Peripheral and Central Inflammatory Signals in the sickness Response This application investigates the hypothesis that inflammation-induced negative energy balance is mediated by mechanisms dependent on cytokine signaling pathways within brain tissue. Systemic inflammatory conditions cause marked weight loss yet the necessity of cytokines in 'sickness'remains unclear and the interaction between inflammation and neuronal regulators of energy balance remains unknown.
The Specific Aims seek to determine the role of key inflammatory pathways in mediating the 'sickness response'by determining 1) whether inflammatory signals in brain tissue are necessary and sufficient to mediate the sickness response', and whether inflammatory signaling in neurons and endothelial cells is necessary to cause 'sickness', and 2) whether hypothalamic melanocortin signaling is necessary for 'sickness'to occur. To accomplish these objectives, studies are proposed using a variety of mutant mouse models to evaluate 'sickness'using methods established in the laboratories of the applicant and the Consultants participating in this proposal, including determining energy intake and expenditure, quantifying hypothalamic and circulating cytokines and bone marrow transplantation to alter the genotype of circulating immune cells.
These aims make an important contribution to understanding the mechanism whereby inflammation affects energy balance and may identify potential therapies for disorders ranging from obesity to chronic wasting illnesses.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Nya-Ngatchou, Jean-Jacques; Corl, Dawn; Onstad, Susan et al. (2015) Point-of-care blood glucose measurement errors overestimate hypoglycaemia rates in critically ill patients. Diabetes Metab Res Rev 31:147-54
Thaler, Joshua P; Yi, Chun-Xia; Schur, Ellen A et al. (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122:153-62
Klaff, Lindy S; Gill, Sean E; Wisse, Brent E et al. (2012) Lipopolysaccharide-induced lung injury is independent of serum vitamin D concentration. PLoS One 7:e49076
Kaiyala, Karl J; Morton, Gregory J; Thaler, Joshua P et al. (2012) Acutely decreased thermoregulatory energy expenditure or decreased activity energy expenditure both acutely reduce food intake in mice. PLoS One 7:e41473
German, Jonathan P; Thaler, Joshua P; Wisse, Brent E et al. (2011) Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology 152:394-404
Choi, Sun Ju; Yablonka-Reuveni, Zipora; Kaiyala, Karl J et al. (2011) Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice. Am J Physiol Endocrinol Metab 300:E1031-7
Morton, Gregory J; Kaiyala, Karl J; Fisher, Jonathan D et al. (2011) Identification of a physiological role for leptin in the regulation of ambulatory activity and wheel running in mice. Am J Physiol Endocrinol Metab 300:E392-401
Oh-I, Shinsuke; Thaler, Joshua P; Ogimoto, Kayoko et al. (2010) Central administration of interleukin-4 exacerbates hypothalamic inflammation and weight gain during high-fat feeding. Am J Physiol Endocrinol Metab 299:E47-53
German, Jonathan P; Wisse, Brent E; Thaler, Joshua P et al. (2010) Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes 59:1626-34
Kaiyala, Karl J; Morton, Gregory J; Leroux, Brian G et al. (2010) Identification of body fat mass as a major determinant of metabolic rate in mice. Diabetes 59:1657-66

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