Leptin plays a key role in the regulation of cardiovascular and metabolic function through its central nervous system effects on appetite, energy expenditure, blood pressure (BP) and sympathetic nervous system (SNS) activity. Despite leptin levels being elevated in obesity its ability to suppress appetite is markedly attenuated, whereas its effect to increase SNS activity and BP are maintained, suggesting that obesity is associated with "selective" leptin resistance.The mechanisms for this differential regulation of appetite, SNS activity, and BP, however, are still unclear. We also observed selective leptin resistance when ambient temperature was reduced from thermoneutral zone (TNZ, 30oC or 86oF) to 15oC; i.e. chronic leptin infusion at 15oC (59oF) markedly raised BP and heart rate (HR) while the reduction in food intake was only transient . Conversely, at TNZ leptin infusion caused pronounced and sustained suppression of food intake but failed to raise BP and HR.We hypothesize that activation of intracellular signaling pathways activated by the leptin receptor (STAT3, IRS2 and SHP2) may contribute differently to the multiple actions of leptin at TNZ compared to colder temperatures. We will use integrative approaches employing molecular, genetic, and integrative physiological and pharmacological tools to test our hypothesis. We will use novel genetically modified mouse models in combination with sophisticated methods for measuring integrative cardiovascular and metabolic functions that will provide important new insights into fundamental mechanisms controlling energy homeostasis, SNS activation, and BP as well as the mechanisms by which leptin exerts divergent control of cardiovascular and metabolic functions.
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