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mTORC1 in leptin receptor‐containing neurons mediates an obesity‐induced increase in sympathetic tone and blood pressure

The adipocyte‐derived hormone leptin acts via the sympathetic nervous system to influence both metabolic homeostasis and blood pressure. Leptin has also been implicated as an important mediator of obesity‐induced elevation in sympathetic nerve activity (SNA) and blood pressure, but the underlying mechanisms remain poorly understood. Here, we investigated the contribution of mechanistic target of rapamycin complex 1 (mTORC1) signaling in leptin receptor (LepRb)‐containing neurons to metabolic, sympathetic and hemodynamic dysregulation associated with obesity. For this, we generated a genetically modified mouse model (LepRbCre/Raptorfl/fl) that lacks a critical subunit of the mTORC1 complex selectively in LepRb expressing cells. Surprisingly, loss of mTORC1 in LepRb‐containing cells had no effect on body weight, fat accumulation, or glucose handling. Furthermore, LepRbCre/Raptorfl/fl mice fed high‐fat or high‐fat/high‐sucrose diet developed obesity to a similar extent as control littermates, indicating that mTORC1 in LepRb expressing cells is dispensable for metabolic homeostasis. On the other hand, while conscious basal renal SNA was significantly elevated in control mice fed high‐fat/high‐sucrose diet relative to control animals on standard diet, this increase in sympathetic tone to the kidneys was attenuated in LepRbCre/Raptorfl/fl mice. Consistent with an impaired cardiovascular autonomic response to diet‐induced obesity in these animals, ganglionic blockade with hexamethonium bromide caused a trend towards a more pronounced decrease in blood pressure in high‐fat/high‐sucrose diet fed control animals as compared to LepRbCre/Raptorfl/fl mice. Interestingly, renal SNA was decreased in response to hexamethonium to a similar extent in all groups, regardless of diet or genotype, indicating an important role for extra‐renal and/or parasympathetic changes in autonomic nerve activity during diet‐induced obesity. High‐fat/high‐sucrose diet treatment also increased blood pressure and decreased cardiac parasympathetic tone in control mice, as determined by radiotelemetry and accompanying spectral analysis, and ICV rapamycin infusion resulted in a trend towards a partial reversal of these effects. Together, these findings indicate that mTORC1 signaling in LepRb‐containing cells is required for obesity‐induced sympathetic nerve activation and hypertension. This signaling pathway may represent an important mechanism for uncoupling obesity from its associated cardiovascular disorders.