Abstract 053: Uncoupling the Metabolic and Cardiovascular Actions of Leptin through mTORC1 Signaling

The adipocyte-derived hormone leptin has a well-established role in the regulation of energy homeostasis, acting in the brain to decrease food intake and promote energy expenditure. Additionally, leptin increases regional sympathetic nerve activity (SNA) and arterial pressure. Multiple intracellular signaling cascades are activated by leptin via its long form receptor (LRb), but the specific roles of these pathways in mediating leptin’s various effects have not been fully understood. Recent evidences suggest that the mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in mediating leptin action. To determine the contribution of mTORC1 to the metabolic and cardiovascular effects of leptin, we generated conditional knockout mice that lack the critical mTORC1 subunit, Raptor, specifically in LRb-expressing cells (LRbCre/Raptorfl/fl). Interestingly, body weight was comparable between LRbCre/Raptorfl/fl mice and controls (29.6±0.8 g vs 31.0±0.8g at 14 weeks of age). Moreover, leptin treatment (1μg/g bw, intraperitoneally, twice daily for 4 days) led to a similar decrease in food intake (-1.6±0.8 g in LRbCre/Raptorfl/fl mice vs -1.1±1.7 g in controls) and body weight (-5.9±0.8% vs -5.7±0.7%) in both groups. Next, we measured arterial pressure using radiotelemetry at baseline and in response to 2 μg intracerebroventricular (ICV) leptin. Baseline mean arterial pressure (MAP) was comparable between LRbCre/Raptorfl/fl mice (108±9 mmHg) and controls (103±7 mmHg). However, ICV leptin significantly increased MAP in control mice (30±14 mmHg), but not in LRbCre/Raptorfl/fl mice (1±9 mmHg, P<0.05 vs controls). The same pattern was observed for systolic and diastolic arterial pressure. Consistent with leptin’s action on MAP, we observed a significant increase in renal SNA in response to ICV leptin in control littermates (106±20%) that was absent in LRbCre/Raptorfl/fl mice (-28±11%, P<0.05 vs controls) as determined by multifiber sympathetic nerve recordings. Our data suggest a critical role for mTORC1 signaling in mediating the cardiovascular sympathetic but not the metabolic actions of leptin, a dissociation that may have important implications for obesity-associated hypertension.