After a period of involuntary overfeeding where calories are provided in excess of caloric expenditure, animals profoundly reduce food intake while body weight and adipes mass increase. Once the overfeeding regimen is terminated, animals continue to have suppressed food intake until body weight decreased to the level of controls. This ability of the body to suppress food intake and fac8litate its own weight loss represents an important regulatory response that is critical for the appropriate regulation of body weight. while we know a great deal about the neurobiological underpinnings of the regulatory responses to underfeeding, almost nothing is known about the endocrine or neuronal changes that mediate the hypohagic response to overfeeding. The hypothesis to be tested in this proposal is that the increase in body adipose mass produced by overfeeding results I high levels of two important negative feedback hormones, insulin and leptin. These two hormones gain access to the central nervous system and act to alter the balance between two opposing hypothalamic neuropeptides. Neuropeptide Y (NPY) increases food intake and decreases energy expenditure while corticotropin releasing hormone (CRH) causes the opposite, decreas4ed food intake and increased energy expenditure. Consequently, increased insulin and leptin are hypothesized to activate the hypothalamic CRH system while inhibiting thehypothalamic NPY system and thereby shift the balance of these two neuropeptides to produce low food intake and weight loss. To test this hypothesis, peripheral levels of insulin and leptin will be determined by radioimmunoassay while gene expression for hypothalmic NPY and CRH will be determined using in situ hybridization and content analysis of microdissected hypothalamic nuclei during and after an involuntary overfeeding regimen. To assess the role of elevated insulin and leptin in the behavioral and hypothalmic changes that occur during overfeeding in normal rats to rats with a genetic mutation that render them insensitive to the central effects of insulin and leptin (the obsess Zucker rat). To assess the role of activation of the CRH system, the effect of CRH receptor antagonists on the hypophagia that follows a period of overfeeding will be determined. Finally, the possibility that some of the same hypothalmic responses that mediate the hypophagia induced by overfeeding might mediate tumor-induced anorexia will be determined by measuring hypothalamic changes in hypophagic tumor-bearing rats. The experiments in this proposal are critical to a complete understanding of body weight regulation and may suggest novel therapeutic strategies for obesity that involve triggering or mimicking the regulatory responses that mediate weight loss after overfeeding. Additionally, if the serious complications of anorexia and body weight loss associates with some tumors and AIDS are produced by inappropriate activation of the regulatory responses to overfeeding, it would suggest therapeutic strategies that block or antagonize these hypothalamic neuropeptide systems.
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| Begg, Denovan P; Steinbrecher, Kris A; Mul, Joram D et al. (2014) Effect of guanylate cyclase-C activity on energy and glucose homeostasis. Diabetes 63:3798-804 |
| Gutierrez-Aguilar, Ruth; Kim, Dong-Hoon; Casimir, Marina et al. (2014) The role of the transcription factor ETV5 in insulin exocytosis. Diabetologia 57:383-91 |
| Mul, Joram D; Begg, Denovan P; Haller, April M et al. (2014) MGAT2 deficiency and vertical sleeve gastrectomy have independent metabolic effects in the mouse. Am J Physiol Endocrinol Metab 307:E1065-72 |
| Mul, Joram D; Begg, Denovan P; Barrera, Jason G et al. (2013) High-fat diet changes the temporal profile of GLP-1 receptor-mediated hypophagia in rats. Am J Physiol Regul Integr Comp Physiol 305:R68-77 |
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| Gutierrez-Aguilar, Ruth; Kim, Dong-Hoon; Woods, Stephen C et al. (2012) Expression of new loci associated with obesity in diet-induced obese rats: from genetics to physiology. Obesity (Silver Spring) 20:306-12 |
| Sandoval, Darleen; Barrera, Jason G; Stefater, Margaret A et al. (2012) The anorectic effect of GLP-1 in rats is nutrient dependent. PLoS One 7:e51870 |
| Kim, Dong-Hoon; Sartor, Maureen A; Bain, James R et al. (2012) Rapid and weight-independent improvement of glucose tolerance induced by a peptide designed to elicit apoptosis in adipose tissue endothelium. Diabetes 61:2299-310 |
| Clegg, Deborah J; Gotoh, Koro; Kemp, Christopher et al. (2011) Consumption of a high-fat diet induces central insulin resistance independent of adiposity. Physiol Behav 103:10-6 |
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