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  • Project II - Differential Control of Metabolic and Cardiovascular Functions by Leptin

    Jussara M. do Carmo, PhD

    Assistant Professor
    Department of Physiology and Biophysics
    Email:  jdocarmo@umc.edu

    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. The specific aims of this proposal are: 

    1) to test the hypothesis that IRS2 deletion in forebrain and/or hindbrain nuclei (nucleus tractus solitarius and dorsal motor nucleus of the vagus) attenuates the chronic cardiovascular response to leptin at 15oC without altering food intake response at TNZ; 

    2) to test the hypothesis that SHP2 deletion in forebrain neurons attenuates the chronic thermogenic and cardiovascular responses to leptin at 15oC without altering the food intake response at TNZ; and

    3) to test the hypothesis that STAT3 deletion in forebrain neurons attenuates the chronic food intake responses to leptin at TNZ without altering the cardiovascular response to leptin at 15oC. 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.

     

    Summary of research

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    Project II Mentors

       GomezSanchez's Faculty Page

    Elise Gomez-Sanchez, PhD, DVM
    Professor-Medicine/Endocrinology
              

     Taylor's Faculty Page

    Herman A. Taylor, MD
    Professor-Medicine/Cardiology