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

Publication date: 24 October 2017
Source:Cell Reports, Volume 21, Issue 4
Author(s): 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
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.

Graphical abstract

Teaser

ChREBP expression in fat strongly correlates with insulin sensitivity in people. Vijayakumar et al. demonstrate that fat-specific knockout of ChREBP in mice is sufficient to cause insulin resistance and cell-autonomous impairments in glucose transport and Glut4 trafficking, potentially by altering substrate flux through specific lipogenic pathways.


http://ift.tt/2yPEckk