Beige fat is dispensable for the metabolic benefits associated with myostatin deletion

Abstract

ObjectiveIncreasing muscle mass and activating beige fat both have great potential for ameliorating obesity and its comorbidities. Myostatin null mice have increased skeletal muscle mass and are protected from obesity and its sequelae. Deletion of myostatin has also been suggested to result in the activation of beige adipocytes, thermogenic fat cells with anti-obesity and anti-diabetes properties. It is not known whether beige fat activation contributes to the protection from obesity in myostatin null mice. MethodsTo investigate the role of beige fat activation in the metabolic benefits associated with myostatin deletion, we crossed myostatin null mice to adipocyte-specific PRDM16 knockout mice. We analyzed this new mouse model using molecular profiling, whole mount three-dimensional tissue imaging, tissue respiration, and glucose and insulin tolerance tests in models of diet-induced obesity. ResultsHere, we report that PRDM16 is required for the activation of beige fat in the absence of myostatin. However, we show in both male and female mice that beige fat activation is dispensable for the protection from obesity, glucose intolerance, insulin resistance, and hepatic steatosis mediated by myostatin deletion. ConclusionThese findings demonstrate that increasing muscle mass can compensate for the inactivation of beige fat and raise the possibility of targeting muscle mass as a therapeutic approach to offset the deleterious effects of adipose tissue dysfunction in obesity and metabolic syndrome.