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Deficiency of angiotensin type 1a receptors in adipocytes reduces differentiation and promotes hypertrophy of adipocytes in lean mice.

ABSTRACT: Adipocytes express angiotensin receptors, but the direct effects of angiotensin II (AngII) stimulating this cell type are undefined. Adipocytes express angiotensin type 1a receptor (AT1aR) and AT2R, both of which have been implicated in obesity. In this study, we determined the effects of adipocyte AT1aR deficiency on adipocyte differentiation and the development of obesity in mice fed low-fat (LF) or high-fat (HF) diets. Mice expressing Cre recombinase under the control of the aP2 promoter were bred with AT1aR-floxed mice to generate mice with adipocyte AT1aR deficiency (AT1aR(aP2)). AT1aR mRNA abundance was reduced significantly in both white and brown adipose tissue from AT1aR(aP2) mice compared with nontransgenic littermates (AT1aR(fl/fl)). Adipocyte AT1aR deficiency did not influence body weight, glucose tolerance, or blood pressure in mice fed either LF or high-fat diets. However, LF-fed AT1aR(aP2) mice exhibited striking adipocyte hypertrophy even though total fat mass was not different between genotypes. Stromal vascular cells from AT1aR(aP2) mice differentiated to a lesser extent to adipocytes compared with controls. Conversely, incubation of 3T3-L1 adipocytes with AngII increased Oil Red O staining and increased mRNA abundance of peroxisome proliferator-activated receptor ? (PPAR?) via AT1R stimulation. These results suggest that reductions in adipocyte differentiation in LF-fed AT1aR(aP2) mice resulted in increased lipid storage and hypertrophy of remaining adipocytes. These results demonstrate that AngII regulates adipocyte differentiation and morphology through the adipocyte AT1aR in lean mice.

SUBMITTER: Putnam K

PROVIDER: S-EPMC3512029 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Deficiency of angiotensin type 1a receptors in adipocytes reduces differentiation and promotes hypertrophy of adipocytes in lean mice.

Putnam Kelly K Batifoulier-Yiannikouris Frederique F Bharadwaj Kalyani G KG Lewis Eboni E Karounos Michael M Daugherty Alan A Cassis Lisa A LA

Endocrinology 20120823 10

Adipocytes express angiotensin receptors, but the direct effects of angiotensin II (AngII) stimulating this cell type are undefined. Adipocytes express angiotensin type 1a receptor (AT1aR) and AT2R, both of which have been implicated in obesity. In this study, we determined the effects of adipocyte AT1aR deficiency on adipocyte differentiation and the development of obesity in mice fed low-fat (LF) or high-fat (HF) diets. Mice expressing Cre recombinase under the control of the aP2 promoter were ...[more]

PMID: 22919058

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Project description:ObjectiveActivation of the Wnt-signaling pathway is known to inhibit differentiation in adipocytes. However, there is a gap in our understanding of the transcriptional network regulated by components of the Wnt-signaling pathway during adipogenesis and in adipocytes during postnatal life. The key intracellular effectors of the Wnt-signaling pathway occur through TCF transcription factors such as TCF7L2 (transcription factor-7-like 2). Several genetic variants in proximity to TCF7L2 have been linked to type 2 diabetes through genome-wide association studies in various human populations. Our work aims to functionally characterize the adipocyte specific gene program regulated by TCF7L2 and understand how this program regulates metabolism.MethodsWe generated Tcf7l2F/F mice and assessed TCF7L2 function in isolated adipocytes and adipose specific knockout mice. ChIP-sequencing and RNA-sequencing was performed on the isolated adipocytes with control and TCF7L2 knockout cells. Adipose specific TCF7L2 knockout mice were challenged with high fat diet and assessed for body weight, glucose tolerance, and lipolysis.ResultsHere we report that TCF7L2 regulates adipocyte size, endocrine function, and glucose metabolism. Tcf7l2 is highly expressed in white adipose tissue, and its expression is suppressed in genetic and diet-induced models of obesity. Genome-wide distribution of TCF7L2 binding and gene expression analysis in adipocytes suggests that TCF7L2 directly regulates genes implicated in cellular metabolism and cell cycle control. When challenged with a high-fat diet, conditional deletion of TCF7L2 in adipocytes led to impaired glucose tolerance, impaired insulin sensitivity, promoted weight gain, and increased adipose tissue mass. This was accompanied by reduced expression of triglyceride hydrolase, reduced fasting-induced free fatty acid release, and adipocyte hypertrophy in subcutaneous adipose tissue.ConclusionsTogether our studies support that TCF7L2 is a central transcriptional regulator of the adipocyte metabolic program by directly regulating the expression of genes involved in lipid and glucose metabolism.

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Deficiency of angiotensin type 1a receptors in adipocytes reduces differentiation and promotes hypertrophy of adipocytes in lean mice.

Publications

Deficiency of angiotensin type 1a receptors in adipocytes reduces differentiation and promotes hypertrophy of adipocytes in lean mice.

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