Obese (ob/ob) mice and rats with obesity-producing hypothalamic knife-cuts become obese even if pairfed to their respective controls. These animals must therefore expend less energy than normal. Our overall goal is to identify neuroendocrine and cellular factors responsible for the enhanced efficiency of dietary energy retention in these obese animals. Experiments are proposed to determine why adrenalectomy blocks further development of obesity in ob/ob mice fed a high-starch diet, but not in ob/ob mice fed high-glucose or high-fat diets. Effects of these dietary treatments on neural control of insulin secretion by isolated pancreatic islets, on unidirectional uptake of thyroid hormones and corticosterone by liver and brain, on sympathetic nervous system activity in heart and brown adipose tissue as assessed by norepinephrine turnover, on brown adipose tissue thermogenic capacity, and on the involvement of thermoregulatory thermogenesis in energy balance in sham- operated and adrenalectomized ob/ob and lean mice will be ascertained. The hypotheses that the central nervous system is the site of glucorticoid action responsible for development of obesity in ob/ob mice, and that hyperinsulinemia is the critical mediator of glucorticoid-induced obesity in ob/ob mice will be evaluated. Selective comparisons between ob/ob mice and rats with hypothalamic knife-cuts will help identify the key factors that permit high retention of dietary energy in these animals. These data should increase our understanding of the diet- dependent metabolic factors in development of obesity, and should aid in defining improved nutritional approaches to cope with the prevention and control of obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK015847-20
Application #
3483130
Study Section
Nutrition Study Section (NTN)
Project Start
1976-05-01
Project End
1992-07-31
Budget Start
1990-09-01
Budget End
1991-07-31
Support Year
20
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Michigan State University
Department
Type
Other Domestic Higher Education
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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