Obesity and chronic stress are major and growing societal and medical problems. Chronic stress may result in either decreased food intake and body weight or increased food intake and body weight in man. In rats, chronic stress usually decreases body weight. High glucocorticoids (B) in the presence of increased food intake and insulin increase body weight and abdominal obesity, whereas high glucocorticoids and decreased food intake and insulin decrease body weight. Our overall hypothesis is that stress-induced B levels act in brain in a feed-forward manner to stimulate amygdala corticotropin-releasing factor (CRF), increasing the autonomic, behavioral and neuroendocrine activity characteristic of chronic stress. However, chronic stress is required to recruit activity in this limbic network. In contrast, B acts in the periphery to increase body energy stores, which in turn inhibit the limbic stress response network. We will test 5 parts of this hypothesis: 1. Rats given high B and no stress will become fat and have inhibited responses to acute stress whereas rats given high B and repeatedly restrained will recruit the central stress-response network and become leaner. 2. Restricted feeding in rats given high B will increase stress responsivity in proportion to weight loss. 3. Denervation of the hindbrain catecholaminergic pathways will block the effects of restricted feeding in rats treated with high B. 4. Blockade of CRF receptors or treatment of CRF cell groups with CRF RNAi will block the recruited responses of the stress response network; and, 5. Sucrose, but not saccharin to drink will reduce activity in the recruited central stress response network. Measurements in each aim include: food intake, body weight, hormones, CRF and catecholaminergic mRNA/peptide expression; 2 tests of anxiety-like behavior, oxygen consumption, core temperature and acute temperature and hormonal response to a novel endotoxin stress. Manipulations will include toxin-induced lesions, CRF receptor pharmacology and specific CRF phenotypic knockouts. If it is so that eating 'comfort food' reduces activity of the chronic stress-recruited central stress response network through the combined negative actions of B and insulin on this network, we will provide new insight to those who are chronically stressed and eat 'comfort' food. The information should be useful for therapeutic advice for overweight, stressed people, and possibly provide insights into mechanisms underlying different types of depressive and anxiety disorders ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK028172-23
Application #
6836003
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Malozowski, Saul N
Project Start
1981-07-01
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
23
Fiscal Year
2005
Total Cost
$333,300
Indirect Cost
Name
University of California San Francisco
Department
Physiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Ginsberg, Abigail B; Pecoraro, Norman C; Warne, James P et al. (2010) Rapid alteration of stress-induced hypothalamic-pituitary-adrenal hormone secretion in the rat: a comparison of glucocorticoids and cannabinoids. Stress 13:248-57
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Akana, Susan F (2008) Feeding and stress interact through the serotonin 2C receptor in developing mice. Physiol Behav 94:569-79
Warne, James P; Foster, Michelle T; Horneman, Hart F et al. (2008) The gastroduodenal branch of the common hepatic vagus regulates voluntary lard intake, fat deposition, and plasma metabolites in streptozotocin-diabetic rats. Am J Physiol Endocrinol Metab 294:E190-200
Warne, J P; Horneman, H F; Akana, S F et al. (2008) Insulin and the constituent branches of the hepatic vagus interact to modulate hypothalamic and limbic neuropeptide mRNA expression differentially. J Neuroendocrinol 20:1067-77
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Warne, J P; Horneman, H F; Ginsberg, A B et al. (2007) Mapping brain c-Fos immunoreactivity after insulin-induced voluntary lard intake: insulin- and lard-associated patterns. J Neuroendocrinol 19:794-808

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