This project is based on evidence that the brain plays an important role in glycemic control. The overarching hypothesis is that in response to either deficient available fuel (glucose) or stored energy (adipose mass), the brain activates neurocircuits to drive increases of feeding and blood glucose to ensure adequate nutrient delivery to the brain. Thus, by analogy to the counter-regulatory response (CRR) to hypoglycemia, the brain recruits and activates multiple, redundant mechanisms in a stepwise manner as depletion of body fat stores progresses following the onset of insulin deficiency and these responses play a key role in the pathogenesis of diabetic hyperglycemia.
In Specific Aim 1, we propose to delineate the a) neuroendocrine responses driving diabetic hyperglycemia, b) time-course over which these responses are recruited, and c) extent to which their reversal explains leptin-mediated glucose lowering.
In Specific Aim 2 we propose to identify neurocircuits that a) promote hyperglycemia by activating neuroendocrine effects and b) underlie leptin-mediated glucose lowering uDM. In support of this, our Preliminary Data, using an optogenetics approach identifies a novel neurocircuit whereby photo-activation of ventromedial hypothalamic (VMN) neurons that project to the bed nucleus of the stria terminalis (aBNST), induces hyperglycemia in otherwise non-diabetic mice. To accomplish these objectives, we will employ optogenetics and DREADDs technologies in combination with surgical, immunohistochemical and state-of-the-art methods for measuring glucose metabolism in established Cre- driven mouse models. Overall, this work has the potential to fundamentally advance our understanding of CNS mechanisms that regulate glucose metabolism and has the potential to facilitate the development of new approaches to diabetes treatment.

Public Health Relevance

The escalating epidemic of diabetes is one of the most pressing and costly medical challenges in our society, yet much about the pathogenesis of this disease is unknown. While most research efforts have focused on defects in insulin secretion and insulin action in peripheral tissues, our proposal investigates the hypothesis that the brain plays a major, previously unsuspected role in hyperglycemia triggered by insulin deficiency. The overarching goal of this proposal is to identify the neuroendocrine mechanisms and associated neurocircuits that drive diabetic hyperglycemia and delineate how these effects occur. This work has the potential to inform our understanding of the brain in diabetes pathogenesis and facilitate novel approaches for its treatment and prevention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK089056-08
Application #
9414024
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2010-07-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
8
Fiscal Year
2018
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
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
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
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
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
Kaiyala, Karl J; Ogimoto, Kayoko; Nelson, Jarrell T et al. (2016) Physiological role for leptin in the control of thermal conductance. Mol Metab 5:892-902
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

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