Constitutive Activation of the Nutrient Sensor mTORC1 in Myeloid Cells Induced by Tsc1 Deletion Protects Mice from Diet‐Induced Obesity

Scope To test whether myeloid cells Tsc1 deletion and therefore constitutive activation of the nutrient sensor mTORC1 protects from high‐fat diet (HFD)‐induced obesity, glucose intolerance, and adipose tissue inflammation. Methods and results Mice with Tsc1 deletion in myeloid cells (MTsc1KO) and littermate controls (MTsc1WT) were fed with HFD for 8 weeks and evaluated for body weight, glucose homeostasis, and adipose tissue inflammation. MTsc1KO mice were protected from HFD‐induced obesity and glucose intolerance. MTsc1KO, however, displayed, independently of the diet, abnormal behavior, episodes of intense movement, and muscle spasms followed by temporary paralysis. To investigate whether obesity protection was due to myeloid cells Tsc1 deletion, bone marrow was transplanted from MTsc1WT and MTsc1KO into irradiated C57BL6/J mice. Mice transplanted with MTsc1KO bone marrow displayed reduced body weight gain, adiposity, and inflammation, and enhanced energy expenditure, glucose tolerance and adipose tissue M2 macrophage content upon HFD feeding, in the absence of abnormal behavior. In vitro, Tsc1 deletion increased in a mTORC1‐dependent manner macrophage polarization to M2 profile and mRNA levels of fatty acid binding protein 4 and PPARγ. Conclusion Constitutive mTORC1 activation in myeloid cells protects mice from HFD‐induced obesity, adipose tissue inflammation, and glucose intolerance by promoting macrophage polarization to M2 pro‐resolution profile and increasing energy expenditure. Mice transplanted with Tsc1‐deficient bone marrow are protected from high‐fat‐diet‐induced obesity, adipose tissue inflammation, and glucose intolerance through a mechanism that involves macrophage polarization to the pro‐resolution M2 profile and an increase in whole‐body energy expenditure. These findings support the important role of macrophages and the nutrient sensor mTORC1 as major modulators of energy balance, metabolism, and inflammation.