shu-9119 and Inflammation

Visfatin, also known as nicotiamide phosphoribosyltransferase or pre-B cell colony enhancing factor, is a pro-inflammatory cytokine whose serum level is increased in sepsis and cancer as well as in obesity. Here we report a pro-inflammatory role of visfatin in the brain, to mediate sickness responses including anorexia, hyperthermia and hypoactivity.. Rats were intracerebroventricularly (ICV) injected with visfatin, and changes in food intake, body weight, body temperature and locomotor activity were monitored. Real-time PCR was applied to determine the expressions of pro-inflammatory cytokines, proopiomelanocortin (POMC) and prostaglandin-synthesizing enzymes in their brain. To determine the roles of cyclooxygenase (COX) and melanocortin in the visfatin action, rats were ICV-injected with visfatin with or without SHU9119, a melanocortin receptor antagonist, or indomethacin, a COX inhibitor, and their sickness behaviors were evaluated.. Administration of visfatin decreased food intake, body weight and locomotor activity and increased body temperature. Visfatin evoked significant increases in the levels of pro-inflammatory cytokines, prostaglandin-synthesizing enzymes and POMC, an anorexigenic neuropeptide. Indomethacin attenuated the effects of visfatin on hyperthermia and hypoactivity, but not anorexia. Further, SHU9119 blocked visfatin-induced anorexia but did not affect hyperthermia or hypoactivity.. Visfatin induced sickness responses via regulation of COX and the melanocortin pathway in the brain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Temperature; Body Weight; Brain; Cytokines; Eating; Indomethacin; Inflammation; Melanocortins; Melanocyte-Stimulating Hormones; Motor Activity; Nicotinamide Phosphoribosyltransferase; Prostaglandin-Endoperoxide Synthases; Rats

In response to illness, animals subvert normal homeostasis and divert their energy utilization to fight infection. An important and unexplored feature of this response is the suppression of physical activity and foraging behavior in the setting of negative energy balance. Inflammatory signaling in the hypothalamus mediates the febrile and anorectic responses to disease, but the mechanism by which locomotor activity (LMA) is suppressed has not been described. Lateral hypothalamic orexin (Ox) neurons link energy status with LMA, and deficiencies in Ox signaling lead to hypoactivity and hypophagia. In the present work, we examine the effect of endotoxin-induced inflammation on Ox neuron biology and LMA in rats. Our results demonstrate a vital role for diminished Ox signaling in mediating inflammation-induced lethargy. This work defines a specific population of inflammation-sensitive, arousal-associated Ox neurons and identifies a proximal neural target for inflammatory signaling to Ox neurons, while eliminating several others.

Topics: Analysis of Variance; Animals; Dark Adaptation; Disease Models, Animal; Drug Administration Routes; Enzyme-Linked Immunosorbent Assay; Food Deprivation; Gene Expression Regulation; Green Fluorescent Proteins; I-kappa B Proteins; Inflammation; Injections, Intraventricular; Interleukin-1beta; Interleukin-6; Intracellular Signaling Peptides and Proteins; Lateral Ventricles; Lethargy; Male; Melanocyte-Stimulating Hormones; Mice; Mice, Transgenic; Motor Activity; Neoplasm Transplantation; Neurons; Neuropeptides; Neurotensin; NF-KappaB Inhibitor alpha; Orexins; Photoperiod; Polysaccharides; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Receptors, Corticotropin; Receptors, Interleukin-11; Receptors, OSM-LIF; RNA, Messenger