Cachexia, or disease-associated wasting, is a common occurrence in cancer, renal failure, and infectious disease. This devastating state of malnutrition is brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. The severity of cachexia in many illnesses is the primary determining factor in both quality of life, and in eventual mortality. Other illness induced morbidities including lethargy and loss of reproductive ability also directly compromise the ability of patients to recover from potentially life-saving or extending interventions, including surgery and cytotoxic chemotherapy, and can diminish the motivational drive to aggressively battle the condition. Although cachexia in chronic disease was described more than two thousand years ago, the central mechanisms underlying this disorder of energy homeostasis is poorly understood. Furthermore, there is currently no effective pharmaceutical treatment. The central melanocortin system plays a critical role in regulating feeding behavior, linear growth, metabolic rate, and insulin sensitivity. We have demonstrated that blockade of signaling through the type 4 melanocortin receptor (MC4-R) by genetic and pharmacologic means prevents many of the features of cachexia that would normally occur during acute inflammation in several models of chronic disease. This has led directly to the development of drugs that dampen or block central melanocortin signaling that are currently being tested as therapeutics for cachexia. This proposal is designed to further elucidate the mechanism whereby inflammation leads to excessive activation of central melanocortin signaling. While the primary cytokine signals producing cachexia during illness have been studied in detail, we have limited understanding of the specific hypothalamic cell groups involved in processing these signals. We have shown that cytokines liberated during the disease process activate pro-opiomelanocortin (POMC) neurons by both direct and indirect mechanisms. We have also shown that cytokines affect the function of MCH and orexin neurons, key players in food intake and arousal, respectively. We hypothesize that inflammation alters the function of these neurons and that this in turn will produces various aspects of the illness response including anorexia, decreased movement, elevated basal metabolic rate, lethargy, and alterations in energy partitioning. We further hypothesize that this cellular mechanism represents a final common pathway for the production of cachexia in a variety of chronic disease states, particularly those in which inflammation is known to play an important role.
The severity of cachexia in chronic disease is often the primary determining factor in both quality of life, and in eventual mortality. Attempts at drug therapy for cachexia with a variety of agents have met with limited success. Our data argues strongly that the hypothalamic melanocortin system plays a critical role in the transduction of illness-induced cachexia and therefore represents an important target for future therapeutic intervention.
|Braun, Theodore P; Szumowski, Marek; Levasseur, Peter R et al. (2014) Muscle atrophy in response to cytotoxic chemotherapy is dependent on intact glucocorticoid signaling in skeletal muscle. PLoS One 9:e106489|
|Zuloaga, Kristen L; Krasnow, Stephanie M; Zhu, Xinxia et al. (2014) Mechanism of protection by soluble epoxide hydrolase inhibition in type 2 diabetic stroke. PLoS One 9:e97529|
|O'Rourke, Robert W; Meyer, Kevin A; Neeley, Christopher K et al. (2014) Systemic NK cell ablation attenuates intra-abdominal adipose tissue macrophage infiltration in murine obesity. Obesity (Silver Spring) 22:2109-14|
|Weymann, K B; Wood, L J; Zhu, X et al. (2014) A role for orexin in cytotoxic chemotherapy-induced fatigue. Brain Behav Immun 37:84-94|
|O'Rourke, Robert W; Gaston, Garen D; Meyer, Kevin A et al. (2013) Adipose tissue NK cells manifest an activated phenotype in human obesity. Metabolism 62:1557-61|
|Jouihan, Sari A; Zuloaga, Kristen L; Zhang, Wenri et al. (2013) Role of soluble epoxide hydrolase in exacerbation of stroke by streptozotocin-induced type 1 diabetes mellitus. J Cereb Blood Flow Metab 33:1650-6|
|O'Rourke, Robert W; Meyer, Kevin A; Gaston, Garen et al. (2013) Hexosamine biosynthesis is a possible mechanism underlying hypoxia's effects on lipid metabolism in human adipocytes. PLoS One 8:e71165|
|Braun, Theodore P; Grossberg, Aaron J; Krasnow, Stephanie M et al. (2013) Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle. FASEB J 27:3572-82|
|Braun, Theodore P; Zhu, Xinxia; Szumowski, Marek et al. (2011) Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis. J Exp Med 208:2449-63|
|O'Rourke, R W; White, A E; Metcalf, M D et al. (2011) Hypoxia-induced inflammatory cytokine secretion in human adipose tissue stromovascular cells. Diabetologia 54:1480-90|
Showing the most recent 10 out of 22 publications