MPP+ Iodide br Methods and procedures br Results br Discussi
Methods and procedures
Discussion Previous studies have shown that celastrol treatment significantly decreased body weight due to decreases in food consumption . Consistent with these findings, we found that the body weight and food intake were significantly decreased in treatment with celastrol mice compared with the obese control mice. These results suggest that celastrol decreases food intake and body weight. Although it is not clear why the celastrol group showed lower body weight and decreased food intake, our results suggest that inhibition of food intake with celastrol may decrease levels of GAL and GALR1/3 in the hypothalamus. GAL, a 29/30-amino-acid neuropeptide, is undoubtedly involved in the regulation of food intake and body weight . First, fed with a high-fat diet, rats showed an increase in GAL level and proliferation of GAL-producing neurons in the hypothalamus [8,9]. In contrast, a stimulatory effect of GAL, intracerebroventricular (i.c.v.) injected directly into paraventricular nucleus (PVN), significantly enhanced daily caloric intake and weight of fat depots . Besides, MPP+ Iodide GAL overexpressive mice increased the intake of a fat-rich diet by 55% than wild-type mice , while GAL knockout mice decreased the intake of fat-rich diet by 48% than controls . Furthermore, chronic administration of GAL by mini-osmotic pumps into the lateral ventricle of GAL knockout mice partially reversed the fat avoidance phenotype . More interestingly, a wealth of evidence revealed that central GAL-induced increase in food intake and body weight is mainly mediated by GALR1 . These suggest that GAL-GALR1 systems help adapt food intake and metabolism to changes in dietary fat. Of note, celastrol has been reported to cross the brain-blood barrier . Results in this study illustrated that the increased abundance of GAL, GALR1 and GALR3 in the hypothalamus of obese mice were highly down-regulated by celastrol treatment, which might indicate that celastrol could reduce fat intake by inhibition of the GAL-GALR1/3 system and subsequently promote the weight loss in obese mice. Moreover, galanin may interact with other appetite-regulating peptides, such as leptin and NPY, to control the appetite and obesity levels of animals . The low GAL and GAL1 mRNA expression in the LHA of GAL-LepRb KO mice consume less high fat diet . The celastrol-treated mice also displayed a marked reduction in levels of leptin and NPY expression of hypothalamus in this study. Our data corroborate previously reported that celastrol strongly decreases the levels of leptin and NPY expression in the hypothalamus of obese mice . Therefore, low GAL and GAL1/3 expression in the hypothalamus of celastrol-treated mice could sufficiently explain the observed decrease in fat consumption. The present study provides evidence that celastrol suppresses food intake, and leads to weight loss by inhibiting GAL and GALR1/3 expression in the hypothalamus of mice fed a high-fat diet. Additionally, celastrol has been shown to inhibit galanin-like peptide (GALP). GALP was discovered in 1999 in the porcine hypothalamus . GALP is a 60 amino-acid neuropeptide that shares sequence homology with galanin (1−13) in position 9–21 and can bind to and activate the three galanin subtype receptors (GALR1–3) . Considerable evidence now supports that GALP stimulates feeding behavior and body weight as well as influences energy metabolism and homeostasis . Also, we have previously demonstrated that obese individuals have higher plasma GAL and GALP concentrations and both peptide concentrations were positively correlative to TG concentrations in obese human . In agreement with these results, the fasting GAL and GALP levels were significantly elevated in the obese control group compared with the normal controls. It is possible that high fat diet induced secretion of galanin is originated both from nerve endings and soma/dendrites of the central nervous system or peripheral tissues, such as gastrointestinal tract, adipose tissue and sympathetic nerve endings. It is plausible that, in diet-induced obesity, the elevated blood level of GAL and GALP will upregulate the expression of the GALR1 located in the hypothalamus, which may, in turn, stimulate the GAL-mediated signaling pathways in the hypothalamus. We found that celastrol possesses an effect on reducing levels of blood GAL and GALP. These results further indicate that celastrol exerts anti-obese effect by suppressing food intake and body weight via the inhibition of GAL system.