The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG
Kathrin LandgrafNora KlötingMartin GerickeNitzan MaixnerEsther Guiu‐JuradoMarkus ScholzA. Veronica WitteFrauke BeyerJulian Tristan SchwartzeMartin LacherArno VillringerPéter KovácsAssaf RudichMatthias BlüherWieland KießAntje Körner
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Abstract:
TMEM18 is the strongest candidate for childhood obesity identified from GWASs, yet as for most GWAS-derived obesity-susceptibility genes, the functional mechanism remains elusive. We here investigate the relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is downregulated in children with obesity. Functionally, downregulation of TMEM18 impairs adipocyte formation in zebrafish and in human preadipocytes, indicating that TMEM18 is important for adipocyte differentiation in vivo and in vitro. On the molecular level, TMEM18 activates PPARG, particularly upregulating PPARG1 promoter activity, and this activation is repressed by inflammatory stimuli. The relationship between TMEM18 and PPARG1 is also evident in adipocytes of children and is clinically associated with obesity and adipocyte hypertrophy, inflammation, and insulin resistance. Our findings indicate a role of TMEM18 as an upstream regulator of PPARG signaling driving healthy adipogenesis, which is dysregulated with adipose tissue dysfunction and obesity.3T3-L1
Peroxisome proliferator
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糖尿病和许多另外的新陈代谢症候群是仔细与肥胖有关。揭示胖免职的内在的机制，越来越多的研究在 adipocytes 开发期间正在集中于 miRNAs 的功能。以前的研究 haveproved 那出 miR-15a/b 戏在多重生理的过程的重要角色；然而，他们的功能在 adipogenesisremain 期间不清楚。揭示这，我们在猪的 pre-adipocyte 在 adipogenesis 期间检测了 miR-15a/b 的表示侧面，并且发现那他们层次在 adipocyte 区别的早阶段增加了并且在白天 4 .Moreover 以后落下的表示，在猪的 pre-adipocytes 的 miR-15a/b 的在表示上支持了 adipocyte 区别， miR-15a/b 的类脂化合物 accumulation.Target 基因被预言并且检验，它表明 Forkhead 盒子蛋白质 O1 ( FoxO1 )是目标 geneof miR-15a/b 。表示水平由 miR-15a/b 在表示上引起了的 FoxO1 的抑制在 adipogenesis.Thus 上有积极效果，我们断定 miR-15a/b 经由镇压在猪的 pre-adipocyte 支持 adipogenesis FoxO1。
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Abstract MicroRNAs (miRNA) modulate gene expression through feed-back and forward loops. Previous studies identified miRNAs that regulate transcription factors, including Peroxisome Proliferator Activated Receptor Gamma (PPARG), in adipocytes, but whether they influence adipogenesis via such regulatory loops remain elusive. Here we predicted and validated a novel feed-forward loop regulating adipogenesis and involved miR-27a/b-3p, PPARG and Secretory Carrier Membrane Protein 3 (SCAMP3). In this loop, expression of both PPARG and SCAMP3 was independently suppressed by miR-27a/b-3p overexpression. Knockdown of PPARG downregulated SCAMP3 expression at the late phase of adipogenesis, whereas reduction of SCAMP3 mRNA levels increased PPARG expression at early phase in differentiation. The latter was accompanied with upregulation of adipocyte-enriched genes, including ADIPOQ and FABP4, suggesting an anti-adipogenic role for SCAMP3. PPARG and SCAMP3 exhibited opposite behaviors regarding correlations with clinical phenotypes, including body mass index, body fat mass, adipocyte size, lipolytic and lipogenic capacity, and secretion of pro-inflammatory cytokines. While adipose PPARG expression was associated with more favorable metabolic phenotypes, SCAMP3 expression was linked to increased fat mass and insulin resistance. Together, we identified a feed-forward loop through which miR-27a/b-3p, PPARG and SCAMP3 cooperatively fine tune the regulation of adipogenesis, which potentially may impact whole body metabolism.
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Abstract The number of adipocytes is relevant to the extent of differentiation from pluripotent stem cells into pre‐adipocytes, whereas the size of adipocytes relates to the extent of differentiation from pre‐adipocytes into mature fat cells and the accumulation of triglyceride. Investigation of the molecular regulatory mechanism of adipocyte differentiation is not only essential for understanding the physiological processes of adipogenesis, but it is also important for identifying new biomarkers and therapeutic targets for some metabolic diseases, such as obesity and diabetes. microRNAs (miRNAs) appear to play important roles in adipocyte differentiation. During adipogenesis, miRNAs can accelerate or inhibit adipocyte differentiation by acting on transcription factors, regulating signalling pathways related to adipogenesis, or blocking the mitotic clonal expansion stage, thus regulating adipocyte development. The regulatory role of some miRNAs varies in different species or different cells. In this review, the biological characteristics of miRNA and the adipocyte differentiation process are concisely discussed. Recent advances in our understanding of the role of miRNAs in adipocytes development or adipogenesis are discussed.
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The effect of adipose tissue on inductive adipogenesis within Matrigel (BD Biosciences) was assessed by using a murine chamber model containing a vascular pedicle. Three-chamber configurations that varied in the access to an adipose tissue source were used, including sealed- and open-chamber groups that had no access and limited access, respectively, to the surrounding adipose tissue, and a sealed-chamber group in which adipose tissue was placed as an autograft. All groups showed neovascularization, but varied in the amount of adipogenesis seen in direct relation to their access to preexisting adipose tissue: open chambers showed strong adipogenesis, whereas the sealed chambers had little or no adipose tissue; adipogenesis was restored in the autograft chamber group that contained 2- to 5-mg fat autografts. These showed significantly more adipogenesis than the sealed chambers with no autograft ( p < 0.01). Autografts with 1mg of fat were capable of producing adipogenesis but did so less consistently than the larger autografts. These findings have important implications for adipose tissue engineering strategies and for understanding de novo production of adipose tissue.
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The Peroxisome Proliferator-Activated Receptors (PPARs) PPARA and PPARD are regulators of lipid metabolism with important roles in energy release through lipid breakdown, while PPARG plays a key role in lipid storage and adipogenesis. The aim of this review is to describe the role of PPARs in lipid metabolism, adipogenesis, and obesity and evaluate the zebrafish as an emerging vertebrate model to study the function of PPARs. Zebrafish are an appropriate model to study human diseases, including obesity and related metabolic diseases, as pathways important for adipogenesis and lipid metabolism which are conserved between mammals and fish. This review synthesizes knowledge on the role of PPARs in zebrafish and focuses on the putative function of PPARs in zebrafish adipogenesis. Using in silico analysis, we confirm the presence of five PPARs ( pparaa , pparab , pparda , ppardb , and pparg ) in the zebrafish genome with 67–74% identity to human and mouse PPARs. During development, pparda/b paralogs and pparg show mRNA expression around the swim bladder and pancreas, the region where adipocytes first develop, whereas pparg is detectable in adipocytes at 15 days post fertilization (dpf). This review indicates that the zebrafish is a promising model to investigate the specific functions of PPARs in adipogenesis and obesity.
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