AIDS is a multifaceted disease characterized by severe immunodeficiency and body wasting (cachexia). Anorexia, comprising either absolute decreases in food intake or inadequate intake relative to energy expenditure, is widely recognized to be a major risk factor in AIDS wasting. We will test the hypothesis that corticotropin-releasing hormone (CRH), a potent inhibitor of feeding, is a significant mediator of the anorexia and hormonal changes contributing to wasting syndromes. CRH could be elevated by several different mechanisms in AIDS, including elevated cytokine expression stimulated by HIV or secondary infection, and loss of glucocorticoid inhibition due to primary adrenal insufficiency. We postulate that protein malnutrition can also result in CRH dysregulation. Elevated plasma cortisol, documented in some AIDS patients, is also suggestive of increased CRH drive and may itself contribute to wasting. We will control adrenal hormone levels in rodent models of wasting (nutrient deprivation or intracerebroventricular IL- 1beta infusion) to evaluate the potential role of malnutrition- or cytokine-induced CRH production in AIDS-related cachexia. We will test the possibility that nutritional supplementation or appetite stimulants ameliorate cachexia at least in part via changes in CRH. We will further assess the CRH dependence of these effects by comparing hypothalamic- pituitary-adrenal (HPA) and feeding activity in normal and CRH-deficient (-/-, knock-out) mice during nutrient restriction or icv IL-1 infusion. This work will elucidate endocrine signals potentially involved in wasting in AIDS and the conditions under which alimentation may be successful in attenuating cachexia.
