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.

National Institute of Health (NIH)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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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
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
Campos, Carlos A; Bowen, Anna J; Schwartz, Michael W et al. (2016) Parabrachial CGRP Neurons Control Meal Termination. Cell Metab 23:811-20
Lee, Woo Je; Tateya, Sanshiro; Cheng, Andrew M et al. (2015) M2 Macrophage Polarization Mediates Anti-inflammatory Effects of Endothelial Nitric Oxide Signaling. Diabetes 64:2836-46
O-Sullivan, InSug; Zhang, Wenwei; Wasserman, David H et al. (2015) FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization. Nat Commun 6:7079
Schwartz, Michael W (2015) Can the history of modern endocrinology shape the future of obesity? Mol Endocrinol 29:155-7
Blevins, James E; Graham, James L; Morton, Gregory J et al. (2015) Chronic oxytocin administration inhibits food intake, increases energy expenditure, and produces weight loss in fructose-fed obese rhesus monkeys. Am J Physiol Regul Integr Comp Physiol 308:R431-8
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
Schur, Ellen A; Melhorn, Susan J; Oh, Seok-Kyun et al. (2015) Radiologic evidence that hypothalamic gliosis is associated with obesity and insulin resistance in humans. Obesity (Silver Spring) 23:2142-8

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