Cellular and molecular basis of leptin resistance

Abstract

Diet-induced obese (DIO) mice and obese humans have high circulating levels of leptin and do not respond to the exogenous hormone suggesting that they develop leptin resistance. However, the underlying cellular and molecular mechanisms that reduce leptin signaling are unknown. As part of a metabolomic screen for biomarkers of a leptin effect, we found that leptin reduced the level of leucine and methionine, mTOR ligands, only in leptin-sensitive animals, raising the possibility that mTOR activation might contribute to leptin resistance. We tested this by first treating DIO, chow-fed, ob/ob and db/db mice with rapamycin, an mTOR inhibitor. Rapamycin reduced food intake and adiposity in DIO mice but not in ob/ob or db/db animals. Whole-brain mapping revealed that the levels of phosphoS6, a marker of mTOR activity, were increased in the arcuate nucleus (ARC) and other hypothalamic nuclei in DIO mice. Subsequent multi-modal single-nucleus RNA sequencing of the ARC in DIO, chow-fed and ob/ob mice revealed that rapamycin altered gene expression exclusively in POMC neurons of DIO mice which also showed normalization of pSTAT3 levels after rapamycin treatment. Consistent with an effect on POMC neurons, rapamycin did not alter food intake or adiposity in mice after an ablation of POMC neurons or in MC4R knockout mice. In contrast, a POMC-specific deletion of Tsc1, which leads to a cell specific increase of mTOR activity, resulted in leptin resistance in chow-fed animals and reduced leptin sensitivity in these and ob/ob mice. In ob/ob-POMCtsc1-/- mice, rapamycin did not reduce food intake or adiposity in the absence of leptin. Finally, POMC-specific deletion of mTOR activators decreased the weight gain in mice fed a HFD. These data suggest that leptin resistance in DIO mice is the result of increased mTOR activity in POMC neurons and that inhibition of mTOR reduces obesity by reversing leptin resistance.