title: The Rho-guanine nucleotide exchange factor PDZ-RhoGEF governs susceptibility to diet-induced obesity and type 2 diabetes.
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.
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Chang
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: Pownall
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Jensen
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Samar
authors.initials: S
authors.lastname: Mouaaz
authors.affiliation: Spatio-Temporal Targeting and Amplification of Radiation Response Program, Office of Research Trainees, University Health Network, Toronto, Canada.
authors.forename: Warren
authors.initials: W
authors.lastname: Foltz
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Lily
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Liadis
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Canada.
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Zhenyue
authors.initials: Z
authors.lastname: Hao
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Previn
authors.initials: P
authors.lastname: Dutt
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bilan
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Amira
authors.initials: A
authors.lastname: Klip
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Tak
authors.initials: T
authors.lastname: Mak
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Vuk
authors.initials: V
authors.lastname: Stambolic
mesh_terms: D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004032:Diet / Q000379:methods*; D004198:Disease Susceptibility; D005347:Fibroblasts / Q000502:physiology; D017353:Gene Deletion; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009765:Obesity / Q000503:physiopathology*; D064067:Rho Guanine Nucleotide Exchange Factors
chemical_list: C574809:ARHGEF11 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors
keywords: Rho signaling; adipose tissue; cell biology; developmental biology; diabetes; insulin; mouse; obesity; stem cells