Genetic ablation of the c-Cbl ubiquitin ligase domain results in increased energy expenditure and improved insulin action.
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.
Molero
Juan C
JC
Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia.
Turner
Nigel
N
Thien
Christine B F
CB
Langdon
Wallace Y
WY
James
David E
DE
Cooney
Gregory J
GJ
D000273:Adipose Tissue / Q000033:anatomy & histology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002153:Calorimetry, Indirect; D017931:DNA Primers; D004734:Energy Metabolism; D017353:Gene Deletion; D005951:Glucose Tolerance Test; D007328:Insulin / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency*; D013851:Thinness / Q000235:genetics
D001786:Blood Glucose; D017931:DNA Primers; D007328:Insulin; D050721:Proto-Oncogene Proteins c-cbl; D019869:Phosphatidylinositol 3-Kinases; C493849:Cbl protein, mouse