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

Citation
Vijayakumar, A., et al. “Absence Of Carbohydrate Response Element Binding Protein In Adipocytes Causes Systemic Insulin Resistance And Impairs Glucose Transport.”. Cell Reports, pp. 1021-1035.
Center Albert Einstein College of Medicine Yale University
Multicenter
Multicenter
Author Archana Vijayakumar, Pratik Aryal, Jennifer Wen, Ismail Syed, Reema P Vazirani, Pedro M Moraes-Vieira, Joao Paulo Camporez, Molly R Gallop, Rachel J Perry, Odile D Peroni, Gerald I Shulman, Alan Saghatelian, Timothy E McGraw, Barbara B Kahn
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
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.

Year of Publication
2017
Journal
Cell reports
Volume
21
Issue
4
Number of Pages
1021-1035
Date Published
10/2017
ISSN Number
2211-1247
DOI
10.1016/j.celrep.2017.09.091
Alternate Journal
Cell Rep
PMID
29069585
PMCID
PMC5771491
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