title: c-Cbl-deficient mice have reduced adiposity, higher energy expenditure, and improved peripheral insulin action.
abstract: Casitas b-lineage lymphoma (c-Cbl) is an E3 ubiquitin ligase that has an important role in regulating the degradation of cell surface receptors. In the present study we have examined the role of c-Cbl in whole-body energy homeostasis. c-Cbl-/- mice exhibited a profound increase in whole-body energy expenditure as determined by increased core temperature and whole-body oxygen consumption. As a consequence, these mice displayed a decrease in adiposity, primarily due to a reduction in cell size despite an increase in food intake. These changes were accompanied by a significant increase in activity (2- to 3-fold). In addition, c-Cbl-/- mice displayed a marked improvement in whole-body insulin action, primarily due to changes in muscle metabolism. We observed increased protein levels of the insulin receptor (4-fold) and uncoupling protein-3 (2-fold) in skeletal muscle and a significant increase in the phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase. These findings suggest that c-Cbl plays an integral role in whole-body fuel homeostasis by regulating whole-body energy expenditure and insulin action.
authors.affiliation: Diabetes and Obesity Program, The Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Molero
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Jensen
authors.forename: Phil C
authors.initials: PC
authors.lastname: Withers
authors.forename: Michelle
authors.initials: M
authors.lastname: Couzens
authors.forename: Herbert
authors.initials: H
authors.lastname: Herzog
authors.forename: Christine B F
authors.initials: CB
authors.lastname: Thien
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
authors.forename: Ken
authors.initials: K
authors.lastname: Walder
authors.forename: Maria A
authors.initials: MA
authors.lastname: Murphy
authors.forename: David D L
authors.initials: DD
authors.lastname: Bowtell
authors.forename: David E
authors.initials: DE
authors.lastname: James
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
mesh_terms: D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001823:Body Composition; D001831:Body Temperature; D001835:Body Weight; D002352:Carrier Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D017403:In Situ Hybridization; D007328:Insulin / Q000378:metabolism*; D007473:Ion Channels; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D010101:Oxygen Consumption; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D011972:Receptor, Insulin / Q000378:metabolism; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000502:physiology*; D000071247:Uncoupling Protein 3
chemical_list: D002352:Carrier Proteins; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D011518:Proto-Oncogene Proteins; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C493849:Cbl protein, mouse; D000103:Acetyl-CoA Carboxylase; D005947:Glucose