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Genetic Ablation of the c-Cbl Ubiquitin Ligase Domain Results in Increased Energy Expenditure and Improved Insulin Action

¹ Diabetes and Obesity Program, The Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
² School of Health Sciences, University of Wollongong, Wollongong, New South Wales, Australia
³ School of Surgery and Pathology, University of Western Australia, Crawley, Western Australia, Australia
⁴ School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia
⁵ St. 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

Abbreviations: ACC, acetyl-CoA carboxylase; AMPK, AMP kinase; c-Cbl, Casitas b-lineage lymphoma; PI, phosphatidylinositol; PGC, peroxisome proliferator–activated receptor- coactivator; UCP, uncoupling protein

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-Cbl^A/– mice). Compared with control animals, c-Cbl^A/– mice display a phenotype that includes reduced adiposity, despite greater food intake; reduced circulating insulin, leptin, and triglyceride levels; and improved glucose tolerance. c-Cbl^A/– mice also display elevated oxygen consumption (13%) and are protected against high-fat diet–induced obesity and insulin resistance. Unlike c-Cbl^A/– mice, mice expressing a mutant c-Cbl with the phosphatidylinositol (PI) 3-kinase binding domain ablated (c-Cbl^F/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.

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