The prevalence of obesity and type 2 diabetes is increasing worldwide and threatens to shorten lifespan. Impaired insulin action in peripheral tissues is a major pathogenic factor. Insulin stimulates glucose uptake in adipose tissue through the GLUT4 (also known as SLC2A4) glucose transporter, and alterations in adipose tissue GLUT4 expression or function regulate systemic insulin sensitivity. Downregulation of human and mouse adipose tissue GLUT4 occurs early in diabetes development. Here we report that adipose tissue GLUT4 regulates the expression of carbohydrate-responsive-element-binding protein (ChREBP; also known as MLXIPL), a transcriptional regulator of lipogenic and glycolytic genes. Furthermore, adipose ChREBP is a major determinant of adipose tissue fatty acid synthesis and systemic insulin sensitivity. We find a new mechanism for glucose regulation of ChREBP: glucose-mediated activation of the canonical ChREBP isoform (ChREBP-α) induces expression of a novel, potent isoform (ChREBP-β) that is transcribed from an alternative promoter. ChREBP-β expression in human adipose tissue predicts insulin sensitivity, indicating that it may be an effective target for treating diabetes.
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Shepherd, P. R. & Kahn, B. B. Glucose transporters and insulin action—implications for insulin resistance and diabetes mellitus. N. Engl. J. Med. 341, 248–257 (1999)
Attie, A. D. & Scherer, P. E. Adipocyte metabolism and obesity. J. Lipid Res. 50 (Suppl.). S395–S399 (2009)
Boden, G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46, 3–10 (1997)
Abel, E. D. et al. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409, 729–733 (2001)
Shepherd, P. R. et al. Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue. J. Biol. Chem. 268, 22243–22246 (1993)
Iizuka, K., Bruick, R. K., Liang, G., Horton, J. D. & Uyeda, K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc. Natl Acad. Sci. USA 101, 7281–7286 (2004)
Roberts, R. et al. Markers of de novo lipogenesis in adipose tissue: associations with small adipocytes and insulin sensitivity in humans. Diabetologia 52, 882–890 (2009)
Hoffstedt, J., Forster, D. & Lofgren, P. Impaired subcutaneous adipocyte lipogenesis is associated with systemic insulin resistance and increased apolipoprotein B/AI ratio in men and women. J. Intern. Med. 262, 131–139 (2007)
Kursawe, R. et al. Cellularity and adipogenic profile of the abdominal subcutaneous adipose tissue from obese adolescents: association with insulin resistance and hepatic steatosis. Diabetes 59, 2288–2296 (2010)
Ranganathan, G. et al. The lipogenic enzymes DGAT1, FAS, and LPL in adipose tissue: effects of obesity, insulin resistance, and TZD treatment. J. Lipid Res. 47, 2444–2450 (2006)
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005)
Horton, J. D., Goldstein, J. L. & Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002)
Brown, M. S. & Goldstein, J. L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89, 331–340 (1997)
Repa, J. J. et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev. 14, 2819–2830 (2000)
Cha, J. Y. & Repa, J. J. The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR. J. Biol. Chem. 282, 743–751 (2007)
Denechaud, P. D., Girard, J. & Postic, C. Carbohydrate responsive element binding protein and lipid homeostasis. Curr. Opin. Lipidol. 19, 301–306 (2008)
Pashkov, V. et al. Regulator of G protein signaling (RGS16) inhibits hepatic fatty acid oxidation in a carbohydrate response element-binding protein (ChREBP)-dependent manner. J. Biol. Chem. 286, 15116–15125 (2011)
Minn, A. H., Hafele, C. & Shalev, A. Thioredoxin-interacting protein is stimulated by glucose through a carbohydrate response element and induces β-cell apoptosis. Endocrinology 146, 2397–2405 (2005)
Ma, L., Robinson, L. N. & Towle, H. C. ChREBṖMlx is the principal mediator of glucose-induced gene expression in the liver. J. Biol. Chem. 281, 28721–28730 (2006)
Kuriyama, H. et al. Compensatory increase in fatty acid synthesis in adipose tissue of mice with conditional deficiency of SCAP in liver. Cell Metab. 1, 41–51 (2005)
Cao, H. et al. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134, 933–944 (2008)
Carvalho, E., Kotani, K., Peroni, O. D. & Kahn, B. B. Adipose-specific overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle. Am. J. Physiol. Endocrinol. Metab. 289, E551–E561 (2005)
Ahima, R. S. & Flier, J. S. Leptin. Annu. Rev. Physiol. 62, 413–437 (2000)
Nadler, S. T. et al. The expression of adipogenic genes is decreased in obesity and diabetes mellitus. Proc. Natl Acad. Sci. USA 97, 11371–11376 (2000)
Caesar, R. et al. A combined transcriptomics and lipidomics analysis of subcutaneous, epididymal and mesenteric adipose tissue reveals marked functional differences. PLoS ONE 5, e11525 (2010)
Gnudi, L., Tozzo, E., Shepherd, P. R., Bliss, J. L. & Kahn, B. B. High level overexpression of glucose transporter-4 driven by an adipose-specific promoter is maintained in transgenic mice on a high fat diet, but does not prevent impaired glucose tolerance. Endocrinology 136, 995–1002 (1995)
Sanchez, J., Palou, A. & Pico, C. Response to carbohydrate and fat refeeding in the expression of genes involved in nutrient partitioning and metabolism: striking effects on fibroblast growth factor-21 induction. Endocrinology 150, 5341–5350 (2009)
Shimano, H. et al. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J. Clin. Invest. 100, 2115–2124 (1997)
Stoeckman, A. K., Ma, L. & Towle, H. C. Mlx is the functional heteromeric partner of the carbohydrate response element-binding protein in glucose regulation of lipogenic enzyme genes. J. Biol. Chem. 279, 15662–15669 (2004)
Kabashima, T., Kawaguchi, T., Wadzinski, B. E. & Uyeda, K. Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver. Proc. Natl Acad. Sci. USA 100, 5107–5112 (2003)
Li, M. V., Chang, B., Imamura, M., Poungvarin, N. & Chan, L. Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module. Diabetes 55, 1179–1189 (2006)
Iizuka, K., Takeda, J. & Horikawa, Y. Hepatic overexpression of dominant negative Mlx improves metabolic profile in diabetes-prone C57BL/6J mice. Biochem. Biophys. Res. Commun. 379, 499–504 (2009)
Shih, H. M., Liu, Z. & Towle, H. C. Two CACGTG motifs with proper spacing dictate the carbohydrate regulation of hepatic gene transcription. J. Biol. Chem. 270, 21991–21997 (1995)
Bernstein, B. E. et al. Methylation of histone H3 Lys 4 in coding regions of active genes. Proc. Natl Acad. Sci. USA 99, 8695–8700 (2002)
Fukasawa, M., Ge, Q., Wynn, R. M., Ishii, S. & Uyeda, K. Coordinate regulation/localization of the carbohydrate responsive binding protein (ChREBP) by two nuclear export signal sites: discovery of a new leucine-rich nuclear export signal site. Biochem. Biophys. Res. Commun. 391, 1166–1169 (2010)
Tsatsos, N. G. & Towle, H. C. Glucose activation of ChREBP in hepatocytes occurs via a two-step mechanism. Biochem. Biophys. Res. Commun. 340, 449–456 (2006)
Fabbrini, E. et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc. Natl Acad. Sci. USA 106, 15430–15435 (2009)
Donnelly, K. L. et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115, 1343–1351 (2005)
Eguchi, J. et al. Transcriptional control of adipose lipid handling by IRF4. Cell Metab. 13, 249–259 (2011)
Kotani, K., Peroni, O. D., Minokoshi, Y., Boss, O. & Kahn, B. B. GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization. J. Clin. Invest. 114, 1666–1675 (2004)
Klöting, N. et al. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab. 6, 79–87 (2007)
Hems, D. A., Rath, E. A. & Verrinder, T. R. Fatty acid synthesis in liver and adipose tissue of normal and genetically obese (ob/ob) mice during the 24-hour cycle. Biochem. J. 150, 167–173 (1975)
Kent, W. J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002)
Fujita, P. A. et al. The UCSC Genome Browser database: update 2011. Nucleic Acids Res. 39, D876–D882 (2010)
Rosenbloom, K. R. et al. ENCODE whole-genome data in the UCSC Genome Browser. Nucleic Acids Res. 38, D620–D625 (2010)
Robertson, G. et al. Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nature Methods 4, 651–657 (2007)
We thank H. Towle for providing reagents and discussion. We thank P. Pissios, I. Astapova, E. Rosen and the Rosen laboratory for discussions, K. Uyeda for providing ChREBP KO mice, and E. Shu for technical assistance. This work was supported by NIH R37 DK43051 (B.B.K.), K08 DK076726 (M.A.H.), BADERC DK057521 (B.B.K., M.A.H.), BNORC DK046200 (M.A.H.), the Picower and JPB Foundations (B.B.K.), a Fellowship from the Radcliffe Institute for Advanced Study (B.B.K.), DK056341 (Nutrition and Obesity Research Unit) (S.K.), DK037948 (S.K.), and the Deutsche Forschungsgemeinschft DFG, KFO152, BL833/1 (M.B.).
The authors declare no competing financial interests.
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Herman, M., Peroni, O., Villoria, J. et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 484, 333–338 (2012). https://doi.org/10.1038/nature10986
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