Tbc1d1 deletion suppresses obesity in leptin-deficient mice

BACKGROUND: Variants in the gene TBC1D1 have been previously associated with obesity-related traits in several species, including humans, mice, rabbits and chicken. While in humans variants in TBC1D1 were linked to obesity, disruption of the Tbc1d1 gene reduced body weight in mice. TBC1D1 has been identified as a regulator of insulin-dependent glucose transport in skeletal muscle, however, its role in energy homeostasis in the obese state remains unclear. The impact of TBC1D1 deficiency on energy homeostasis, glucose and lipid metabolism in an established mouse model of obesity was examined. METHODS: Obese leptin (ob/ob)- and Tbc1d1-double-deficient mice (D1KO-ob/ob) were generated by crossing obese B6.V.Lep(ob/ob)-mice with lean Tbc1d1-deficient mice on a C57BL/6J background. Male mice on either standard (SD) or high-fat diet (HFD) were analyzed for body weight, body composition, food intake, voluntary physical activity and energy expenditure by indirect calorimetry. Glucose and insulin tolerance as well as glucose transport and fatty acid oxidation in skeletal muscle were analyzed. RESULTS: In obese mice, Tbc1d1 deficiency resulted in reduced body weight on both SD and HFD. However, food intake was unchanged on SD or even increased in HFD-fed Tbc1d1-deficient mice without alterations in voluntary physical activity. Despite substantially reduced insulin-stimulated glucose transport and increased fatty acid oxidation in intact isolated skeletal muscle, obese Tbc1d1-deficient mice showed no gross changes in glycemia and glucose tolerance compared with obese controls. Indirect calorimetry revealed that obese Tbc1d1-deficient mice had a decreased respiratory quotient together with increased daily energy expenditure. CONCLUSIONS: In obese leptin-deficient mice, lack of TBC1D1 has no impact on feeding behavior or energy intake but results in increased energy expenditure, altered energy substrate preference with increased fatty acid oxidation and suppression of obesity. TBC1D1 may have an evolutionary conserved role in regulating energy homeostasis in vertebrates.