Role of Foxa-2 in adipocyte metabolism and differentiation
Christian Wolfrum, David Q. Shih, Satoru Kuwajima, Andrew W. Norris, C. Ronald Kahn, Markus Stoffel
Christian Wolfrum, David Q. Shih, Satoru Kuwajima, Andrew W. Norris, C. Ronald Kahn, Markus Stoffel
View: Text | PDF
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

×

Figure 5

Options: View larger image (or click on image) Download as PowerPoint
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.