c-Cbl-deficient mice have reduced adiposity, higher energy expenditure, and improved peripheral insulin action.
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.
Molero
Juan C
JC
Diabetes and Obesity Program, The Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Jensen
Thomas E
TE
Withers
Phil C
PC
Couzens
Michelle
M
Herzog
Herbert
H
Thien
Christine B F
CB
Langdon
Wallace Y
WY
Walder
Ken
K
Murphy
Maria A
MA
Bowtell
David D L
DD
James
David E
DE
Cooney
Gregory J
GJ
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
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