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  • Project I - Cardiometabolic Regulation by CNS Mechanisms

    Alexandre A. daSilva, PhD

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

    Diabetes, with its associated metabolic and cardiovascular derangements, is a major cause of morbidity and mortality worldwide. Although much is known about insulin's role in glucose homeostasis, advances in insulin and insulin receptor biology have not provided adequate therapy for many diabetic and insulin resistant individuals. Thus, seeking other pathways that contribute to the regulation of glycemic levels is important. We recently demonstrated that chronic CNS leptin infusion completely normalized plasma glucose levels instreptozotocin (STZ) insulin-deficient diabetic animals, suggesting that the antidiabetic actions of leptin are mediated via the CNS and are independent of insulin.

    The CNS effects of leptin on glucose homeostasis appear to be mediated by leptin-induced stimulation of proopiomelanocortin (POMC) neurons that release a-melanocyte stimulating hormone (α-MSH) which, in turn, activates melanocortin 4 receptors (MC4R). We showed that pharmacological antagonism or genetic disruption of MC4R completely abolished the chronic antidiabetic effects of leptin. Recent observations also indicate that MC4R activation in different areas of the brain exerts divergent control of appetite and energy expenditure. Thus, we hypothesize that depending on its specific sites of CNS action the leptin-MC4R axis may also exhibit divergent control of its antidiabetic effects.

    Although we showed that chronic blockade of adrenergic receptors (α1, β1, β2, and β3) did not impair the CNS antidiabetic action of leptin, it is possible that increased parasympathetic activity (PSA) to the liver may reduce gluconeogenesis and contribute to leptin's ability to restore euglycemia in diabetic animals. Another exciting possibility supported by new preliminary data is that activation of the leptin-MC4R pathway may enhance glucose uptake in peripheral tissues via a non-autonomic mechanism.

    Based on our previous studies and compelling preliminary data, our central hypothesis (Figure 1) is that the powerful antidiabetic actions of leptin require activation of MC4R in the paraventricular nucleus of the hypothalamus (PVN) leading to long-term increases in glucose utilization in peripheral tissues while MC4R activation in the brainstem (principally in the dorsal motor nucleus of the vagus (DMV) and nucleus of the tractus solitarius (NTS)) increases PSA to the liver leading to reduced gluconeogenesis and sympathetic activity to peripheral tissues leading to acute enhancement of glucose uptake.

    The specific aims of this proposal are:

    1) MC4R activation in the PVN contributes to the chronic CNS-mediated antidiabetic actions of leptin mainly through stimulation of glucose utilization in peripheral tissues by a mechanism that is independent of the autonomic nervous system.

    2)  MC4R activation in the DMV/NTS contributes to the CNS-mediated antidiabetic actions of leptin mainly by suppressing liver gluconeogenesis and by short-term stimulation of glucose uptake in peripheral tissues via the autonomic nervous system.

    These studies will employ genetically engineered mouse models in which the role of MC4R in specific CNS regions in mediating the antidiabetic actions of leptin will be examined. We will use a novel mouse model with mutated MC4R (loxTB-MC4R-/- mice) where the MC4R is "rescued" specifically in the PVN or brainstem nuclei by specific expression of Cre-recombinase in these areas. Integrative physiological methods using in vivo and in vitro studies in combination with genetic models provide a novel and powerful approach to determining the complex CNS circuits and pathways by which the leptin-MC4R axis regulates peripheral glucose homeostasis.

     


    Summary of research

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    Project I Mentors

     Lohmeier's Faculty Page
    Thomas E. Lohmeier, PhD
    Prof-Physiology & Biophysics
    Email:  tlohmeier@umc.edu 
                      
             Gomez-Sanchez's Faculty Page
    Celso E. Gomez-Sanchez, MD
    Prof-Medicine/Endocrinology