The incidence and prevalence of diabetes is increasing globally. This is a major health concern given that diabetes is associated with a higher risk of cardiovascular disease and both macro- and micro-vascular disease including blindness, amputation and renal disease. In addition to its role in energy homeostasis, the adiposity hormone, leptin, is strongly implicated in the control of glucose metabolism during uncontrolled insulin-deficient diabetes (uDM). In support of this, systemic administration of pharmacological doses of leptin normalizes blood glucose levels in a rodent model of uDM. Our data implicate the brain in this effect as infusion of leptin directly into the brain completely normalizes blood glucose levels in a rodent model of uDM independent of its effects to reduce food intake. Moreover, this effect involves a novel, insulin-independent mechanism characterized by reduced rates of hepatic glucose production (HGP) and increased rates of tissue glucose uptake. The primary goal of this proposal is to delineate the distinct hypothalamic neuronal subsets which mediate the specific actions of leptin to lower HGP and those that increase glucose uptake. Based on our Preliminary Data showing that leptin administration selectively to the VMN attenuates diabetic hyperglycemia in uDM and that this effect is accompanied by normalization of increased hepatic glucogenic gene expression, we hypothesize that the VMN mediates leptin-induced suppression of HGP. Moreover, we hypothesize that leptin-mediated suppression of HGP is mediated by hypothalamic brain-derived neurotrophic factor (BDNF) neurons. This hypothesis is supported by our Preliminary Data demonstrating that administration of BDNF directly into the brain lowers blood glucose levels in uDM via a potent suppression of HGP, without effects on tissue glucose uptake. To accomplish these objectives, we will employ advanced gene-therapy based approaches in combination with pharmacological, immunohistochemical and surgical approaches along with sophisticated tracer dilution techniques. Furthermore, we will utilize these approaches in combination with established conditional knockout mouse models using Cre-loxP recombination technology. Together, these studies will expand our understanding of the distinct hypothalamic neuronal subsets which mediate the specific actions of leptin to lower HGP or increase glucose uptake. Performance of these studies is thereby hoped to inform the development of more effective diabetes treatment strategies.

Public Health Relevance

While treatment of hyperglycemia in type 1 diabetes is generally held to require exogenous insulin, recent evidence suggests that pharmacological doses of leptin can also induce this effect. Our recent findings implicate the brain in this effect and demonstrate that leptin administration directly in the brain normalizes diabetic hyperglycemia in a rodent model of type 1 diabetes by reducing glucose output by the liver and increasing glucose uptake in peripheral tissues. The overarching goal of this proposal is to delineate the distinct hypothalamic neuronal subsets which mediate the specific actions of leptin to lower hepatic glucose production and those that increase glucose uptake.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1-GRB-R (J1))
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Castle, Arthur
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Meek, Thomas H; Morton, Gregory J (2016) The role of leptin in diabetes: metabolic effects. Diabetologia 59:928-32
Meek, Thomas H; Nelson, Jarrell T; Matsen, Miles E et al. (2016) Functional identification of a neurocircuit regulating blood glucose. Proc Natl Acad Sci U S A 113:E2073-82
Bernier-Latmani, Jeremiah; Cisarovsky, Christophe; Demir, Cansaran Saygili et al. (2015) DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport. J Clin Invest 125:4572-86
Meek, Thomas H; Dorfman, Mauricio D; Matsen, Miles E et al. (2015) Evidence That in Uncontrolled Diabetes, Hyperglucagonemia Is Required for Ketosis but Not for Increased Hepatic Glucose Production or Hyperglycemia. Diabetes 64:2376-87
Morton, Gregory J; Meek, Thomas H; Matsen, Miles E et al. (2015) Evidence against hypothalamic-pituitary-adrenal axis suppression in the antidiabetic action of leptin. J Clin Invest 125:4587-91
Berkseth, Kathryn E; Guyenet, Stephan J; Melhorn, Susan J et al. (2014) Hypothalamic gliosis associated with high-fat diet feeding is reversible in mice: a combined immunohistochemical and magnetic resonance imaging study. Endocrinology 155:2858-67
Meek, Thomas H; Matsen, Miles E; Damian, Vincent et al. (2014) Role of melanocortin signaling in neuroendocrine and metabolic actions of leptin in male rats with uncontrolled diabetes. Endocrinology 155:4157-67
Morton, Gregory J; Meek, Thomas H; Schwartz, Michael W (2014) Neurobiology of food intake in health and disease. Nat Rev Neurosci 15:367-78
Meek, Thomas H; Wisse, Brent E; Thaler, Joshua P et al. (2013) BDNF action in the brain attenuates diabetic hyperglycemia via insulin-independent inhibition of hepatic glucose production. Diabetes 62:1512-8
Morton, Gregory J; Matsen, Miles E; Bracy, Deanna P et al. (2013) FGF19 action in the brain induces insulin-independent glucose lowering. J Clin Invest 123:4799-808

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