Central Pharmacological Targets

Under normal circumstances, body weight is regulated with remarkable precision. Indeed, body mass and fat mass are regulated to within 0.5 to 1% per year under basal conditions, even in the face of disturbances in energy balance brought about by changes in food intake or exercise. The mechanism whereby this fidelity is maintained has been the subject of an intense research effort over the last decade. The investigation into the mechanisms of peripheral feedback control of food intake and body mass intensified dramatically with the discovery of the peptide hormone leptin. Leptin is secreted by adipocytes and regulates adiposity and metabolic rate by reducing food intake and increasing energy expenditure.1-4 Remarkably, leptin is a member of the IL-6 (interleukin-6) superfamily of proteins and has many biochemical features of a cytokine molecule.1, 5 Experimental elevation of leptin within the physiological range produces weight loss and hypophagia, while decreased leptin levels lead to the complex neuroendocrine response that occurs during starvation.6, 7 Leptin secretion is increased by both central and systemic immunological challenge and has therefore been proposed as a potential mediator of inflammation-induced anorexia.8-11 Thus, the data regarding the mechanisms whereby leptin regulates body weight may provide us with important clues for understanding body weight regulation during chronic illness. For example, in addition to peripheral mechanisms, we now understand that the responsibility for maintaining energy homeostasis is shared by several regions of the brain, including the brainstem, hypothalamus, limbic structures, and the cortex (for recent reviews, see References 12 and 13. Indeed, leptin is thought to exert its effects on feeding and metabolism primarily via regulation of hypothalamic neurons.14-19 The majority of research has focused on understanding feeding regulatory centers in the hypothalamus and brainstem, and we now have a basic understanding of the neuroanatomical organization of these regions. This chapter will first discuss the central anatomy involved in the regulation of energy homeostasis and then highlight what is known about the role of the various neuronal systems in the development of cachexia. Because research in this area remains in its infancy, much of this discussion will, by necessity, be speculative, particularly as it relates to human disease. Nonetheless, research in this field has already provided exciting possibilities for the pharmacotherapy of cachexia and an understanding of the central control of body weight and muscle mass will continue to be essential for medical professionals working to combat this devastating disorder of nutrient balance.