This project is based upon our recently published evidence that the brain can rapidly, potently and selectively increase insulin-independent glucose lowering (referred to as """"""""glucose effectiveness,"""""""" or GE). The overarching goals are to employ state-of-the-art methods in defined mouse models that allow us to identify neurocircuitry underlying this effect, investigate their physiological relevance, and determine if defects in this CNS control system contribute to reduced GE and glucose intolerance in diet-induced obesity (DIO). We propose two specific aims:
Specific Aim 1. To identify neurons regulating GE and determine their physiological role in glucose homeostasis. We will use Minimal Model analysis of glucose and insulin data from a frequently sampled intravenous glucose tolerance test (FSIGT) to measure insulin secretion, insulin sensitivity and GE. Proposed studies will 1) test a model of discrete neuronal subsets in hypothalamus and hindbrain proposed to mediate the actions of leptin and FGF19 to increase GE, and 2) determine if glucose intolerance results when the function of these neurocircuits is impaired.
Specific Aim 2. To determine if neuronal control of GE is impaired in diet-induced obesity (DIO). Studies will be conducted in mice with DIO to determine 1) if reduced GE and glucose intolerance can be ameliorated by manipulating the activity of specified neurons that comprise the neurociruitry controlling GE, and 2) whether these neurons are targets of obesity-associated gliosis and neuron injury. By expanding our understanding of the role of the brain in the control of GE in normal and obese mice, these studies will shed new light on the pathogenesis of glucose intolerance and diabetes and inform future approaches to the treatment of these disorders.

Public Health Relevance

The escalating epidemic of obesity and type 2 diabetes represents one of the most pressing and costly biomedical challenges confronting modern society, yet much about the pathogenesis of these disorders remains unknown. This proposal is based upon evidence of a previously unrecognized role for the brain in glucose homeostasis involving regulatory mechanisms that overlap with and complement those of properly functioning pancreatic islets. By delineating these central mechanisms, our studies will lay the groundwork for future therapies that may be needed if we are to more effectively confront the diabetes epidemic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK083042-19A1
Application #
8756761
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
1994-09-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
19
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Bentsen, Marie Aare; Mirzadeh, Zaman; Schwartz, Michael W (2018) Revisiting How the Brain Senses Glucose-And Why. Cell Metab :
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
Campos, Carlos A; Bowen, Anna J; Han, Sung et al. (2017) Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus. Nat Neurosci 20:934-942
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
Schwartz, Michael W; Seeley, Randy J; Zeltser, Lori M et al. (2017) Obesity Pathogenesis: An Endocrine Society Scientific Statement. Endocr Rev 38:267-296
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
Blevins, James E; Thompson, Benjamin W; Anekonda, Vishwanath T et al. (2016) Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization. Am J Physiol Regul Integr Comp Physiol 310:R640-58
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

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