Abstract 022: mTORC1 is Required for the Cardiovascular but Not the Metabolic Actions of Leptin

Obesity represents a major risk factor for the development of hypertension, and inappropriate leptin action has been implicated as an essential mediator of obesity-associated hypertension. Leptin plays a critical role in energy homeostasis, acting through the brain to stimulate energy expenditure and suppress food intake. Leptin also increases sympathetic outflow to a variety of target organs, including those involved in blood pressure regulation. Here, we investigate the role of mTORC1 as a potential mediator of leptin’s cardiovascular and metabolic actions. For this, we generated conditional knockout mice that lack the critical mTORC1 subunit, Raptor, specifically in leptin receptor (LRb) expressing cells (LRb Cre /Rap fl/fl ). LRb Cre /Rap fl/fl displayed similar body weight, food intake and body composition as compared to littermate controls when fed a normal chow diet (body weight=29.6±0.8 g vs 31.0±0.8g at 14 weeks of age). Control and LRb Cre /Rap fl/fl mice also developed diet-induced obesity to a similar extent when fed either a 45% high-fat (37.2±3.1g g vs 40.9±2.2) or high-fat/high-sucrose diet (35.4±1.1g vs 35.2±2.7g). Additionally, fasting blood glucose (77.3±6.7mg/dL vs. 71.8±4.3mg/dL) as well as insulin (AUC=7788 ±1013, n=3 vs. 8964±884, n=4) and glucose (AUC=39750±2075, n=3 vs. 44259±1948, n=4) tolerance in high fat/high-sucrose diet fed mice were not changed in LRb Cre /Rap fl/fl mice as compared to littermate controls. Conversely, while baseline mean arterial pressure (MAP) was comparable between LRb Cre /Rap fl/fl mice (108±9 mmHg) and controls (103±7 mmHg), intracerebroventricular administration of leptin significantly increased MAP in control mice (30±14 mmHg), but not in LRb Cre /Rap fl/fl mice (1±9 mmHg, P Cre /Rap fl/fl mice displayed a blunted renal sympathetic nerve response to leptin (-4±15%, n=9 vs. 127±16%, n=9, P