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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Foxa-2 regulates genes involved in glucose uptake, glycolysis, lipolysis...
Foxa-2 regulates genes involved in glucose uptake, glycolysis, lipolysis, and energy dissipation. (a) Undifferentiated and differentiated 3T3-L1 cells containing the indicated expression vector were assayed for Hprt, Foxa-2, Foxc-2, Ir, Irs-2, Hsl, Lpl, Glut-4, M2Pk, Hk-2, Ucp-2, and Ucp-3 mRNA expression by RT-PCR. Fold regulation in undifferentiated, control 3T3-L1 cells (pcDNA3) versus Foxa-2–expressing cells: Ir: 3.3 ± 0.5*; Irs-2: 1.7 ± 0.3*; Lpl: 2.6 ± 0.4**; M2Pk: 3.3 ± 0.2***; Hk-2: 3.2 ± 0.3***; Ucp-2: 2.1 ± 0.7*; Ucp-3: 2.3 ± 0.4*. Expression levels of M2Pk were increased (3.4 ± 0.2**) in differentiated 3T3-L1–expressing Foxa-2 compared with control (pcDNA3). (b) Increased expression of metabolic genes in differentiated 3T3-L1 cells with enforced expression of Foxa-2 by adenoviral (Adeno) transduction. The 3T3-L1 cells were differentiated for 7 days and infected with control (no transgene) and recombinant adenovirus expressing Foxa-2. Cells were harvested after 48 hours, and gene expression was measured by RT-PCR. Experiments were carried out in triplicate. (c) Increased expression of metabolic enzymes in adipose tissue of ob/ob mice. Gene expression in fat tissue in ob/ob animals and wild-type littermates was measured by RT-PCR. Each lane indicates a different animal. Quantitative measurements of gene expression were obtained by densitometry, and ob/ob/WT indicates the ratio of adipocyte mRNA expression levels of the means of WT and ob/ob mice. The levels of significance of the comparison of WT versus ob/ob are shown on the right. *P = 0.05; **P = 0.01; ***P = 0.005.