This application proposes investigations of the role of the ovarian hormone estradiol in feeding and bodyweight in female rats. Sexual differentiation in the physiological controls of eating may contribute to the increased vulnerability of women to anorexia nervosa, bulimia nervosa, and some forms of obesity or exacerbate the course of these disorders. Furthermore, disordered meal size is the crucial behavioral change in eating disorders, including the binge eating of obesity, and estradiol potently controls meal size in animals by tonically and phasically increasing the satiating potency of food. Therefore, this application proposes to determine the peripheral and central mechanisms through which estradiol modulates the satiating potencies of gastric and intestinal food stimuli that are known physiological controls of meal size. State-of-the-art behavioral, physiological, and molecular techniques are used. There are eight specific aims: (1) Determine whether estradiol tonically or phasically increases gastric satiation, using rats with inflatable pyloric cuffs. (2) Determine whether estradiol tonically or phasically increases intestinal satiation using duodenal nutrient infusions. (3) Determine whether estradiol receptors in the nucleus tractus solitarius and adjacent caudal brainstem are sufficient for the estrogenic control of feeding by testing the effects of microinjecitons of estradiol directly into the caudal brainstem; (4) Identify brain areas in which increases in neuronal activity, as measured by quantitative c-Fos immunocytochemistry, accompany tonic or phasic estrogenic increases in gastric or intestinal satiation. (5) Determine cellular sites of initiation of the tonic and phasic estrogenic controls of meal size by identifying cellular co-localization of feeding-elicited c-Fos expression and estradiol receptor-alpha expression. (6) Determine the necessity of abdominal vagal and splanchnic afferents in the tonic and phasic estrogenic controls of meal size in rats with selective abdominal afferent denervations. (7) Determine the tonic and phasic effects of estradiol on the neurophysiological responses of single vagal afferent fibers to meal-related food stimuli. (8) Determine the tonic and phasic effects of estradiol on glutamate synaptogenesis in the brainstem by using immunocytochemical detection of synaptic proteins. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054523-13
Application #
7373544
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (02))
Program Officer
Yanovski, Susan Z
Project Start
1994-05-01
Project End
2009-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
13
Fiscal Year
2008
Total Cost
$265,676
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Asarian, Lori; Geary, Nori (2013) Sex differences in the physiology of eating. Am J Physiol Regul Integr Comp Physiol 305:R1215-67
Thammacharoen, Sumpun; Geary, Nori; Lutz, Thomas A et al. (2009) Divergent effects of estradiol and the estrogen receptor-alpha agonist PPT on eating and activation of PVN CRH neurons in ovariectomized rats and mice. Brain Res 1268:88-96
Thammacharoen, Sumpun; Lutz, Thomas A; Geary, Nori et al. (2008) Hindbrain administration of estradiol inhibits feeding and activates estrogen receptor-alpha-expressing cells in the nucleus tractus solitarius of ovariectomized rats. Endocrinology 149:1609-17
Geary, Nori (2007) Curt Richter and the female rat. Appetite 49:376-87
Asarian, Lori; Geary, Nori (2007) Estradiol enhances cholecystokinin-dependent lipid-induced satiation and activates estrogen receptor-alpha-expressing cells in the nucleus tractus solitarius of ovariectomized rats. Endocrinology 148:5656-66
Clegg, Deborah J; Brown, Lynda M; Zigman, Jeffrey M et al. (2007) Estradiol-dependent decrease in the orexigenic potency of ghrelin in female rats. Diabetes 56:1051-8
Asarian, Lori; Geary, Nori (2006) Modulation of appetite by gonadal steroid hormones. Philos Trans R Soc Lond B Biol Sci 361:1251-63
Eisen, S; Phillips, R J; Geary, N et al. (2005) Inhibitory effects on intake of cholecystokinin-8 and cholecystokinin-33 in rats with hepatic proper or common hepatic branch vagal innervation. Am J Physiol Regul Integr Comp Physiol 289:R456-R462
Geary, Nori (2004) Endocrine controls of eating: CCK, leptin, and ghrelin. Physiol Behav 81:719-33
Geary, Nori (2004) On Gerard P. Smith's scientific character and thought. Physiol Behav 82:159-66

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