Although insulin remains the cornerstone of therapy for type 1 diabetes in humans, recent evidence suggests that induction of hyperleptinemia fully ameliorates hyperglycemia in streptozotocin (STZ)-induced diabetic rats and our recent findings implicate the brain in this effect. Our new Preliminary Data show that this leptin effect involves a novel, insulin-independent mechanism characterized by reduced rates of hepatic glucose production (HGP) and increased rates of tissue glucose uptake and establishes that the brain has the capacity to normalize blood glucose levels in uDM. These observations are distinct from any previously described central nervous system (CNS) leptin action and support the overarching goal of this proposal to delineate the neuronal circuits and peripheral mechanisms activated by leptin that mediate its anti-diabetic effects. Specifically, we hypothesize that leptin inhibition of sympathetic outflow to the liver and pancreas reduces HGP in uDM, and that this effect involves the melanocortin pathway. Moreover, we hypothesize that leptin-induced activation of a subset of thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus (PVN) stimulates glucose uptake, and thereby contributes to the glucose-lowering effects of leptin in uDM. To accomplish these objectives, we will employ sophisticated tracer dilution techniques, in combination with pharmacological, surgical and immunohistochemical approaches and established conditional knockout mouse models using Cre- loxP recombination technology. The data generated in this proposal is therefore expected to identify specific neuronal subsets downstream of leptin action that link communication between the brain and peripheral tissues to control both HGP and glucose uptake. Performance of these studies has the potential to facilitate the development of new approaches to diabetes treatment.

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 action in the brain normalizes diabetic hyperglycemia in a model of uncontrolled, insulin-deficient diabetes (uDM) by increasing glucose uptake and reducing glucose output by the liver. The overarching goal of this proposal is to determine how the brain communicates to peripheral tissues to mediate the anti-diabetic effects of leptin and the data generated is expected to facilitate the development of new approaches for the control of blood sugars.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK089056-05
Application #
8826104
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Meek, Thomas H; Matsen, Miles E; Faber, Chelsea L et al. (2018) In Uncontrolled Diabetes, Hyperglucagonemia and Ketosis Result From Deficient Leptin Action in the Parabrachial Nucleus. Endocrinology 159:1585-1594
Faber, Chelsea L; Matsen, Miles E; Velasco, Kevin R et al. (2018) Distinct Neuronal Projections From the Hypothalamic Ventromedial Nucleus Mediate Glycemic and Behavioral Effects. Diabetes 67:2518-2529
Dorfman, Mauricio D; Krull, Jordan E; Scarlett, Jarrad M et al. (2017) Deletion of Protein Kinase C ? in POMC Neurons Predisposes to Diet-Induced Obesity. Diabetes 66:920-934
Dorfman, Mauricio D; Krull, Jordan E; Douglass, John D et al. (2017) Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice. Nat Commun 8:14556
Deem, Jennifer D; Muta, Kenjiro; Scarlett, Jarrad M et al. (2017) How Should We Think About the Role of the Brain in Glucose Homeostasis and Diabetes? Diabetes 66:1758-1765
Kaiyala, Karl J; Ogimoto, Kayoko; Nelson, Jarrell T et al. (2017) Response to Leptin-deficient mice are not hypothermic, they are anapyrexic. Mol Metab 6:313-314
Morton, Gregory J; Muta, Kenjiro; Kaiyala, Karl J et al. (2017) Evidence That the Sympathetic Nervous System Elicits Rapid, Coordinated, and Reciprocal Adjustments of Insulin Secretion and Insulin Sensitivity During Cold Exposure. Diabetes 66:823-834
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
Scarlett, Jarrad M; Rojas, Jennifer M; Matsen, Miles E et al. (2016) Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents. Nat Med 22:800-6
Meek, Thomas H; Morton, Gregory J (2016) The role of leptin in diabetes: metabolic effects. Diabetologia 59:928-32

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