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Genetic ablation of the c-Cbl ubiquitin ligase domain results in increased energy expenditure and improved insulin action.

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2006

Diabetes 2006 Dec;55(12):341

Genetic ablation of the c-Cbl ubiquitin ligase domain results in increased energy expenditure and improved insulin action.

Cooney, GJ.;James, DE;Langdon, WY;Molero, JC;Thien, CB;Turner, N

Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia.

Service type: Knock-in mice

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-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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