This proposal examines the effects of diet-induced obesity (DIO) and non-insulin dependent diabetes mellitus (NIDDM) on the ATP-sensitive K+ (K-ATP) channel located on neurons in the arcuate nucleus (ARC) which integrate metabolic signals concerning energy balance. The overall objective is to investigate the mechanisms by which arcuate glucosensing neurons sense and respond to changes in glucose homeostasis. To achieve this objective the following two hypotheses will be tested using a rodent model of DIO and NIDDM. HYPOTHESIS I is that the K-ATP channel regulates the generation of action potentials on ARC neurons by responding to changes in intracellular ATP. This hypothesis derives from our knowledge of the pancreatic beta-cell in which ATP is a critical regulator of K-ATP channel activity and insulin secretion. HYPOTHESIS II is that central and peripheral signals which regulate energy homeostasis will also regulate the ARC K-ATP channel via their effects on phosphorylation. These hypotheses will be tested using whole cell and single channel patch clamp recordings of ARC K-ATP channel currents in isolated cells as well as intact brain slices. These studies will provide new insights into the way in which the brain controls and is controlled by changes in glucose metabolism in obesity and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055619-04
Application #
6626977
Study Section
Metabolism Study Section (MET)
Program Officer
Sato, Sheryl M
Project Start
2000-02-01
Project End
2004-11-30
Budget Start
2003-01-01
Budget End
2003-11-30
Support Year
4
Fiscal Year
2003
Total Cost
$211,208
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pharmacology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
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Fioramonti, Xavier; Marsollier, Nicolas; Song, Zhentao et al. (2010) Ventromedial hypothalamic nitric oxide production is necessary for hypoglycemia detection and counterregulation. Diabetes 59:519-28
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Murphy, Beth Ann; Fakira, Kurt A; Song, Zhentao et al. (2009) AMP-activated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose-inhibited neurons. Am J Physiol Cell Physiol 297:C750-8
Murphy, Beth Ann; Fioramonti, Xavier; Jochnowitz, Nina et al. (2009) Fasting enhances the response of arcuate neuropeptide Y-glucose-inhibited neurons to decreased extracellular glucose. Am J Physiol Cell Physiol 296:C746-56
Cotero, Victoria E; Routh, Vanessa H (2009) Insulin blunts the response of glucose-excited neurons in the ventrolateral-ventromedial hypothalamic nucleus to decreased glucose. Am J Physiol Endocrinol Metab 296:E1101-9

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