Effects of Peripheral Neurotensin on Appetite Regulation and Its Role in Gastric Bypass Surgery

TY - JOUR

T1 - Effects of Peripheral Neurotensin on Appetite Regulation and Its Role in Gastric Bypass Surgery

AU - Ratner, Cecilia

AU - Skov, Louise J

AU - Raida, Zindy

AU - Bächler, Thomas

AU - Bellmann-Sickert, Kathrin

AU - Le Foll, Christelle

AU - Sivertsen, Bjørn

AU - Dalbøge, Louise S

AU - Hartmann, Bolette

AU - Beck-Sickinger, Annette G

AU - Madsen, Andreas N

AU - Jelsing, Jacob

AU - Holst, Jens J

AU - Lutz, Thomas A

AU - Andrews, Zane B

AU - Holst, Birgitte

PY - 2016/9

Y1 - 2016/9

N2 - Neurotensin (NT) is a peptide expressed in the brain and in the gastrointestinal tract. Brain NT inhibits food intake, but the effects of peripheral NT are less investigated. In this study, peripheral NT decreased food intake in both mice and rats, which was abolished by a NT antagonist. Using c-Fos immunohistochemistry, we found that peripheral NT activated brainstem and hypothalamic regions. The anorexigenic effect of NT was preserved in vagotomized mice but lasted shorter than in sham-operated mice. This in combination with a strong increase in c-Fos activation in area postrema after ip administration indicates that NT acts both through the blood circulation and the vagus. To improve the pharmacokinetics of NT, we developed a pegylated NT peptide, which presumably prolonged the half-life, and thus, the effect on feeding was extended compared with native NT. On a molecular level, the pegylated NT peptide increased proopiomelanocortin mRNA in the arcuate nucleus. We also investigated the importance of NT for the decreased food intake after gastric bypass surgery in a rat model of Roux-en-Y gastric bypass (RYGB). NT was increased in plasma and in the gastrointestinal tract in RYGB rats, and pharmacological antagonism of NT increased food intake transiently in RYGB rats. Taken together, our data suggest that NT is a metabolically active hormone, which contributes to the regulation of food intake.

AB - Neurotensin (NT) is a peptide expressed in the brain and in the gastrointestinal tract. Brain NT inhibits food intake, but the effects of peripheral NT are less investigated. In this study, peripheral NT decreased food intake in both mice and rats, which was abolished by a NT antagonist. Using c-Fos immunohistochemistry, we found that peripheral NT activated brainstem and hypothalamic regions. The anorexigenic effect of NT was preserved in vagotomized mice but lasted shorter than in sham-operated mice. This in combination with a strong increase in c-Fos activation in area postrema after ip administration indicates that NT acts both through the blood circulation and the vagus. To improve the pharmacokinetics of NT, we developed a pegylated NT peptide, which presumably prolonged the half-life, and thus, the effect on feeding was extended compared with native NT. On a molecular level, the pegylated NT peptide increased proopiomelanocortin mRNA in the arcuate nucleus. We also investigated the importance of NT for the decreased food intake after gastric bypass surgery in a rat model of Roux-en-Y gastric bypass (RYGB). NT was increased in plasma and in the gastrointestinal tract in RYGB rats, and pharmacological antagonism of NT increased food intake transiently in RYGB rats. Taken together, our data suggest that NT is a metabolically active hormone, which contributes to the regulation of food intake.

U2 - 10.1210/en.2016-1329

DO - 10.1210/en.2016-1329

M3 - Journal article

C2 - 27580810

SN - 0013-7227

VL - 157

SP - 3482

EP - 3492

JO - Endocrinology

JF - Endocrinology

IS - 9

ER -