Obesity in humans remains a significant health problem in the United States. Research with humans and with animal models has established that obesity is multifaceted, involving altered energy expenditure and altered energy intake. Recent work has also shown that genetic background contributes to the development of obesity in humans and illustrates the complexity of this disorder. Despite this complexity, many of the metabolic alterations that are seen in obesity are consistent with altered activity of the sympathetic and parasympathic nervous systems. This proposal focuses on one aspect of this altered activity -- the serotonergic input to the ventromedial nucleus (VMN) of the hypothalamus which has been shown to be reduced in obese Zucker rats. The two major objectives of this proposal are related to the general theme that altered VMN serotonergic activity is an important contributor to the altered regulation of energy balance that occurs in obesity. The first objective of this study is to determine if the altered VMN serotonergic activity of obese rats occurs before increased adiposity, decreased thermogenesis, or hyperinsulinemia. For this, we will examine 2, 4, 7 and 12 day old Zucker/Brown Norway (ZBN) obese (fafa) vs. lean (Fafa) pups. The use of ZBN pups, rather than Zucker pups, allows one to distinguish fafa from Fafa littermates at any age because of the presence of a restriction fragment length polymorphism closely linked to the fa locus. This is a major advantage of the ZBN hybrids because it has not been possible to reliably distinguish fafa from Fafa pups in the Zucker strain before day 7 of age. The ontogeny data from the ZBN pups will indicate if the altered VMN serotonergic activity of fafa rats occurs early in the sequence of events initiated by the mutant fa gene. The second objective of this study is to evaluate three possible mechanisms for the attenuated VMN serotonergic activity in fafa rats: (1) altered reception and/or transduction of signals arriving at the raphe (site of origin of serotonergic projections to the VMN); (2) altered release and/or reuptake of serotonin in the VMN; and (3) altered input to the dorsal raphe. These mechanisms will be evaluated using in vivo (microdialysis) and in vitro (slice) preparations from 12 wk old Zucker fafa vs. FaFa (lean) rats. This study will enhance our understanding of the mechanisms underlying the altered autonomic signaling associated with the abnormal nutrient partitioning characteristic of obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK032907-12S2
Application #
6039705
Study Section
Nutrition Study Section (NTN)
Program Officer
Yanovski, Susan Z
Project Start
1984-04-01
Project End
2001-06-30
Budget Start
1999-04-01
Budget End
2001-06-30
Support Year
12
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California Davis
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Ohliger-Frerking, P; Horwitz, B A; Horowitz, J M (2003) Serotonergic dorsal raphe neurons from obese zucker rats are hyperexcitable. Neuroscience 120:627-34
Ohliger-Frerking, Patricia; Horowitz, John M; Horwitz, Barbara A (2002) Enhanced adrenergic excitation of serotonergic dorsal raphe neurons in genetically obese rats. Neurosci Lett 332:107-10
De Fanti, B A; Hamilton, J S; Horwitz, B A (2001) Meal-induced changes in extracellular 5-HT in medial hypothalamus of lean (Fa/Fa) and obese (fa/fa) Zucker rats. Brain Res 902:164-70
Jekabsons, M B; Horwitz, B A (2001) Nucleotide effects on liver and muscle mitochondrial non-phosphorylating respiration and membrane potential. Biochim Biophys Acta 1503:314-28
De Fanti, B A; Gavel, D A; Hamilton, J S et al. (2000) Extracellular hypothalamic serotonin levels after dorsal raphe nuclei stimulation of lean (Fa/Fa) and obese (fa/fa) Zucker rats. Brain Res 869:14-Jun
Jekabsons, M B; Gregoire, F M; Schonfeld-Warden, N A et al. (1999) T(3) stimulates resting metabolism and UCP-2 and UCP-3 mRNA but not nonphosphorylating mitochondrial respiration in mice. Am J Physiol 277:E380-9
De Fanti, B A; Backus, R C; Hamilton, J S et al. (1998) Lean (Fa/Fa) but not obese (fa/fa) Zucker rats release cholecystokinin at PVN after a gavaged meal. Am J Physiol 275:E1-5
Aylwin, M L; Horowitz, J M; Bonham, A C (1997) NMDA receptors contribute to primary visceral afferent transmission in the nucleus of the solitary tract. J Neurophysiol 77:2539-48
Oberbauer, A M; Stern, J S; Johnson, P R et al. (1997) Body composition of inactivated growth hormone (oMt1a-oGH) transgenic mice: generation of an obese phenotype. Growth Dev Aging 61:169-79
Specter, S E; Stern, J S; Horwitz, B A (1996) Hypothalamic monoaminergic activity in obese Zucker rats in response to acute and chronic dietary stimuli. Am J Physiol 270:E677-88

Showing the most recent 10 out of 30 publications