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


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.

SUBMITTER: Vijayakumar A 

PROVIDER: S-EPMC5771491 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Vijayakumar Archana A   Aryal Pratik P   Wen Jennifer J   Syed Ismail I   Vazirani Reema P RP   Moraes-Vieira Pedro M PM   Camporez Joao Paulo JP   Gallop Molly R MR   Perry Rachel J RJ   Peroni Odile D OD   Shulman Gerald I GI   Saghatelian Alan A   McGraw Timothy E TE   Kahn Barbara B BB  

Cell reports 20171001 4


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-auto  ...[more]

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