The classic glucostatic hypothesis suggests that energy metabolism is regulated in part by glucose-sensitive cells in or near the ventromedial hypothalamus (VMH), impairments in which can cause obesity. The proposed studies are based on the hypothesis that some hypothalamic cells sense glucose through a mechanism similar to the mechanism in pancreatic beta cells. Glucose induces c-fos and jun-b mRNAs, as well as electrical activity, in the VMH. VMH cells appear to express pancreas-specific glucokinase (pGK), implicated as an important component of the glucose sensing mechanism in pancreatic beta cells. The proposed studies will examine how closely VMH mechanisms parallel pancreatic mechanisms, and if these mechanisms are impaired in genetic obesity. Are VMH responses to glucose mediated by glucose metabolism? VMH in brain slices in vitro will be exposed to glucose or metabolites for 30 minutes, and induction of jun- b and c-fos mRNAs, as well as electrical activity, will be assessed. Are pancreatic glucokinase or other metabolic enzymes involved in glucose sensing by hypothalamic cells? Pancreatic glucokinase activity in hypothalamus will be increased by gene transfer using an adeno-associated virus (AAV) expressing pGK. Conversely, glucokinase expression will be attenuated by anti-sense nucleotides. Rats will be monitored chronically for changes in metabolism and adiposity, after which molecular and electrical responses to glucose will be assessed. Effects of fasting on pyruvate dehydrogenase El alpha and pyruvate carboxylase (and other genes) will be assessed. Is glucose-regulated gene expression in VMH impaired in genetic obesity? Responses of VMH to glucose in fa/fa genetically obese rats will be assessed as in the previous studies. In addition, pGK expression in VMH of fa-fa rats will be increased by gene transfer, and subsequent gene expression and metabolism (including body weight) will be assessed. These studies should clarify mechanisms relevant to the metabolic derangements of obesity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Metabolism Study Section (MET)
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Smith, Philip F
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Mount Sinai School of Medicine
Other Basic Sciences
Schools of Medicine
New York
United States
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