Genetic Ablation of the c-Cbl Ubiquitin Ligase Domain Results in Increased Energy Expenditure and Improved Insulin Action
- Juan C. Molero1,
- Nigel Turner12,
- Christine B.F. Thien3,
- Wallace Y. Langdon3,
- David E. James14 and
- Gregory J. Cooney15
- 1Diabetes and Obesity Program, The Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- 2School of Health Sciences, University of Wollongong, Wollongong, New South Wales, Australia
- 3School of Surgery and Pathology, University of Western Australia, Crawley, Western Australia, Australia
- 4School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
- 5St. Vincent’s Hospital Clinical School, University of New South Wales, Sydney, New South Wales, Australia
- Address correspondence and reprint requests to Prof. David E. James, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia. E-mail: d.james{at}garvan.org.au
Abstract
Casitas b-lineage lymphoma (c-Cbl) is a multiadaptor protein with E3-ubiquitin ligase activity residing within its RING finger domain. We have previously reported that c-Cbl–deficient mice exhibit elevated energy expenditure, reduced adiposity, and improved insulin action. In this study, we examined mice expressing c-Cbl protein with a loss-of-function mutation within the RING finger domain (c-CblA/− mice). Compared with control animals, c-CblA/− mice display a phenotype that includes reduced adiposity, despite greater food intake; reduced circulating insulin, leptin, and triglyceride levels; and improved glucose tolerance. c-CblA/− mice also display elevated oxygen consumption (13%) and are protected against high-fat diet–induced obesity and insulin resistance. Unlike c-CblA/− mice, mice expressing a mutant c-Cbl with the phosphatidylinositol (PI) 3-kinase binding domain ablated (c-CblF/F mice) exhibited an insulin sensitivity, body composition, and energy expenditure similar to that of wild-type animals. These results indicate that c-Cbl ubiquitin ligase activity, but not c-Cbl–dependent activation of PI 3-kinase, plays a key role in the regulation of whole-body energy metabolism.
- ACC, acetyl-CoA carboxylase
- AMPK, AMP kinase
- c-Cbl, Casitas b-lineage lymphoma
- PI, phosphatidylinositol
- PGC, peroxisome proliferator–activated receptor-γ coactivator
- UCP, uncoupling protein
Footnotes
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J.C.M. and N.T. contributed equally to this work.
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted August 30, 2006.
- Received July 12, 2006.
- DIABETES
