The object of this proposal is to investigate two functions of the nervous system in metabolism: A) to regulate body adiposity by controlling food intake and B) to respond to stress by changing glucose metabolism. For (A) we propose to test our hypothesis that insulin is a metabolic satiety signal for the regulation of food intake which indicates the size of adipose tissue stores. In dogs we propose to assess insulin uptake and distribution into, and clearance from CSF and its potential transport through brain interstitial fluid. In baboons we propose to assess the role, mechanism, and site(s) of action for CCK as a gut and neural peptide which suppresses single meal food intake. We also propose to evaluate potential interactions between CCK and the brain insulin satiety signal. The contribution of a change in CNS IGF-II or its receptor to the insulin effect will also be studied. Abnormal operation of the insulin related weight regulation system will be assessed in the Zucker fatty rat (fa/fa) by studies of the regulation of insulin uptake and effectiveness of action, in food restricted and adrenalectomized fa/fa and lean controls (Fa/Fa and Fa/fa). The potential contribution of IGF-II and its receptors to this genetic obesity will also be assessed. For (B) we propose to assess the role of hepatic neural innervation alone and in conjunction with pancreatic innervation and the adrenal in the development of endogenous hyperglycemia in the dog during activation of the sympathoadrenal system by nerve stimulation and stress. Studies will compare the ability of different types and severities of stress to activate all or part of this neural system. The relative importance of sympathetic neuropeptides such as galanin, and the amines such as norepinephrine and epinephrine in the hyperglycemia will also be evaluated. These studies are designed to understand the role of the nervous system in body weight regulation and stress hyperglycemia, two important contributors to hyperglycemia in man.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK012829-25
Application #
3224937
Study Section
Metabolism Study Section (MET)
Project Start
1975-12-01
Project End
1995-11-30
Budget Start
1992-12-01
Budget End
1993-11-30
Support Year
25
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Williams, Diana L; Schwartz, Michael W; Bastian, L Scot et al. (2008) Immunocytochemistry and laser capture microdissection for real-time quantitative PCR identify hindbrain neurons activated by interaction between leptin and cholecystokinin. J Histochem Cytochem 56:285-93
Wisse, Brent E; Ogimoto, Kayoko; Morton, Gregory J et al. (2007) Central interleukin-1 (IL1) signaling is required for pharmacological, but not physiological, effects of leptin on energy balance. Brain Res 1144:101-6
Wisse, Brent E; Kim, Francis; Schwartz, Michael W (2007) Physiology. An integrative view of obesity. Science 318:928-9
Wisse, Brent E; Ogimoto, Kayoko; Tang, Jingjing et al. (2007) Evidence that lipopolysaccharide-induced anorexia depends upon central, rather than peripheral, inflammatory signals. Endocrinology 148:5230-7
Wisse, Brent E; Ogimoto, Kayoko; Schwartz, Michael W (2006) Role of hypothalamic interleukin-1beta (IL-1beta) in regulation of energy homeostasis by melanocortins. Peptides 27:265-73
Pardini, Aaron W; Nguyen, Hong T; Figlewicz, Dianne P et al. (2006) Distribution of insulin receptor substrate-2 in brain areas involved in energy homeostasis. Brain Res 1112:169-78
Mundinger, Thomas O; Cummings, David E; Taborsky Jr, Gerald J (2006) Direct stimulation of ghrelin secretion by sympathetic nerves. Endocrinology 147:2893-901
Gelling, Richard W; Morton, Gregory J; Morrison, Christopher D et al. (2006) Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes. Cell Metab 3:67-73
Trevaskis, James; Walder, Ken; Foletta, Victoria et al. (2005) Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1, a novel neuronal protein that regulates energy balance. Endocrinology 146:3757-64
Porte Jr, Daniel; Baskin, Denis G; Schwartz, Michael W (2005) Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans. Diabetes 54:1264-76

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