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

Ying-Ju Chang,Warren Foltz,Minna Woo,Tak Mak,Amira Klip,Nicole Liadis,Scott Pownall,Lily Zhou,Thomas E Jensen,Vuk Stambolic,Philip J Bilan,Zhenyue Hao,Previn Dutt,Samar Mouaaz

doi:10.7554/elife.06011

Abstract

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 their proliferative potential. On a whole organism level, PDZ-RhoGEF deletion resulted in an acute increase in energy expenditure, selectively impaired early adipose tissue development and decreased adiposity in adults. PDZ-RhoGEF-deficient mice were protected from diet-induced obesity and T2D. Mechanistically, PDZ-RhoGEF enhanced insulin/IGF-1 signaling in adipose tissue by controlling ROCK-dependent phosphorylation of the insulin receptor substrate-1 (IRS-1). Our results demonstrate that PDZ-RhoGEF acts as a key determinant of mammalian metabolism and obesity-associated pathologies.

Highlights

While our data show that PDZ-Rho GTPase-specific guanine nucleotide exchange factors (RhoGEFs) is dispensable for many cellular processes that it had previously been linked to, we discovered its direct involvement in controlling adipose tissue homeostasis through regulation of adipocyte numbers and energy expenditure
We further verified the complete deletion of Arhgef11 (-/, KO) by immunoblotting with a rabbit polyclonal antibody raised against the N-terminal fragment of PDZ-RhoGEF (Figure 1—figure supplement 1D)
PDZ-RhoGEF KO animals were born at the expected Mendelian ratio and were grossly indistinguishable from their wild type (WT) and heterozygous littermates

Summary

Introduction

While it is generally recognized that obesity arises as a result of a complex interplay of genetic factors that govern predisposition for white adipose tissue expansion, as well as environmental factors, such as diet, the molecular mechanisms underlying this condition are not fully understood. Adipose tissue growth results from an increase in both adipocyte size and number and occurs as part of normal development, as well as during the onset of obesity (Faust et al, 1978; Prins and O’Rahilly, 1997). Genetic disruption of the insulin receptor (IR), the insulin receptor substrate (IRS) genes, as well as PKBa/Akt and PKBb/Akt, respectively, the major mediators of insulin signaling, lead to impaired adipogenesis (Miki et al, 2001; Tseng et al, 2004; Yun et al, 2008)

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