To achieve normal growth, development, and quality of life, individuals must maintain adequate intake of nutrition and be free from prolonged metabolic derangement. Unfortunately, people affected with either acute or chronic diseases often show disorders of nutrient balance. In some cases, a devastating state of malnutrition known as cachexia arises, brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. This combination is found in a number of disorders including cancer, cystic fibrosis, AIDS, rheumatoid arthritis, and renal failure, and is an important determinant of morbidity and mortality in these conditions. Experimental models have demonstrated the importance of cytokines in mediating illness-induced anorexia and cachexia but the neuronal systems involved in transducing this signal have not beep fully defined. Work in this lab and in others has demonstrated that hypothalamic melanocortin receptors play a critical role in regulating feeding behavior, linear growth, metabolic rate, and insulin sensitivity. Stimulation of the hypothalamic melanocortin-4 receptor (MC4-R) produces relative anorexia, while prolonged antagonism of this receptor stimulates feeding and results in excessive weight gain and growth. More recently, we have been able to demonstrate that in both acute and chronic disease models, blockade of the MC4-R results in a dramatic attenuation of cachexia. Current research goals fall into two general areas as described in this grant. First, we will examine the contribution and unique function of both the melanocortin-4 receptor (MC4-R) as well as as well as the MC3-R in acute and chronic cachexia. Second, the mechanisms by which circulating cytokines and tumor-derived factors activate the hypothalamic melanocortin system will be defined. Additionally, the process of habituation to cytokine-mediated anorexia will be investigated in the context of central melanocortin function. Ultimately, this work may lead to investigation of drug therapy for this widespread medical problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK062207-02
Application #
6644832
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2002-08-15
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$131,760
Indirect Cost
Name
Oregon Health and Science University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
DeBoer, Mark D; Scarlett, Jarrad M; Levasseur, Peter R et al. (2009) Administration of IL-1beta to the 4th ventricle causes anorexia that is blocked by agouti-related peptide and that coincides with activation of tyrosine-hydroxylase neurons in the nucleus of the solitary tract. Peptides 30:210-8
Scarlett, Jarrad M; Zhu, Xinxia; Enriori, Pablo J et al. (2008) Regulation of agouti-related protein messenger ribonucleic acid transcription and peptide secretion by acute and chronic inflammation. Endocrinology 149:4837-45
Deboer, Mark D; Zhu, Xinxia; Levasseur, Peter R et al. (2008) Ghrelin treatment of chronic kidney disease: improvements in lean body mass and cytokine profile. Endocrinology 149:827-35
DeBoer, Mark D; Zhu, Xin Xia; Levasseur, Peter et al. (2007) Ghrelin treatment causes increased food intake and retention of lean body mass in a rat model of cancer cachexia. Endocrinology 148:3004-12
Scarlett, Jarrad M; Jobst, Erin E; Enriori, Pablo J et al. (2007) Regulation of central melanocortin signaling by interleukin-1 beta. Endocrinology 148:4217-25
Cheung, Wai W; Kuo, Huey-Ju; Markison, Stacy et al. (2007) Peripheral administration of the melanocortin-4 receptor antagonist NBI-12i ameliorates uremia-associated cachexia in mice. J Am Soc Nephrol 18:2517-24
Mak, Robert H; Cheung, Wai; Cone, Roger D et al. (2006) Mechanisms of disease: Cytokine and adipokine signaling in uremic cachexia. Nat Clin Pract Nephrol 2:527-34
Mak, R H; Cheung, W; Cone, R D et al. (2006) Leptin and inflammation-associated cachexia in chronic kidney disease. Kidney Int 69:794-7
Cheung, Wai; Yu, Pin X; Little, Brian M et al. (2005) Role of leptin and melanocortin signaling in uremia-associated cachexia. J Clin Invest 115:1659-65
Mak, Robert H; Cheung, Wai; Cone, Roger D et al. (2005) Orexigenic and anorexigenic mechanisms in the control of nutrition in chronic kidney disease. Pediatr Nephrol 20:427-31

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