Date

June 2007

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

Disorders in food intake and energy homeostasis, characterized by anorexia and increased metabolic rate, are frequent manifestations in animals with acute and chronic diseases. Proinflammatory cytokines released in response to pathophysiological conditions are hypothesized to mediate these responses by acting upon neural systems in the brain that are involved in the regulation of feeding behavior and energy homeostasis. The central melanocortin system is a well-characterized neural system that has a key role in the regulation of feeding behavior and energy homeostasis. Recently, studies have demonstrated that blockade of central melancortin signaling attenuates cytokine and illness-induced anorexia suggesting that the central melanocortin system might have an important role in mediating the anorectic effects of cytokines. The goal of this thesis was to investigate the ability of individual cytokines to regulate the activity of the central melanocortin system and to characterize the response of the central melanocortin system to acute and chronic inflammatory states. In the first part of this thesis work, we investigated the ability of interleukin-1 ~ (ILl~) to regulate central melanocortin signaling. We demonstrated that proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) co-expressed the type I interleukin-1 receptor (IL-l R) and that intracerebroventrieular (i.c.v.) injection of1L-I~ induced the expression of Fos protein in ARC POMC neurons. IL-l~ increased the frequency of action potentials of ARC POMC neurons. The release of a-melanocyte-stimulating hormone (a-MSH) from hypothalamic explants was increased by IL-l~ in a dose-dependent fashion that was not blocked by inhibitors of prostaglandin synthesis. These data suggest that IL-l p may increase central melanocortin signaling by directly activating ARC POM~ neurons. In the second part of this thesis work, we investigated the regulation of agouti-related protein (AgRP) during acute and chronic disease processes. We demonstrated that AgRP mRNA expression was increased during acute inflammation induced by injection of lipopolysaccharide and during chronic inflammation in rodent models of cancer and renal failure. AgRP neurons were found to co-express IL-lR and i.c.v. IL-lP induced the expression ofFos protein in AgRP neurons. The release of AgRP from hypothalamic explants was decreased by IL-l p in a dose-dependent fashion that was not blocked by inhibitors of prostaglandin synthesis. These data suggest that the secretion of AgRP is decreased in response to proinflammatory signals released during inflammatory states, while simultaneously the biosynthetic capacity of AgRP neurons to produce AgRP is increased. This data suggests that AgRP neurons may participate with ARC POMC neurons in mediating the anorexic and metabolic responses to acute and chronic disease processes. In the final part of this thesis work, we investigated the role of the central melanocortin system in the pathogenesis of cardiac cachexia, a wasting disease that often develops in patients with congestive heart failure (CHF). We demonstrated that genetic and pharmacologic blockade ofthe central melanocortin system attenuated the development of cardiac cachexia in two independent rodent models of CHF. Collectively, the data presented in this thesis support the central melanocortin system as being a key mediator of cytokine signaling and suggest that compounds that block central melancortin signaling may have potential therapeutic use in treating disorders in food intake and energy homeostasis that occur in humans with acute and chronic diseases.

Identifier

doi:10.6083/M44M92K4

Division

Neuroscience Graduate Program

School

School of Medicine

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