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Intragastric administration of the bitter agonist denatonium benzoate (DB) increases satiation in healthy volunteers
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Abstracts / Appetite 57S (2011) S1–S49
Intragastric administration of the bitter agonist denatonium benzoate (DB) increases satiation in healthy volunteers P. JANSSEN, S. JANSSEN, I. DEPOORTERE, J. TACK TARGID, KULeuven, Leuven, Belgium Aim: In mice intragastric administration of bitter receptor agonists decreased food intake (PNAS 108: p2094). We set out to investigate the effect of DB on satiation and intragastric pressure (IGP) during intragastric nutrient drink infusion in humans. Methods: 10 healthy volunteers were recruited in a blinded crossover study. After an overnight fast an infusion catheter and a manometry probe were positioned in the proximal stomach. After a stabilization period DB (±0.15 and 1 mol/kg) or vehicle was infused intragastrically; 30 min later a nutrient drink (1.5 kcal/ml) was intragastrically infused at 60 ml/min. Satiation and gastrointestinal symptoms (e.g. nausea) were scored every minute. The experiment ended when subjects scored maximum satiation. Results are expressed as mean ± S.E.M. and compared using ANOVA. Results: Volunteers did not report any symptoms after DB treatment, however satiation scores were increased during nutrient drink infusion (P = 0.51 and 0.015 for 0.15 and 1 mol/kg DB respectively). At maximum satiation the ingested volume after treatment with 0.15 mol/kg DB (848 ± 103 ml) and 1 mol/kg DB (791 ± 76 ml) was lower than after placebo treatment (920 ± 74 ml; P = 0.06 and 0.02 respectively). IGP during nutrient drink infusion tended to be elevated after treatment with the highest dose of DB (P = 0.25; n = 6). Conclusion: The bitter agonist, DB, dose-dependently increased satiation and reduced the volume of nutrients ingested upon maximal satiation. The contribution of bitter taste receptors (T2Rs) and changes in gastric motor physiology requires further investigation. doi:10.1016/j.appet.2011.05.186 Peripheral Y2 receptor activation inhibits gastric accommodation during intragastric nutrient infusion in rats P. JANSSEN, S. VERSCHUEREN, C. VAN HEIJNINGEN, J. TACK Translational Research Center for Gastrointestinal Disorders, KULeuven, Leuven, Belgium Aim: PYY3–36 inhibits food intake in rats. We set out to determine whether Y2 receptors are involved in the regulation of gastric accommodation in conscious Wistar HAN rats by measuring the intragastric pressure (IGP) during intragastric nutrient infusion. Methods: After an overnight fast, a previously implanted gastric fistula was connected to a nutrient drink infusion system and a manometer to measure IGP (n = 27). IGP was measured before and during the infusion of a nutrient drink (0.5 ml/min; 1.5 kcal/ml) until 10 ml was infused. Rats were treated with 0, 33 and 100 pmol/kg/min PYY3–36 (intravenous infusion during the whole experiment) in combination with the Y2 receptor antagonists JNJ31020028 (JNJ; 10 mg/kg), BIIE0246 (2 mg/kg) or vehicle which were given subcutaneously before the start of the experiment. Tests were also performed after subdiaphragmatic vagotomy. IGP during nutrient drink infusion was compared by calculating the area under the IGP curve; data were represented as mean ± S.E.M. and compared using ANOVA. Results: PYY3–36 elevated IGP during nutrient drink infusion (94 ± 6, 114 ± 10 and 146 ± 14 mmHg min for 0, 33 and 100 pmol/kg/min PYY3–36 ; P = 0.11 and 0.01 vs. placebo respectively). BIIE0246 and JNJ significantly suppressed the PYY3–36 -induced IGP increase during nutrient drink infusion (P < 0.05 and <0.01 respectively). Also in vagotomized rats the effect of PYY3–36 was significantly inhibited by JNJ (P < 0.05). Conclusion: PYY3–36 enhanced the IGP increase during nutrient drink infusion before and after vagotomy. Y2 receptor antagonists decreased this IGP increase. These results indicate that PYY3–36 inhibits gastric accommodation during nutrient drink infusion through activation
of peripheral Y2 receptors and this might provide an alternative explanation for its effect on food intake. doi:10.1016/j.appet.2011.05.187 Intragastric pressure is a major determinant of satiation P. JANSSEN, S. VERSCHUEREN, J. TACK Translational Research Center for Gastrointestinal Disorders (TARGID), KULeuven, Leuven, Belgium Aim: We previously showed a correlation between intragastric pressure (IGP) and satiation scores during intragastric nutrient drink infusion. Our aim is to investigate the relation between IGP and satiation during intragastric nutrient infusion while artificially increasing the IGP. Methods: In 11 fasted healthy volunteers an infusion catheter and a manometry probe were positioned in the proximal stomach. Using a custom-made system we could increase the pressure on the stomach (increasing the IGP) or on the lower abdomen (control; no effect on IGP). During the baseline period we determined the pressure on the stomach necessary to obtain an IGP increase of 5 mmHg (=maximum pressure applied; the same pressure was maximally applied on the lower abdomen). After a stabilization period a nutrient drink (Nutridrink; 1.5 kcal/ml) was intragastrically infused at 60 ml/min. The pressure on the stomach/abdomen was progressively increased during this infusion until the previously determined maximal pressure. The subjects scored satiation using a 6-point Likert scale until maximum, when the experiment ended. Results are presented as mean ± S.E.M. and compared using a paired t-test. Results: At maximal satiation the volume nutrient drink ingested was significantly smaller when external pressure was applied to the stomach (939 ± 71 ml) vs. the control situation (1084 ± 75 ml; P < 0.05). During nutrient drink infusion IGP increased significantly faster when external pressure was applied to the stomach (0.41 ± 0.05 vs. 0.29 ± 0.05 mmHg/60 ml respectively; P < 0.05). However, the satiation score increase per mmHg IGP increase was similar in both groups: 0.85 ± 0.09 vs. 0.84 ± 0.10 satiation score point increase per mmHg IGP increase. Conclusion: We observed a close correlation between IGP and satiation score increase. These observations indicate that IGP is a major determinant of satiation. doi:10.1016/j.appet.2011.05.188 Toll-like receptor 2 is involved in sickness responses induced by acute inflammation in the brain S.H. JIN 1 , S.G. KANG 2 , B.J. LEE 1 1 Department of Biological Sciences, University of Ulsan, Ulsan, South Korea 2 School of Biomedical and Biotechnology Science, Inje University, Kimhae, South Korea Sickness responses such as anorexia, fever and hypoactivity are closely associated with inflammatory diseases. Especially, acute inflammation in the brain elicits a profound negative energy balance. Previous evidences have shown that a number of cytokines and pathogens induce sickness responses by activating inflammation in the brain. Moreover, recent studies have suggested that toll-like receptor 4 (TLR4) and MyD88 play critical roles for the mediation of anorexia and/or metabolic disorders induced in the acute and chronic inflammatory conditions in the brain. In this study, we tried to identify TLR2 action in the sickness responses induced by acute inflammation. Adult male mice were intracerebroventricularly injected with Pam3CSK, a synthetic TLR2 ligand, and change in their sickness behaviors was observed. Administration of Pam3CSK induced decreases in food intake, body weight and locomotor activity, but resulted in an increased body temperature. However, TLR2 and MyD88 knockout mice showed mitigated responses to the Pam3CSK injection. These results suggest that TLR2
Abstracts / Appetite 57S (2011) S1–S49
Intragastric administration of the bitter agonist denatonium benzoate (DB) increases satiation in healthy volunteers P. JANSSEN, S. JANSSEN, I. DEPOORTERE, J. TACK TARGID, KULeuven, Leuven, Belgium Aim: In mice intragastric administration of bitter receptor agonists decreased food intake (PNAS 108: p2094). We set out to investigate the effect of DB on satiation and intragastric pressure (IGP) during intragastric nutrient drink infusion in humans. Methods: 10 healthy volunteers were recruited in a blinded crossover study. After an overnight fast an infusion catheter and a manometry probe were positioned in the proximal stomach. After a stabilization period DB (±0.15 and 1 mol/kg) or vehicle was infused intragastrically; 30 min later a nutrient drink (1.5 kcal/ml) was intragastrically infused at 60 ml/min. Satiation and gastrointestinal symptoms (e.g. nausea) were scored every minute. The experiment ended when subjects scored maximum satiation. Results are expressed as mean ± S.E.M. and compared using ANOVA. Results: Volunteers did not report any symptoms after DB treatment, however satiation scores were increased during nutrient drink infusion (P = 0.51 and 0.015 for 0.15 and 1 mol/kg DB respectively). At maximum satiation the ingested volume after treatment with 0.15 mol/kg DB (848 ± 103 ml) and 1 mol/kg DB (791 ± 76 ml) was lower than after placebo treatment (920 ± 74 ml; P = 0.06 and 0.02 respectively). IGP during nutrient drink infusion tended to be elevated after treatment with the highest dose of DB (P = 0.25; n = 6). Conclusion: The bitter agonist, DB, dose-dependently increased satiation and reduced the volume of nutrients ingested upon maximal satiation. The contribution of bitter taste receptors (T2Rs) and changes in gastric motor physiology requires further investigation. doi:10.1016/j.appet.2011.05.186 Peripheral Y2 receptor activation inhibits gastric accommodation during intragastric nutrient infusion in rats P. JANSSEN, S. VERSCHUEREN, C. VAN HEIJNINGEN, J. TACK Translational Research Center for Gastrointestinal Disorders, KULeuven, Leuven, Belgium Aim: PYY3–36 inhibits food intake in rats. We set out to determine whether Y2 receptors are involved in the regulation of gastric accommodation in conscious Wistar HAN rats by measuring the intragastric pressure (IGP) during intragastric nutrient infusion. Methods: After an overnight fast, a previously implanted gastric fistula was connected to a nutrient drink infusion system and a manometer to measure IGP (n = 27). IGP was measured before and during the infusion of a nutrient drink (0.5 ml/min; 1.5 kcal/ml) until 10 ml was infused. Rats were treated with 0, 33 and 100 pmol/kg/min PYY3–36 (intravenous infusion during the whole experiment) in combination with the Y2 receptor antagonists JNJ31020028 (JNJ; 10 mg/kg), BIIE0246 (2 mg/kg) or vehicle which were given subcutaneously before the start of the experiment. Tests were also performed after subdiaphragmatic vagotomy. IGP during nutrient drink infusion was compared by calculating the area under the IGP curve; data were represented as mean ± S.E.M. and compared using ANOVA. Results: PYY3–36 elevated IGP during nutrient drink infusion (94 ± 6, 114 ± 10 and 146 ± 14 mmHg min for 0, 33 and 100 pmol/kg/min PYY3–36 ; P = 0.11 and 0.01 vs. placebo respectively). BIIE0246 and JNJ significantly suppressed the PYY3–36 -induced IGP increase during nutrient drink infusion (P < 0.05 and <0.01 respectively). Also in vagotomized rats the effect of PYY3–36 was significantly inhibited by JNJ (P < 0.05). Conclusion: PYY3–36 enhanced the IGP increase during nutrient drink infusion before and after vagotomy. Y2 receptor antagonists decreased this IGP increase. These results indicate that PYY3–36 inhibits gastric accommodation during nutrient drink infusion through activation
of peripheral Y2 receptors and this might provide an alternative explanation for its effect on food intake. doi:10.1016/j.appet.2011.05.187 Intragastric pressure is a major determinant of satiation P. JANSSEN, S. VERSCHUEREN, J. TACK Translational Research Center for Gastrointestinal Disorders (TARGID), KULeuven, Leuven, Belgium Aim: We previously showed a correlation between intragastric pressure (IGP) and satiation scores during intragastric nutrient drink infusion. Our aim is to investigate the relation between IGP and satiation during intragastric nutrient infusion while artificially increasing the IGP. Methods: In 11 fasted healthy volunteers an infusion catheter and a manometry probe were positioned in the proximal stomach. Using a custom-made system we could increase the pressure on the stomach (increasing the IGP) or on the lower abdomen (control; no effect on IGP). During the baseline period we determined the pressure on the stomach necessary to obtain an IGP increase of 5 mmHg (=maximum pressure applied; the same pressure was maximally applied on the lower abdomen). After a stabilization period a nutrient drink (Nutridrink; 1.5 kcal/ml) was intragastrically infused at 60 ml/min. The pressure on the stomach/abdomen was progressively increased during this infusion until the previously determined maximal pressure. The subjects scored satiation using a 6-point Likert scale until maximum, when the experiment ended. Results are presented as mean ± S.E.M. and compared using a paired t-test. Results: At maximal satiation the volume nutrient drink ingested was significantly smaller when external pressure was applied to the stomach (939 ± 71 ml) vs. the control situation (1084 ± 75 ml; P < 0.05). During nutrient drink infusion IGP increased significantly faster when external pressure was applied to the stomach (0.41 ± 0.05 vs. 0.29 ± 0.05 mmHg/60 ml respectively; P < 0.05). However, the satiation score increase per mmHg IGP increase was similar in both groups: 0.85 ± 0.09 vs. 0.84 ± 0.10 satiation score point increase per mmHg IGP increase. Conclusion: We observed a close correlation between IGP and satiation score increase. These observations indicate that IGP is a major determinant of satiation. doi:10.1016/j.appet.2011.05.188 Toll-like receptor 2 is involved in sickness responses induced by acute inflammation in the brain S.H. JIN 1 , S.G. KANG 2 , B.J. LEE 1 1 Department of Biological Sciences, University of Ulsan, Ulsan, South Korea 2 School of Biomedical and Biotechnology Science, Inje University, Kimhae, South Korea Sickness responses such as anorexia, fever and hypoactivity are closely associated with inflammatory diseases. Especially, acute inflammation in the brain elicits a profound negative energy balance. Previous evidences have shown that a number of cytokines and pathogens induce sickness responses by activating inflammation in the brain. Moreover, recent studies have suggested that toll-like receptor 4 (TLR4) and MyD88 play critical roles for the mediation of anorexia and/or metabolic disorders induced in the acute and chronic inflammatory conditions in the brain. In this study, we tried to identify TLR2 action in the sickness responses induced by acute inflammation. Adult male mice were intracerebroventricularly injected with Pam3CSK, a synthetic TLR2 ligand, and change in their sickness behaviors was observed. Administration of Pam3CSK induced decreases in food intake, body weight and locomotor activity, but resulted in an increased body temperature. However, TLR2 and MyD88 knockout mice showed mitigated responses to the Pam3CSK injection. These results suggest that TLR2