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Role of Foxa-2 in adipocyte metabolism and differentiation
Christian Wolfrum, … , C. Ronald Kahn, Markus Stoffel
Christian Wolfrum, … , C. Ronald Kahn, Markus Stoffel
Published August 1, 2003
Citation Information: J Clin Invest. 2003;112(3):345-356. https://doi.org/10.1172/JCI18698.
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Article Metabolism

Role of Foxa-2 in adipocyte metabolism and differentiation

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Abstract

Hepatocyte nuclear factors-3 (Foxa-1–3) are winged forkhead transcription factors that regulate gene expression in the liver and pancreatic islets and are required for normal metabolism. Here we show that Foxa-2 is expressed in preadipocytes and induced de novo in adipocytes of genetic and diet-induced rodent models of obesity. In preadipocytes Foxa-2 inhibits adipocyte differentiation by activating transcription of the Pref-1 gene. Foxa-2 and Pref-1 expression can be enhanced in primary preadipocytes by growth hormone, suggesting that the antiadipogenic activity of growth hormone is mediated by Foxa-2. In differentiated adipocytes Foxa-2 expression leads to induction of gene expression involved in glucose and fat metabolism, including glucose transporter-4, hexokinase-2, muscle-pyruvate kinase, hormone-sensitive lipase, and uncoupling proteins-2 and -3. Diet-induced obese mice with haploinsufficiency in Foxa-2 (Foxa-2+/–) develop increased adiposity compared with wild-type littermates as a result of decreased energy expenditure. Furthermore, adipocytes of these Foxa-2+/– mice exhibit defects in glucose uptake and metabolism. These data suggest that Foxa-2 plays an important role as a physiological regulator of adipocyte differentiation and metabolism.

Authors

Christian Wolfrum, David Q. Shih, Satoru Kuwajima, Andrew W. Norris, C. Ronald Kahn, Markus Stoffel

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Figure 1

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Foxa-2 is expressed in adipose tissue of obese mice. (a) Liver cell extr...
Foxa-2 is expressed in adipose tissue of obese mice. (a) Liver cell extracts from wild-type mice and adipocyte extracts from wild-type, ob/ob, db/db, and NZO mice were separated by SDS-PAGE and analyzed by Western blotting for Foxa-2 expression. TATA-binding protein (Tbp) expression was measured as a control for loading. (b) Visceral (v.) and subcutaneous (s.) fat RNA from wild-type and ob/ob mice was analyzed for Foxa-2 expression by Northern blotting. Membrane was rehybridized with a probe for cyclophilin as control. (c) Preadipocyte (Pre) and adipocyte (Ad) protein extracts from ob/ob mice were separated by SDS-PAGE and analyzed by Western blotting for Foxa-2 and aP2 expression. (d–f) Confocal image immunostaining of visceral fat from ob/ob mouse using anti–Foxa-2 Ab’s (d) and TO-PRO-3 (molecular probes) for nuclear staining (e). Images were superimposed (f). Foxa-2 protein is present in cytoplasm and nuclei. (g) Semiquantitative RT-PCR of Foxa-2 and Ucp-1 in white (WAT) and brown (BAT) adipose tissue of three ob/ob and three wild-type littermate mice. Hprt, hypoxanthine phosphoribosyltransferase.
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