Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes

Sauma, Lilian; Franck, Niclas; Paulsson, Johan; Westermark, Gunilla T.; Kjølhede, Preben; Strålfors, Peter; Söderström, Mats; Nyström, Fredrik

doi:10.1007/s00125-006-0515-x

Cited by 21 publications

(18 citation statements)

References 27 publications

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“…PPARg mRNA levels were reported in paired samples of human VAT and SAT, but the data are rather inconsistent. In contrast, and in line with our observations, comparative data at the protein level consistently showed reduced levels and activity of PPARg in human VAT (46)(47)(48), further supporting the notion of posttranslational regulation of PPARg by FABP4. Our finding of higher FABP4 levels in VAT relative to their levels in SAT in obese diabetic individuals may explain why obesity-associated pathology correlates better with visceral fat mass than with overall adiposity (4-8).…”

Section: Discussionsupporting

confidence: 90%

FABP4 Attenuates PPARγ and Adipogenesis and Is Inversely Correlated With PPARγ in Adipose Tissues

et al. 2014

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Fatty acid binding protein 4 (FABP4, also known as aP2) is a cytoplasmic fatty acid chaperone expressed primarily in adipocytes and myeloid cells and implicated in the development of insulin resistance and atherosclerosis. Here we demonstrate that FABP4 triggers the ubiquitination and subsequent proteasomal degradation of peroxisome proliferator-activated receptor g (PPARg), a master regulator of adipogenesis and insulin responsiveness. Importantly, FABP4-null mouse preadipocytes as well as macrophages exhibited increased expression of PPARg, and complementation of FABP4 in the macrophages reversed the increase in FABP4 expression. The FABP4-null preadipocytes exhibited a remarkably enhanced adipogenesis compared with wild-type cells, indicating that FABP4 regulates adipogenesis by downregulating PPARg. We found that the FABP4 level was higher and PPARg level was lower in human visceral fat and mouse epididymal fat compared with their subcutaneous fat. Furthermore, FABP4 was higher in the adipose tissues of obese diabetic individuals compared with healthy ones. Suppression of PPARg by FABP4 in visceral fat may explain the reported role of FABP4 in the development of obesity-related morbidities, including insulin resistance, diabetes, and atherosclerosis. Adiposity is closely correlated with important physiological parameters such as blood pressure, systemic insulin sensitivity, dyslipidemia, and serum triglyceride levels (1,2), rendering obesity to an independent risk factor for myocardial infarction, stroke, type 2 diabetes, and certain cancers (3). Among adipose tissues, visceral fat is more closely correlated with obesity-associated pathologies than overall adiposity (4-8).The nuclear receptor peroxisome proliferatoractivated receptor g (PPARg) is a master regulator of adipose cell differentiation, playing a critical role in systemic lipid and glucose metabolism (9). PPARg is activated by natural or synthetic agonists such as the antidiabetic thiazolidinedione (TZD) (10). Activated PPARg is a master regulator of adipogenesis, acting as a transcription factor of genes expressed in mature adipocytes, including fatty acid binding protein (FABP4), CD36, lipoprotein lipase (LPL), and adiponectin, all of which contain peroxisome proliferator response elements (PPREs) (11). PPARg is also expressed in myeloid cells, and its activation promotes an anti-inflammatory phenotype (11). Disruption of PPARg specifically in myeloid cells also predisposes METABOLISMmice to the development of diet-induced obesity, insulin resistance, and glucose intolerance (12), whereas activation of PPARg within macrophages promotes lipid efflux, thereby stabilizing atherosclerotic lesions (13). A major target gene of PPARg is the lipid transporter FABP4, also known as aP2 (14). PPARg induces FABP4 almost exclusively in adipocytes and macrophages. FABP4 acts as a fatty acids chaperone, which couples intracellular lipids to biological targets and signaling pathways (15,16). FABP4 has been implicated in several aspects of the metabolic syndro...

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Section: Discussionsupporting

confidence: 90%

FABP4 Attenuates PPARγ and Adipogenesis and Is Inversely Correlated With PPARγ in Adipose Tissues

et al. 2014

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“…These latter effects may diminish the main anti-adipogenic effects of vitamin A in fat depots demonstrating ‘high' PPARγ expression, such as SF compared with VF [37]. Thus, consistent with our findings, the anti-adipogenic effects of vitamin A may be seen mainly in VF (a fat depot with ‘lower PPARγ expression') and less so in SF (a fat depot with ‘higher PPARγ expression') [37]. …”

Section: Discussionsupporting

confidence: 79%

“…This research also shows that vitamin A or its metabolites may exert some proadipogenic effects by promoting intracellular lipid accumulation but only in mature adipocytes expressing PPARγ [20,23]. These latter effects may diminish the main anti-adipogenic effects of vitamin A in fat depots demonstrating ‘high' PPARγ expression, such as SF compared with VF [37]. Thus, consistent with our findings, the anti-adipogenic effects of vitamin A may be seen mainly in VF (a fat depot with ‘lower PPARγ expression') and less so in SF (a fat depot with ‘higher PPARγ expression') [37].…”

Section: Discussionmentioning

confidence: 99%

Dietary Vitamin A and Visceral Adiposity: A Modulating Role of the Retinol-Binding Protein 4 Gene

Goodwin

Abrahamowicz²,

Leonard

et al. 2015

Lifestyle Genomics

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Background/Aims: Visceral fat (VF) compared with subcutaneous fat (SF) is more closely associated with cardiometabolic disease. Dietary vitamin A (retinol) may reduce adiposity through its effects on adipogenesis differentially in VF and SF, and this effect may be modulated by retinol-binding protein-4 (RBP4). We investigated whether intake of vitamin A is associated with either VF or SF, and whether this association is moderated by the RBP4 genotype (rs10882272, C/T) previously associated with circulating retinol levels. Methods: This was a cross-sectional association study in a sample of 947 adolescents from a French-Canadian founder population. VF and SF were quantified with magnetic resonance imaging, and vitamin A intake was assessed with a 24-hour food recall. All participants were genotyped to determine their RBP4 variant. Results: Dietary intake of vitamin A was negatively associated with VF; however, it was not associated with SF. These relationships were independent of age, sex, height and energy intake, and were modulated by the RBP4 variant. The T allele promoted adiposity-reducing effects of vitamin A in VF and adiposity-enhancing effects in SF, while the C allele had adiposity-reducing effects in both VF and SF. Conclusions: Dietary vitamin A may reduce abdominal adiposity and promote visceral to subcutaneous body fat redistribution during adolescence in an RBP4-dependent manner. These observational findings provide the basis for future interventional studies, which together with genetic information may inject further causality in the association between dietary vitamin A intake and abdominal adiposity.

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“…In the course of development, both human and rodent adipocytes express more PPARγ in subcutaneous than in visceral fat depots [34] and maintain this expression pattern even in cultured adipocytes isolated from these fat depots for several generations, which may highlight their origin from different lineages [28, 30]. Correspondently, PPARγ activity is increased in subcutaneous compared to visceral fat tissues [35], which may account for the high expression of PPARγ target genes that define properties of subcutaneous fat. PPARγ-mediated activation of adiponectin has already been recognized as a major mechanism for insulin sensitivity associated with subcutaneous fat [36, 37].…”

Section: ) Transcriptional Network Defining Fat Depotsmentioning

confidence: 99%

The contribution of vitamin A to autocrine regulation of fat depots

Yasmeen

Jeyakumar

Reichert

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Morbidity and mortality associated with increased white fat accumulation in visceral fat depots has focused attention on the pathways regulating the development of this tissue during embryogenesis, in adulthood, and while under the influence of obesogenic diets. Adipocytes undergo clonal expansion, differentiation (adipogenesis) and maturation through a complex network of transcriptional factors, most of which are expressed at similar levels in visceral and subcutaneous fat. Rigorous research attempts to unfold the pathways regulating expression and activity of adipogenic transcription factors that act in a fat-depot-specific manner. Peroxisome proliferator-activated receptor-γ (PPARγ) is the master regulator of adipogenesis, and is expressed at higher levels in subcutaneous than in visceral depots. PPARγ expression in adipogenesis is mediated by CCAAT/enhancer binding proteins (C/EBPs) and several transcription factors acting in conjunction with C/EBPs, although alternative pathways through zinc-finger protein-423 (ZFP423) transcription factor are sufficient to induce PPARγ expression and adipogenesis. Vitamin A and its metabolites, retinaldehyde and retinoic acid, are transcriptionally-active molecules that are generated in adipose tissue by the aldehyde dehydrogenase-1 family of enzymes (Aldh1). In this review, we discuss the role of Aldh1 enzymes in the generation of retinoic acid during adipogenesis, in the regulation of the transcriptional network and PPARγ in a fat-depot-specific manner, and suggest the important contribution of this autocrine pathway in the development of visceral obesity.

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Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes

Cited by 21 publications

References 27 publications

FABP4 Attenuates PPARγ and Adipogenesis and Is Inversely Correlated With PPARγ in Adipose Tissues

FABP4 Attenuates PPARγ and Adipogenesis and Is Inversely Correlated With PPARγ in Adipose Tissues

Dietary Vitamin A and Visceral Adiposity: A Modulating Role of the Retinol-Binding Protein 4 Gene

The contribution of vitamin A to autocrine regulation of fat depots

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