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 ? ?
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