The overall goal of this research is to characterize neuroendocrine and cellular factors responsible for the enhanced efficiency of dietary energy retention in obesity-prone animals. The genetically obese (ob/ob) mouse will be used in most of the proposed studies. This animal has a mutation in the ob gene that leads to production of a truncated and presumably nonfunctional ob protein in adipose tissue. Wild-type ob protein is secreted from adipose tissue to regulate food intake and energy balance. One hypothesis to be tested is that mutation of the ob gene in ob/ob mice leads to altered regulation in the central nervous system of the neuropeptide Y and corticotropin releasing hormone systems, and that these alterations also depend on the presence of glucocorticoids or selected dietary factors including dietary glucose or fat. Studies are proposed to determine how intracerebroventricular injection of dexamethasone and/or wild-type ob protein into adrenalectomized ob/ob mice fed various diets affects neuropeptide V and corticotropin releasing hormone secretion in selected hypothalamic sites. In parallel studies hypothalamic blocks from adrenalectomized ob/ob mice will be treated in vitro with dexamethasone and/or ob protein. Neuropeptide Y and corticotropin releasing hormone secretion will be measured. Another hypothesis to be tested is that the ob gene mutation causes an early developmental imprint in pancreatic islets that leads to a persistent defect in regulation of insulin secretion distal to glucose-induced insulin secretion per se. Pancreatic islets from 2 wk old ob/ob and lean mice will be cultured to characterize the metabolic basis for this defect. Islets from neonatal ob/ob and +/+ mice will be examined to see if an imprint is expressed between birth and 2 wk of age in ob/ob mice. These data should increase our understanding of the diet and neurohormonal-dependent metabolic factors that interact with ob protein in regulation of body fatness, and should aid in defining improved nutritional approaches to the prevention and control of obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK015847-28
Application #
2900117
Study Section
Nutrition Study Section (NTN)
Program Officer
Yanovski, Susan Z
Project Start
1976-05-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2001-03-31
Support Year
28
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Michigan State University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Mistry, Anahita M; Swick, Andrew G; Romsos, Dale R (2004) Leptin acts peripherally to limit meal-induced increases in plasma insulin concentrations in mice: a brief communication. Exp Biol Med (Maywood) 229:1033-7
Lee, Joo-Won; Swick, Andrew G; Romsos, Dale R (2003) Leptin constrains phospholipase C-protein kinase C-induced insulin secretion via a phosphatidylinositol 3-kinase-dependent pathway. Exp Biol Med (Maywood) 228:175-82
Lee, Joo-Won; Romsos, Dale R (2003) Leptin administration normalizes insulin secretion from islets of Lep(ob)/Lep(ob) mice by food intake-dependent and -independent mechanisms. Exp Biol Med (Maywood) 228:183-7
Mistry, Anahita M; Romsos, Dale R (2002) Intracerebroventricular leptin administration reduces food intake in pregnant and lactating mice. Exp Biol Med (Maywood) 227:616-9
Lee, J W; Romsos, D R (2001) Leptin-deficient mice commence hypersecreting insulin in response to acetylcholine between 1 and 2 weeks of age. Exp Biol Med (Maywood) 226:906-11
Jang, M; Mistry, A; Swick, A G et al. (2000) Leptin rapidly inhibits hypothalamic neuropeptide Y secretion and stimulates corticotropin-releasing hormone secretion in adrenalectomized mice. J Nutr 130:2813-20
Mistry, A M; Swick, A; Romsos, D R (1999) Leptin alters metabolic rates before acquisition of its anorectic effect in developing neonatal mice. Am J Physiol 277:R742-7
Jang, M; Romsos, D R (1998) Neuropeptide Y and corticotropin-releasing hormone concentrations within specific hypothalamic regions of lean but not ob/ob mice respond to food-deprivation and refeeding. J Nutr 128:2520-5
Mistry, A M; Swick, A G; Romsos, D R (1997) Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice. J Nutr 127:2065-72
Chen, N G; Swick, A G; Romsos, D R (1997) Leptin constrains acetylcholine-induced insulin secretion from pancreatic islets of ob/ob mice. J Clin Invest 100:1174-9

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