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Cell Rep. 2017 Oct 24;21(4):1021-1035. doi: 10.1016/j.celrep.2017.09.091.

Absence of Carbohydrate Response Element Binding Protein in Adipocytes Causes Systemic Insulin Resistance and Impairs Glucose Transport.

Author information

1
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston MA 02215, USA.
2
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
3
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
5
Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology, Helmsley Center for Genomic Medicine, La Jolla, CA 92037, USA.
6
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston MA 02215, USA. Electronic address: bkahn@bidmc.harvard.edu.

Abstract

Lower adipose-ChREBP and de novo lipogenesis (DNL) are associated with insulin resistance in humans. Here, we generated adipose-specific ChREBP knockout (AdChREBP KO) mice with negligible sucrose-induced DNL in adipose tissue (AT). Chow-fed AdChREBP KO mice are insulin resistant with impaired insulin action in the liver, muscle, and AT and increased AT inflammation. HFD-fed AdChREBP KO mice are also more insulin resistant than controls. Surprisingly, adipocytes lacking ChREBP display a cell-autonomous reduction in insulin-stimulated glucose transport that is mediated by impaired Glut4 translocation and exocytosis, not lower Glut4 levels. AdChREBP KO mice have lower levels of palmitic acid esters of hydroxy stearic acids (PAHSAs) in serum, and AT. 9-PAHSA supplementation completely rescues their insulin resistance and AT inflammation. 9-PAHSA also normalizes impaired glucose transport and Glut4 exocytosis in ChREBP KO adipocytes. Thus, loss of adipose-ChREBP is sufficient to cause insulin resistance, potentially by regulating AT glucose transport and flux through specific lipogenic pathways.

KEYWORDS:

ChREBP; Glut4 trafficking; PAHSA; adipose tissue inflammation; adipose-carbohydrate response element binding protein; de novo lipogenesis; glucose transport; palmitic acid hydroxy stearic acid; systemic insulin resistance

PMID:
29069585
PMCID:
PMC5771491
DOI:
10.1016/j.celrep.2017.09.091
[Indexed for MEDLINE]
Free PMC Article

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