Mo2114 Enhancement of Ghrelin Secretion Is a Potential New Therapy Against Stress-Induced Functional...

AG

AA

bst

ract

shigher stages of fibrosis (r=0.16, p,0.03). The levels of the apoptosis biomarker M30 alsocorrelated with both the presence of histologic NASH (r=0.28, p,0.00016) and the presenceof fibrosis (r=0.36, p,1.07e-6), but not with BMI. The levels of PTH were positivelycorrelated with BMI (r=0.23, p,0.003) and negatively correlated with the levels of ALT(r=-0.18, p,0.025) and triglycerides (r=-0.213, p,0.01). The levels of the Vitamin Dbinding protein showed a positive correlation with the levels of triglycerides (r=0.336,p,0.0012) and a negative correlation with the degree of histologic hepatocyte ballooning(r=-0.231, p,0.02) in the liver biopsies. In addition, both Vitamin D levels (p=0.045) andVitamin D binding protein levels (p=0.019) were significantly lower in the non-Caucasiangroup (n=135) within the cohort. Conclusions: The hormonal regulation of Vitamin Dmetabolism is substantially modified in very obese patients with NAFLD who are undergoingbariatric surgery. Further research is needed to elucidate the roles of individual componentsof the Vitamin D metabolic pathway and their molecular targets in morbidly obese patientswith NAFLD.

Mo2114

Enhancement of Ghrelin Secretion Is a Potential New Therapy Against Stress-Induced Functional Abnormality of the Upper Gastrointestinal TractKoji Yakabi, Shoki Ro, Mitsuko Ochiai, Shino Ohno, Yumi Harada, Masamichi Noguchi,Tomohisa Hattori

Background/aim: Stress is associated with the development of functional gastrointestinal(GI) tract disorders and worsening of their symptoms. Urocortin 1 (UCN), a stress-relatedhormone, is known to act as an endogenous ligand of CRF receptors, and intracerebroventric-ular (ICV) injection of UCN results in suppressed feeding activity, delayed gastric emptying,and reduced GI motility. In this study, we investigated the effects of exogenous acyl ghrelinadministration in a stress model and examined whether enhanced secretion of endogenousghrelin improves the functional abnormality of GI motility. We explored the possibility ofa drug with ghrelin-enhancing action for treatment of FD-like symptoms. Methods: Wemeasured plasma ghrelin levels at 1 h, 2 h and 4 h after UCN administration on fasted malerats. We also administered rat acyl ghrelin [3 nmol/kg intravenous (IV)] or rikkunshito[RKT; Gastroenterology, 2008 Vol. 134 (1000 mg/kg orally)], which is a ghrelin secretionpromoter, after ICV injection of UCN and measured the cumulative food intake. We thenadministered RKT and the ghrelin receptor antagonist ([D-Lys3] GHRP-6; 4 μmol/kg IV)concurrently and investigated whether the action was mediated by ghrelin. We measuredgastric emptying using a test meal containing glass beads, the gastroduodenal propulsionusing a fluorescence-labeled dextran and gastroduodenal motility using a strain gauge forcetransducer in a free-moving condition. We then evaluated the action of exogenous acylghrelin or RKT. Results: There was a significant decrease in plasma acyl ghrelin levels 1and 2 h after ICV injection of UCN; these levels recovered 4 h later. During this perioduntil 4 h later, food intakes decreased significantly. Exogenous rat acyl ghrelin injectionsignificantly recovered this decrease, and plasma acyl ghrelin levels were significantlyrecovered with RKT. The results for food intakes were also similar; this effect was abolishedby the coadministration of ghrelin receptor antagonist. In fasted condition, ICV injectionof UCN eliminated phase III-like contraction and demonstrated contraction of during thedigestive phase. Administration of RKT contributed to the recovery of spontaneous phaseIII-like contraction. During the digestive phase, ICV injection of UCNdecreased the amplitudeof contraction in the stomach while increasing the amplitude in the duodenum. Addition-ally,gastric emptying and gastroduodenal propulsion were evidently delayed . Administrationof exogenous rat acyl ghrelin or RKT improved these abnormalities. This effect was abolishedby coadministration of ghrelin receptor antagonist. Conclusions: Supplementation of exoge-nous acyl ghrelin or RKT may improve the functional abnormality of upper GI motility byincreasing ghrelin secretion. Therefore, they may be effective for treat functional GI disorders.

Fig.1 Effect of rikkunshito with coadministration [D-Lys3]-GHRP-6 on delayed gastricempting after ICV injection of Urocortin1

S-746AGA Abstracts

Fig.2 Effect of rikkunshito after ICV injection of Urocortin1 on fast motility on antrumand duodenum

Mo2115

Rikkunshito Ameliorates Anorexia and Cachexia by Ghrelin Secretion viaSerotonin 2B Receptor Antagonism in Cachexia Model of Pulmonary FibrosisShigehisa Yanagi, Hironobu Tsubouchi, Koji Toshinai, Sachiko Mogami, Chihiro Yamada,Seiichi Iizuka, Masamitsu Nakazato

Background: In the terminal stages of pulmonary fibrosis and chronic obstructive pulmonarydisease, dyspnea develops and transitions to cachexia associated with emaciation and muscleweakness.Weight loss is an important prognostic factor, and treatment of cachexia is expectedto improve patient outcome. Ghrelin is a releasing factor for growth hormone, and also hasorexigenic and anti-inflammatory effects. Rikkunshito (RKT) is a traditional medicine thathas been approved by the Ministry of Health, Labor and Welfare of Japan as a remedy fordysfunction of the gastrointestinal tract. Recently, the mechanisms were reported to berelated to improvement of ghrelin secretion via serotonin 2B receptor (5HT2B-R) antagonism(Gastroenterology 2008, 134:2004-2013). In addition, RKT is reported to ameliorate anorexiain tumor-bearing animals via ghrelin secretion (Transl Psychiatry 2011, 1:e23). In this study,we examined the ghrelin secretion and orexigenic effects of 5HT2B-R antagonist, and theeffects of RKT on cachexia in mice with chronic respiratory disturbance. Methods: Ten-week-old male C57BL/6J mice received endotracheal instillation of bleomycin sulfate (BLM,3.0 mg/kg). Body weight and food intake were measured daily and weight of the gastrocne-mius muscle was measured on Day 11. Lung fibrosis and inflammation were examinedhistologically. Plasma acyl ghrelin levels were measured by ELISA and were compared tothose of pair-fed control mice (mice given an identical amount of food as the BLM mice)to eliminate the influence of food intake. RKT (1.0 g/kg, p.o.) was administered to BLMmice once daily (from day −3 to the day of autopsy). Ghrelin receptor antagonist ((D-Lys3)-GHRP-6; 5 or 10 μmol/kg, i.p.) or 5HT2B-R antagonist (SB215505; 0.5 mg/kg, i.p.) wereadministered to BLM mice once daily for 7 or 5 days. Results: In BLM cachexia modelmice, body weight, food intake and gastrocnemius muscle weight were significantly lowerwhen compared to control mice on Day 11. Plasma acyl ghrelin concentrations of BLM micewere significantly lower than those in pair-fed control mice (fig. 1). RKT ameliorated thedecreased body weight, and food intake and muscle weight were equivalent to levels seenin control mice. In addition, lung inflammation and fibrosis were inhibited by RKT (fig.2).Ghrelin antagonist significantly inhibited the increased food intake by RKT (fig. 1), and5HT2B-R antagonist significantly improved the decreased food intake in BLM mice (control;0.46±0.19 g, BLM; 0.20±0.11 g, SB215505; 0.48±0.19 g). BLM-induced lung fibrosis wasameliorated by serotonin 2B-R antagonist. Conclusion: In this cachexia model of pulmonaryfibrosis, plasma ghrelin levels decreased, although food intake remained low. RKT wasconsidered to improve cachexia via ghrelin secretion by 5HT2B-R antagonism.