as contributors to the metabolic actions of miR-378 and miR-378*, previous studies have implicated carnitine O-acetyltransferase and MED13 in metabolic syndrome and obesity. Our findings identify miR-378 and miR-378* as integral components of a regulatory circuit that functions under conditions of metabolic stress to control systemic energy homeostasis and the overall oxidative capacity of insulin target tissues. Thus, these miRNAs provide potential targets for pharmacologic intervention in obesity and metabolic syndrome.
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Saéz-López, Cristina, Marta Rivera-Giménez, Cristina Hernández, Rafael Simó, and David M. Selva. "SHBG-C57BL/ksJ-db/db: A New Mouse Model to Study SHBG Expression and Regulation During Obesity Development." Endocrinology 156, no. 12 (October 6, 2015): 4571–81. http://dx.doi.org/10.1210/en.2015-1677.
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Low plasma sex hormone-binding globulin (SHBG) levels in overweight individuals are a biomarker for the metabolic syndrome and are predictive of type 2 diabetes and cardiovascular disease risk. There are no in vivo models to study SHBG expression and regulation during obesity development. The main reason for this is that the obesity-prone rodent models cannot be used to study this issue, because rodents, unlike humans, do not express the SHBG gene in their livers. We have developed a unique mouse model that expresses the human SHBG, and it develops obesity, by crossing the human SHBG transgenic mice with the C57BL/ksJ-db/db mice. The results obtained with the SHBG-C57BL/ksJ-db/db mouse model have allowed us to determine that the SHBG overexpression in the C57BL/ksJ-db/db reduced the body weight gain but did not change the metabolic profile of these mice. Moreover, we elucidated the molecular mechanisms and transcription factors causing the SHBG down-regulation during obesity development, which involved changes in liver hepatocyte nuclear factor 4α and peroxisome proliferator-activated receptor-γ mRNA and protein levels. Furthermore, these results were confirmed using human liver biopsies. Importantly, we also showed that this model resembles what occurs in human obese subjects, because plasma SHBG and total testosterone levels where reduced in obese mice when compared with lean mice. Future research using this unique mouse model will determine the role of SHBG in the development and progression of obesity, type 2 diabetes, or fatty liver disease.
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Steinberg, Gregory R., S. Lance Macaulay, Mark A. Febbraio, and Bruce E. Kemp. "AMP-activated protein kinase — the fat controller of the energy railroadThis paper is one of a selection of papers published in this Special issue, entitled Second Messengers and Phosphoproteins—12th International Conference." Canadian Journal of Physiology and Pharmacology 84, no. 7 (July 2006): 655–65. http://dx.doi.org/10.1139/y06-005.
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AMP-activated protein kinase plays an important role in the regulation of lipid metabolism in response to metabolic stress and energy demand. It is also under endocrine control. AMPK acts at multiple steps and has a central role controlling fatty acid, triglyceride, and cholesterol synthesis, as well as the oxidation of fatty acids through direct phosphorylation effects and the control of gene transcription. As such, it can be considered to be the fat controller of the energy railroad. It is thought that AMPK may be a major mediator of the health benefits of exercise in mitigating the development of obesity and age-onset diseases.