Role of Foxa-2 in adipocyte metabolism and differentiation.

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.

[1]  Klaus H. Kaestner,et al.  Targeted Disruption of the Gene Encoding Hepatocyte Nuclear Factor 3γ Results in Reduced Transcription of Hepatocyte-Specific Genes , 1998, Molecular and Cellular Biology.

[2]  M. Stoffel,et al.  Profound defects in pancreatic beta-cell function in mice with combined heterozygous mutations in Pdx-1, Hnf-1alpha, and Hnf-3beta. , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  B. Spiegelman,et al.  Regulation of adipocyte gene expression in differentiation and syndromes of obesity/diabetes. , 1993, The Journal of biological chemistry.

[4]  P. Carlsson,et al.  FOXC2 Is a Winged Helix Gene that Counteracts Obesity, Hypertriglyceridemia, and Diet-Induced Insulin Resistance , 2001, Cell.

[5]  J E Darnell,et al.  Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes , 1989, Molecular and cellular biology.

[6]  J. Nielsen,et al.  Characterization of the inhibitory effect of growth hormone on primary preadipocyte differentiation. , 1998, Molecular endocrinology.

[7]  B. Kahn,et al.  Transgenic GLUT-4 overexpression in fat enhances glucose metabolism: preferential effect on fatty acid synthesis. , 1995, The American journal of physiology.

[8]  C. Smas,et al.  Function of pref-1 as an inhibitor of adipocyte differentiation , 2000, International Journal of Obesity.

[9]  B. Kahn,et al.  Amelioration of insulin resistance in streptozotocin diabetic mice by transgenic overexpression of GLUT4 driven by an adipose-specific promoter. , 1997, Endocrinology.

[10]  Q. Tong,et al.  Function of GATA transcription factors in preadipocyte-adipocyte transition. , 2000, Science.

[11]  M. Stoffel,et al.  Profound defects in pancreatic β-cell function in mice with combined heterozygous mutations in Pdx-1, Hnf-1α, and Hnf-3β , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[12]  J. Olefsky.  The effects of spontaneous obesity on insulin binding, glucose transport, and glucose oxidation of isolated rat adipocytes. , 1976, The Journal of clinical investigation.

[13]  J. Nielsen,et al.  Growth hormone and prolactin stimulate the expression of rat preadipocyte factor-1/delta-like protein in pancreatic islets: molecular cloning and expression pattern during development and growth of the endocrine pancreas. , 1997, Endocrinology.

[14]  K. Kaestner,et al.  Foxa2 Controls Pdx1 Gene Expression in Pancreatic β-Cells In Vivo , 2002 .

[15]  M. Rodbell.  METABOLISM OF ISOLATED FAT CELLS. I. EFFECTS OF HORMONES ON GLUCOSE METABOLISM AND LIPOLYSIS. , 1964, The Journal of biological chemistry.

[16]  S. Burley,et al.  Binding of the winged‐helix transcription factor HNF3 to a linker histone site on the nucleosome , 1998, The EMBO journal.

[17]  J. Northrop,et al.  TNF alpha-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPARgamma without effects on Pref-1 expression. , 1997, Endocrinology.

[18]  J. Rossant,et al.  HNF-3β is essential for node and notochord formation in mouse development , 1994, Cell.

[19]  D. Accili,et al.  The forkhead transcription factor Foxo1 regulates adipocyte differentiation. , 2003, Developmental cell.

[20]  J. Nielsen,et al.  Growth Hormone and Prolactin Stimulate the Expression of Rat Preadipocyte Factor-1/Δ-Like Protein in Pancreatic Islets: Molecular Cloning and Expression Pattern during Development and Growth of the Endocrine Pancreas. , 1997, Endocrinology.

[21]  J. Rossant,et al.  HNF-3 beta is essential for node and notochord formation in mouse development. , 1994, Cell.

[22]  J. Darnell,et al.  Sequential expression of HNF-3β and HNF-3α by embryonic organizing centers: the dorsal lip/node, notochord and floor plate , 1993, Mechanisms of Development.

[23]  J. Rossant,et al.  Regulation of a transcription factor network required for differentiation and metabolism. , 1998, Science.

[24]  Bruce M. Spiegelman,et al.  Obesity and the Regulation of Energy Balance , 2001, Cell.

[25]  H. Sul,et al.  Only the large soluble form of preadipocyte factor-1 (Pref-1), but not the small soluble and membrane forms, inhibits adipocyte differentiation: role of alternative splicing. , 2002, The Biochemical journal.

[26]  M. Stoffel,et al.  Pancreatic beta cell-specific transcription of the pdx-1 gene. The role of conserved upstream control regions and their hepatic nuclear factor 3beta sites. , 2000, The Journal of biological chemistry.

[27]  J. Flier,et al.  Adipose Tissue as an Endocrine Organ , 2014 .

[28]  Thomas M. Jessell,et al.  The winged-helix transcription factor HNF-3β is required for notochord development in the mouse embryo , 1994, Cell.

[29]  B. Lowell,et al.  Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. , 2000, Diabetes.

[30]  B. Spiegelman,et al.  Molecular regulation of adipogenesis. , 2000, Annual review of cell and developmental biology.

[31]  K. Kaestner,et al.  Foxa2 controls Pdx1 gene expression in pancreatic beta-cells in vivo. , 2002, Diabetes.

[32]  J. Darnell,et al.  Sequential expression of HNF-3 beta and HNF-3 alpha by embryonic organizing centers: the dorsal lip/node, notochord and floor plate. , 1993, Mechanisms of development.

[33]  D. Accili,et al.  Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1 , 2002, Nature Genetics.

[34]  Jonathan P. Katz,et al.  Inactivation of the winged helix transcription factor HNF3alpha affects glucose homeostasis and islet glucagon gene expression in vivo. , 1999, Genes & development.

[35]  M. Rodbell.  The metabolism of isolated fat cells , 1965 .

[36]  H. Sul,et al.  Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation , 1993, Cell.

[37]  M. Koptides,et al.  Preparation of transcriptionally active nuclear extracts from mammalian tissues. , 1996, BioTechniques.

[38]  A. Golay,et al.  Pathways from obesity to diabetes , 2002, International Journal of Obesity.

[39]  T. Hayamizu,et al.  Transcription Factor FoxA (HNF3) on a Nucleosome at an Enhancer Complex in Liver Chromatin* , 2001, The Journal of Biological Chemistry.

[40]  K. Kaestner,et al.  The Hepatocyte Nuclear Factor 3 (HNF3 or FOXA) Family in Metabolism , 2000, Trends in Endocrinology & Metabolism.

[41]  Y. Kido,et al.  The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. , 2002, The Journal of clinical investigation.

[42]  M. Stoffel,et al.  Impaired glucose homeostasis and neonatal mortality in hepatocyte nuclear factor 3alpha-deficient mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[43]  H. Sul,et al.  Cleavage of membrane-associated pref-1 generates a soluble inhibitor of adipocyte differentiation , 1997, Molecular and cellular biology.

[44]  S. Margolis,et al.  Lipid synthesis in isolated intestinal cells. , 1978, Journal of lipid research.

[45]  C. Remacle,et al.  Interferon‐γ and interleukin‐1β inhibit adipoconversion in cultured rodent preadipocytes , 1992, Journal of cellular physiology.

[46]  R. Costa,et al.  The DNA-binding specificity of the hepatocyte nuclear factor 3/forkhead domain is influenced by amino-acid residues adjacent to the recognition helix , 1994, Molecular and cellular biology.

[47]  N. Bégin-Heick,et al.  Growth and maturation of primary‐cultured adipocytes from lean and ob/ob mice , 1995, Journal of cellular biochemistry.