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

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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Altered insulin sensitivity in primary adipocytes of Foxa-2+/– and wild-...
Altered insulin sensitivity in primary adipocytes of Foxa-2+/– and wild-type littermates. Primary adipocytes were isolated from Foxa-2+/– and wild-type littermate animals that had received a high-fat diet for 42 days. Parameters of glucose metabolism, lipogenesis and lipolysis were measured. (a–e) Glucose metabolism into different pathways at 10 and 100 nM insulin in isolated adipocytes from Foxa-2+/– (gray) and wild-type (black) littermates. [U-14C]Glucose uptake in isolated adipocytes from epidydimal fat (a), [U-14C]glucose incorporation (incorp) into CO2 (b), lactate (c), lipid glycerol (d), and lipid fatty acids (e), measured after 2 hours of incubation in the absence (control) or presence of insulin. (f) Glycerol release from adipocytes in the presence or absence of insulin (ins) after stimulation of lipolysis with isoperenterol (Isop). (g) Measurements of relative gene expression levels of metabolic genes in adipocytes of Foxa-2+/– and wild-type littermates (100%) using semiquantitative RT-PCR. All mice were female, 15 weeks of age, n = 7, means ± SD. *P = 0.05; **P = 0.01; ***P = 0.001; #P = 10–5.