Sex Hormone Binding Globulin Controls Sex-Specific Lipolytic Activity in Human Abdominal Subcutaneous Adipocytes
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PROVIDER: PRJNA1217021 | ENA |
REPOSITORIES: ENA
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Project description:Regulation of lipid metabolism is fundamental for metabolic health, and adipose tissue is a central component in this process. Adipose tissue differs considerably between women and men in terms of a higher subcutaneous capacity for storage, which is linked to metabolic health, in women. Sex hormone-binding globulin (SHBG) contributes to the regulation of circulating sex hormone bioavailability and has been shown to predict risk of metabolic dysfunction. Here, we investigate the sex-specific relationship of SHBG with metabolic status and adipocyte-dependent lipolysis. We measured serum concentrations of sex hormones, SHBG, fasting glucose, and insulin in a cohort of 63 women and 27 men from which adipose biopsies were collected and mature adipocytes isolated. In women, high serum SHBG concentrations were strongly associated with low in vivo Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and lower unstimulated ex vivo lipolysis but higher isopropanol stimulated ex vivo lipolysis. In contrast, no effect of SHBG on the above-mentioned parameters were observed in men. In vitro cultured human adipocytes also increased lipolytic activity in response to SHBG, but only in the absence of testosterone, suggesting that testosterone inhibits the catecholamine-induced lipolysis of SHBG in adipose tissue. In conclusion, we identify SHBG as a novel sex-specific regulator of adipocyte lipolysis and lipid metabolism. At the same time, our data emphasize sex-dependent effects of SHBG on adipocyte lipid metabolism, and we propose testosterone binding to SHBG as a driving factor mediating these sex differences.
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2007-08-25 | E-GEOD-2508 | biostudies-arrayexpress
Project description:Adipose tissue (AT) distribution is an important determinant of cardiometabolic health. Increased visceral adiposity has been associated with a higher risk of obesity-related diseases. An important step in deciphering the molecular complexity of subcutaneous AT (SAT) and visceral AT (VAT) is to elucidate the molecular composition of the principal AT cell type, adipocytes. We present a comprehensive protein expression profile of abdominal subcutaneous (SA) and omental visceral adipocytes (VA). We isolated adipocytes from paired AT biopsies obtained during bariatric surgery of 19 morbidly obese women (BMI > 30 kg/m2) and performed state-of-the-art mass spectrometry to investigate their proteome profiles. We identified 3,686 proteins groups and found 1,140 differentially expressed proteins (adj. p-value < 0.05), of which 576 proteins were upregulated in SA and 564 in VA samples. In addition to providing a global protein profile of abdominal SA and omental VA, we also present the most differentially expressed pathways and processes distinguishing SA from VA. We show that SA are significantly more active in processes linked to vesicular transport and secretion, and also to increased lipid metabolism activity. Conversely, the expression of proteins involved in the mitochondrial energy metabolism and translational or biosynthetic activity is higher in VA. We also performed prediction analyses of differentially expressed putative secreted proteins, which revealed a significantly higher number of potentially secreted proteins in SA compared to VA. Our analysis represents a valuable resource of protein expression profiles in abdominal SA and omental VA, highlighting key differences in their role in obesity. Additionally, we predict possible protein targets among secreted proteins, which may be utilized for the further investigation of the role of different AT depots in obesity using peripheral blood.
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Project description:Obesity is characterized by the excess of body fat leading to impaired health. Abdominal fat is particularly harmful and is associated with cardiovascular and metabolic diseases and cancer. In contrast, subcutaneous fat is generally considered less detrimental. The mechanisms that establish the cellular characteristics of these distinct fat types in humans are not fully understood. Here, we explored whether differences of their gene regulatory mechanisms can be investigated in vitro. For this purpose, we in vitro differentiated human visceral and subcutaneous pre-adipocytes into mature adipocytes and obtained their gene expression profiles and genome-wide H3K4me3, H3K9me3 and H3K27ac patterns. Subsequently, we compared those data with public gene expression data from visceral and subcutaneous fat tissues. We found that the in vitro differentiated adipocytes show significant differences in their transcriptional landscapes, which correlate with biological pathways that are characteristic for visceral and subcutaneous fat tissues, respectively. Unexpectedly, visceral adipocyte enhancers are rich on motifs for transcription factors involved in the Hippo-YAP pathway, cell growth and inflammation, which are not typically associated with adipocyte function. In contrast, enhancers of subcutaneous adipocytes show enrichment of motifs for common adipogenic transcription factors, such as C/EBP, NFI and PPARgamma, implicating substantially disparate gene regulatory networks in visceral and subcutaneous adipocytes. Consistent with the role in obesity, predominantly the histone modification pattern of visceral adipocytes is linked to obesity-associated diseases. Thus, this work suggests that the properties of visceral and subcutaneous fat tissues can be studied in vitro and provides preliminary insights into their gene regulatory processes.
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Project description:An Affimetrix GeneChip Human Genome U133 Plus 2.0 Array was used to study the effect of oleoylethnolamide on gene expression. The addition of 0.01 mM oleoylethanolamide (OEA) to human subcutaneous adipocytes significantly affected the expression of 1013 genes, with 556 being up-regulated and 457 being down-regulated. Human subcutaneous adipocytes were incubated with oleoylethanolamide (0.01 mM). After 24 hr, the gene expression in human subcutanous adipocytes was analyzed using Affymetrix microarrays.
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Project description:Under caloric restriction, bone marrow adipocytes (BM-Ad) do not decrease in size conversely to white adipocytes, suggesting their unique metabolic properties. We compared human primary BM-Ad with paired subcutaneous adipocytes (SC-Ad) using proteomic and lipidomic approaches. We found that while SC-Ad and BM-Ad share similar morphological features, they possess distinct lipid metabolism. BM-Ad shows enrichment in proteins involved in cholesterol metabolism correlating with increased free cholesterol content while proteins involved in lipolysis were downregulated. In particular, monoacylglycerol lipase expression was strongly reduced in BM-Ad, leading to accumulation of monoacylglycerol. Consequently, basal and induced lipolytic responses were absent in BM-Ad, affirming their differences in metabolic fitness upon caloric restriction. These specific metabolic features are not recapitulated in vitro using common protocols to differentiate bone marrow mesenchymal stem cells. Thus, contrary to classical SC-Ad, BM-Ad display a specific lipid metabolism, as they are devoid of lipolytic activity and exhibit a cholesterol-orientated metabolism.
2020-01-29 | PXD016322 | Pride