Visfatin Induces Sickness Responses in the Brain

BACKGROUND/OBJECTIVE: 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. METHODOLOGY: 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. PRINCIPAL FINDINGS: 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. CONCLUSIONS: Visfatin induced sickness responses via regulation of COX and the melanocortin pathway in the brain

Characteristics of pediatric rhabdomyolysis and the associated risk factors for acute kidney injury: a retrospective multicenter study in Korea

Background The clinical features of pediatric rhabdomyolysis differ from those of the adults with rhabdomyolysis; however, multicenter studies are lacking. This study aimed to investigate the characteristics of pediatric rhabdomyolysis and reveal the risk factors for acute kidney injury (AKI) in such cases. Methods This retrospective study analyzed the medical records of children and adolescents diagnosed with rhabdomyolysis at 23 hospitals in South Korea between January 2007 and December 2016. Results Among 880 patients, those aged 3 to 5 years old composed the largest subgroup (19.4%), and all age subgroups were predominantly male. The incidence of AKI was 11.3%. Neurological disorders (53.6%) and infection (39.0%) were the most common underlying disorder and cause of rhabdomyolysis, respectively. The median age at diagnosis in the AKI subgroup was older than that in the non-AKI subgroup (12.2 years vs. 8.0 years). There were no significant differences in body mass index, myalgia, dark-colored urine, or the number of causal factors between the two AKI-status subgroups. The multivariate logistic regression model indicated that the following factors were independently associated with AKI: multiorgan failure, presence of an underlying disorder, strong positive urine occult blood, increased aspartate aminotransferase and uric acid levels, and reduced calcium levels. Conclusions Our study revealed characteristic clinical and laboratory features of rhabdomyolysis in a Korean pediatric population and highlighted the risk factors for AKI in these cases. Our findings will contribute to a greater understanding of pediatric rhabdomyolysis and may enable early intervention against rhabdomyolysis-induced AKI

Effects of melanocortin receptors 3/4 antagonist on visfatin-induced sickness behaviors.

<p>Two-month-old male rats were ICV-injected with visfatin or vehicle 30 min after ICV injection of SHU9119 and were allowed access to food immediately after the final treatment. (A) Change in food intake was measured 24 h after the injections of SHU9119 and visfatin. (B, C) Changes in locomotor activity (B) and body temperature (C) were monitored in rats IP-implanted with telemetry-transmitters. In C, time 0 indicates visfatin injection. Data are represented as mean ± SEM (n = 6). **P<0.01 and ***P<0.001 vs. control rats injected with 0.9% saline solution; ^##P<0.01 vs. visfatin-injected rats.</p

Effects of visfatin on locomotor activity and body temperature.

<p>Locomotor activity and body temperature were measured for 24 h after ICV administration of visfatin. (A) ICV injection of visfatin resulted in decreased locomotor activity during the dark period, but there was no change in activity during the light period. (B) Body temperature began to increase 2 h after ICV injection of visfatin and remained high until about 20 h after injection. Mean temperature after the injection time (at 0 h) was significantly different between groups. Data are represented as mean ± SEM (n = 10). ***P<0.001 vs. control rats injected with 0.9% saline solution.</p

Effect of ICV administration of visfatin on α-MSH synthesis in the ARC.

<p>To determine the effect of visfatin on α-MSH synthesis, visfatin was ICV-injected into the lateral ventricles of rats deprived of food for one day. Ninety minutes after the injection, the rats were sacrificed and their brains were fixed via transcardiac perfusion for IHC or were sliced for excising the ARC using a micropunch. Expressions of α-MSH (A) and POMC (B) were determined through IHC and real-time PCR, respectively. To determine the effects of prostaglandins on visfatin-induced changes in POMC expression, indomethacin (Indo) was IP-injected 30 min prior to injection of visfatin, and its effect was determined using real-time PCR (C). 3V = third ventricle. Data (in B and C) are represented as mean ± SEM (n = 6). *P<0.05 and **P<0.01 vs. control rats injected with 0.9% saline solution; ^###P<0.001 vs. fasting. Scale bar  = 50 µm.</p

Effect of COX inhibitor on visfatin-induced sickness behaviors.

<p>To determine the involvement of prostaglandins on visfatin-induced sickness behaviors, rats were IP-injected with indomethacin (Indo) 30 min prior to injection with visfatin. Parameters such as body temperature, locomotor activity and food intake were observed for one day after injection of visfatin. Indomethacin completely blocked the visfatin-induced increase in body temperature (A) and partially attenuated the effects of visfatin on locomotor activity (B) and body weight (C). However, indomethacin did not affect the visfatin-induced decrease in food intake (D). Data are represented as mean ± SEM (n = 6). **P<0.01 and ***P<0.001 vs. control rats injected with 0.9% saline solution; ^#P<0.05 and ^###P<0.001 vs. visfatin-injected rats.</p

Visfatin-induced increases in hypothalamic mRNA levels of pro-inflammatory cytokines and prostaglandin-synthesizing enzymes.

<p>RNA was extracted from rat hypothalami 6 h after ICV injection of visfatin. mRNA expressions encoding TNF-α, IL-1β, COX2 and mPGES-1 were determined using real-time PCR. Visfatin significantly stimulated the expressions of TNF-α (A), IL-1β (B), COX2 (C) and mPGES-1 (D) mRNA in the hypothalamus. Data are represented as mean ± SEM (n = 6). **P<0.01 and ***P<0.001 vs. control rats injected with 0.9% saline solution.</p