Spexin is a novel neuropeptide discovered by bioinformatics and has been proposed as a regulator of energy balance. However, its precise role and underlying mechanisms remain unclear. In this study, we investigated the role of spexin and its receptor, galanin receptor 2 (GALR2), in regulation of energy balance in the mediobasal hypothalamus of mice. Administration of spexin into the third ventricle near the hypothalamus (I3V) significantly decreased food intake and body weight with no change in energy expenditure in mice. The central spexin-induced anorexia and weight loss were reinstated by pre-I3V administration of GALR2 antagonist, M871, indicating hypothalamic GALR2-mediated action of spexin in the regulation of energy balance. In addition, we showed that I3V administration of spexin-based selective GALR2 agonist significantly reduced food intake and body weight in a dose-dependent manner with no signs of illness assessed by a conditioned taste aversion test, suggesting a novel role of hypothalamic GALR2 in the regulation of energy balance. Furthermore, we found that activation of GALR2 induced by spexin increased phosphorylation of CREB in the mediobasal hypothalamus of mice and cells overexpressing GALR2 different from galanin, suggesting a ligand-dependent switch of G protein coupled with GALR2. Taken together, these results suggested a critical role of hypothalamic spexin and GALR2 in the regulation of energy balance in mice. Disclosure N. Ha: None. N. Kim: None. C. Kim: None. M. Song: None. H. Lee: None. B. Jin: None. M. Park: None. J. Seong: None. S. Kim: None. D. Kim: None.
Prevention of rebound weight gain after dieting is essential to treat obesity. However, its attempts have been unsuccessful and the underlying mechanism remains unclear. In this study, we sought to investigate the role of adipose tissue (AT) vasculature in rebound weight gain after calorie restriction in obese mice fed a high-fat diet (HFD). Obese mice were randomly assigned to 4 groups including mice fed HFD ad libitum (CON), mice under 40% calorie restriction for 5 weeks (CR), 3 days of HFD ad libitum after CR (CRAL), or CRAL treated with TNP-470, an angiogenesis inhibitor (TNP). We compared parameters of energy balance, AT morphometry and remodeling, and hypothalamic neuropeptides gene expression among the groups. Rebound weight gain and food intake were significantly lower and the level of brown AT UCP-1 gene expression was higher in TNP group than CRAL group. Fat mass was significantly lower in TNP group than CRAL group and it was similar to CR group while lean mass was not different between TNP and CRAL groups. Notably, the CD31-positive area was not different in AT between CON, CR, and CRAL groups, indicating that AT vasculature was maintained independently of nutritional status. However, that tended to be lower in AT of TNP group compared to other groups, implicating that inhibition of AT vasculature might be crucial to suppress rebound weight gain after calorie restriction. Consistently, circulating leptin levels were significantly lower in TNP group than CRAL group. However, the pattern of hypothalamic neuropeptides gene expression was different from the changes in food intake among the groups, suggesting an existence of novel regulatory signals independent of melanocortin system. Taken together, these results suggested a critical role of AT vasculature in regulating rebound weight gain and hyperphagia after calorie restriction independent of hypothalamic melanocortin system. Disclosure H. Lee: None. M. Song: None. N. Ha: None. B. Jin: None. S. Choi: None. D. Kim: None.
Objectives: To verify foregut hypothesis, we conducted simple bariatric surgery to evaluate the effects of those operations on body weight, glucose tolerance and insulin sensitivity in mice. Methods: We applied operation techniques which involved gastrojejunostomy (GJ), GJ with duodenojejunal exclusion (GJDE), and sham operation (control). Jejunostomy site was located in the mid-jejunum with 1.0 cm pore size. Three different fed conditions were applied; 1) C57BL/6 mice fed with 60% high-fat diet (HFD) before and after surgery (n=8). ICR mice had been fed with chow diet, followed by 2) 45% HFD (n=9), and 3) 60% HFD (n=12) after surgery. Results: In HFD fed C57BL/6 mice, body weight following operations was significantly reduced during first 2 weeks in GJDE and GJ mice compared to control mice, thereafter the difference was gradually attenuated. OGTT and ITT at 5 and 7 weeks after surgery showed that glucose levels were significantly lower, and insulin sensitivity was significantly improved in GJ and GJDE mice compared to control. In addition, in response to high glucose administration, insulin level was significantly increased in GJ and GJDE mice. In lean ICR mice, body weight in GJ and GJDE operated mice (45% HFD after surgery) were significantly lowered than that of control mice since 3 weeks after surgery. There were no difference in glucose tolerance between groups until 7 weeks, however, AUC glucose were significantly lower in GJDE mice than GJ and control mice after 10 weeks. ITT also showed GJDE mice were more insulin sensitive than GJ and control mice. GJ and GJDE operated mice with 60% HFD after surgery also showed similar results indicating delayed improvement in insulin sensitivity with proximal intestinal bypass. Conclusion: This simple operation of proximal intestinal bypass demonstrated its effects on improvement in glucose tolerance and insulin sensitivity in mice. Mice preconditioned with HFD before surgery was also benefited by improvement in insulin secretion. Disclosure H. Jang: None. N. Ha: None. M. Song: None. H. Lee: None. B. Jin: None. D. Kim: None. N. Kim: None.
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