The Rho-guanine nucleotide exchange factor PDZ-RhoGEF governs susceptibility to diet-induced obesity and type 2 diabetes
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The Rho-guanine nucleotide exchange factor PDZ-RhoGEF governs susceptibility to diet-induced obesity and type 2 diabetes. / Chang, Ying-Ju; Pownall, Scott; Jensen, Thomas Elbenhardt; Mouaaz, Samar; Foltz, Warren; Zhou, Lily; Liadis, Nicole; Woo, Minna; Hao, Zhenyue; Dutt, Previn; Bilan, Philip J.; Klip, Amira; Mak, Tak; Stambolic, Vuk.
I: eLife, Bind 4, e06011, 2015.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
Y1 - 2015
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
VL - 4
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e06011
ER -
ID: 147091485