The Rho-guanine nucleotide exchange factor PDZ-RhoGEF governs susceptibility to diet-induced obesity and type 2 diabetes

TY - JOUR

T1 - The Rho-guanine nucleotide exchange factor PDZ-RhoGEF governs susceptibility to diet-induced obesity and type 2 diabetes

AU - Chang, Ying-Ju

AU - Pownall, Scott

AU - Jensen, Thomas Elbenhardt

AU - Mouaaz, Samar

AU - Foltz, Warren

AU - Zhou, Lily

AU - Liadis, Nicole

AU - Woo, Minna

AU - Hao, Zhenyue

AU - Dutt, Previn

AU - Bilan, Philip J.

AU - Klip, Amira

AU - Mak, Tak

AU - Stambolic, Vuk

N1 - CURIS 2016 NEXS 015

PY - 2015/10/29

Y1 - 2015/10/29

N2 - Adipose tissue is crucial for the maintenance of energy and metabolic homeostasis and its deregulation can lead to obesity and type II diabetes (T2D).Using gene disruption in the mouse, we discovered a function for a RhoA-specific guanine nucleotide exchange factor PDZ-RhoGEF (Arhgef11) in white adipose tissue biology. While PDZ-RhoGEF was dispensable for a number of RhoA signaling-mediated processes in mouse embryonic fibroblasts, including stress fiber formation and cell migration, it's deletion led to a reduction in theirproliferative potential. On a whole organism level, PDZ-RhoGEF deletion resultedin an acute increase in energy expenditure, selectively impaired early adiposetissue development and decreased adiposity in adults. PDZ-RhoGEF-deficientmice were protected from diet-induced obesity and T2D. Mechanistically, PDZ-RhoGEF enhanced insulin/IGF-1 signaling in adipose tissue by controllingROCK-dependent phosphorylation of the insulin receptor substrate-1 (IRS-1).Our results demonstrate that PDZ-RhoGEF acts as a key determinant ofmammalian metabolism and obesity-associated pathologies.

AB - Adipose tissue is crucial for the maintenance of energy and metabolic homeostasis and its deregulation can lead to obesity and type II diabetes (T2D).Using gene disruption in the mouse, we discovered a function for a RhoA-specific guanine nucleotide exchange factor PDZ-RhoGEF (Arhgef11) in white adipose tissue biology. While PDZ-RhoGEF was dispensable for a number of RhoA signaling-mediated processes in mouse embryonic fibroblasts, including stress fiber formation and cell migration, it's deletion led to a reduction in theirproliferative potential. On a whole organism level, PDZ-RhoGEF deletion resultedin an acute increase in energy expenditure, selectively impaired early adiposetissue development and decreased adiposity in adults. PDZ-RhoGEF-deficientmice were protected from diet-induced obesity and T2D. Mechanistically, PDZ-RhoGEF enhanced insulin/IGF-1 signaling in adipose tissue by controllingROCK-dependent phosphorylation of the insulin receptor substrate-1 (IRS-1).Our results demonstrate that PDZ-RhoGEF acts as a key determinant ofmammalian metabolism and obesity-associated pathologies.

U2 - 10.7554/eLife.06011

DO - 10.7554/eLife.06011

M3 - Journal article

C2 - 26512886

SN - 2050-084X

VL - 4

JO - eLife

JF - eLife

M1 - e06011

ER -