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

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Cite this article as: eLife 2015;4:e06011 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.

Article and author information

Author details

  1. Ying-Ju Chang

    Princess Margaret Cancer Center, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Scott Pownall

    Princess Margaret Cancer Center, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Thomas Elbenhardt Jensen

    Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Samar Mouaaz

    Princess Margaret Cancer Center, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Warren Foltz

    Spatio-Temporal Targeting and Amplification of Radiation Response Program, Office of Research Trainees, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Lily Zhou

    Princess Margaret Cancer Center, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Nicole Liadis

    Princess Margaret Cancer Center, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Mina Woo

    Toronto General Research Institute, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Zhenyue Hao

    Princess Margaret Cancer Center, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Previn Dutt

    Princess Margaret Cancer Center, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. Philip J Bilan

    Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  12. Amira Klip

    Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Tak Mak

    Princess Margaret Cancer Center, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  14. Vuk Stambolic

    Princess Margaret Cancer Center, University Health Network, Toronto, Canada
    For correspondence
    vuks@uhnresearch.ca
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal work was conducted according to the Policies and Guidelines of the Canadian Council on Animal Care and the Province of Ontario's Animals for Research Act. The protocol was approved by the Animal Care Committee of Princess Margaret Cancer Center at University Health Network (permit Number:933 and 2176).

Reviewing Editor

  1. Amy J Wagers, Harvard University, United States

Publication history

  1. Received: December 13, 2014
  2. Accepted: October 25, 2015
  3. Accepted Manuscript published: October 29, 2015 (version 1)
  4. Version of Record published: December 23, 2015 (version 2)

Copyright

© 2015, Chang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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