Neuroendocrine Control of Energy Balance and Insulin Sensitivity In response to input from hormones such as insulin and leptin, which circulate in proportion to body fat mass, hypothalamic neuronal systems adjust feeding behavior and autonomic outflow in ways that promote homeostasis of both energy stores and fuel metabolism. Recent work from our program and elsewhere has established the hypothalamic arcuate nucleus (ARC) as a key brain area involved in both processes and identified neuronal signal transduction via the insulin receptor substrate - phosphatidylinositol-3-OH kinase (IRS-PI3K) pathway as a pivotal mediator of the actions of both insulin and leptin in this brain area. A key, unanswered question is whether signaling downstream of PI3K involving mammalian target of rapamycin (mTOR), atypical protein kinase C (aPKC) isoforms, or both pathways mediate the effects of adiposity- related hormones on energy balance and glucose metabolism;and whether signaling via these pathways is disrupted in common forms of obesity. The overarching aims of this proposal are therefore 1) to clarify the role of the ARC in comparison to other leptin-sensitive brain areas as a mediator of leptin action in the control of glucose homeostasis;2) to determine the roles played in the ARC by mTOR and aPKCs as mediators of neuronal signal transduction downstream of PI3K in the action of leptin on glucose metabolism;and 3) to determine whether dysfunction within either or both of these signal transduction pathways contribute to the effect of diet-induced obesity (DIO) on glucose metabolism. To accomplish these goals, we will employ state-of-the-art histochemical, biochemical, physiological and gene therapy techniques in both normal rats and in genetically obese, insulin-resistant Koletsky (fak/fak) rats that lack all leptin receptor to investigate whether disorders of this control system cause both weight gain and insulin resistance, cardinal features that link obesity with type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052989-14
Application #
8021861
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Yanovski, Susan Z
Project Start
1997-09-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
14
Fiscal Year
2011
Total Cost
$307,167
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
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
van Praag, Henriette; Fleshner, Monika; Schwartz, Michael W et al. (2014) Exercise, energy intake, glucose homeostasis, and the brain. J Neurosci 34:15139-49
Morton, Gregory J; Kaiyala, Karl J; Foster-Schubert, Karen E et al. (2014) Carbohydrate feeding dissociates the postprandial FGF19 response from circulating bile acid levels in humans. J Clin Endocrinol Metab 99:E241-5
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Morton, Gregory J; Meek, Thomas H; Schwartz, Michael W (2014) Neurobiology of food intake in health and disease. Nat Rev Neurosci 15:367-78
Guyenet, Stephan J; Nguyen, Hong T; Hwang, Bang H et al. (2013) High-fat diet feeding causes rapid, non-apoptotic cleavage of caspase-3 in astrocytes. Brain Res 1512:97-105
Lu, Min; Sarruf, David A; Li, Pingping et al. (2013) Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues. J Biol Chem 288:10722-35
Lee, Donghoon; Thaler, Joshua P; Berkseth, Kathryn E et al. (2013) Longer T(2) relaxation time is a marker of hypothalamic gliosis in mice with diet-induced obesity. Am J Physiol Endocrinol Metab 304:E1245-50
Schwartz, Michael W; Baskin, Denis G (2013) Leptin and the brain: then and now. J Clin Invest 123:2344-5
Berkseth, Kathryn E; Schur, Ellen; Schwartz, Michael W (2013) A role for natriuretic peptides in the central control of energy balance? Diabetes 62:1379-81

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