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Casitas b-Lineage Lymphoma–Deficient Mice Are Protected Against High-Fat Diet–Induced Obesity and Insulin Resistance

¹ Diabetes and Obesity Program, The Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
² Metabolic Research Unit, Deakin University Geelong, Victoria, Australia
³ St. Vincent’s Hospital Clinical School, University of New South Wales, Sydney, New South Wales, Australia
⁴ School of Biotechnology and Biomolecular Sciences, 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; c-Cbl, Casitas b-lineage lymphoma; HAD, hydroxyacyl CoA dehydrogenase; IRS-1, insulin receptor substrate-1

Casitas b-lineage lymphoma (c-Cbl) is a multiadaptor protein with E3-ubiquitin ligase activity involved in regulating the degradation of receptor tyrosine kinases. We have recently reported that c-Cbl^–/– mice exhibit a lean phenotype and enhanced peripheral insulin action likely due to elevated energy expenditure. In the study reported here, we examined the effect of a high-fat diet on energy homeostasis and glucose metabolism in these animals. When c-Cbl^–/– mice were fed a high-fat diet for 4 weeks, they maintained hyperphagia, higher whole-body oxygen consumption (27%), and greater activity (threefold) compared with wild-type animals fed the same diet. In addition, the activity of several enzymes involved in mitochondrial fat oxidation and the phosphorylation of acetyl CoA carboxylase was significantly increased in muscle of high-fat–fed c-Cbl–deficient mice, indicating a greater capacity for fat oxidation in these animals. As a result of these differences, fat-fed c-Cbl^–/– mice were 30% leaner than wild-type animals and were protected against high-fat diet–induced insulin resistance. These studies are consistent with a role for c-Cbl in regulating nutrient partitioning in skeletal muscle and emphasize the potential of c-Cbl as a therapeutic target in the treatment of obesity and type 2 diabetes.

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