title: Ghrelin O-acyltransferase knockout mice show resistance to obesity when fed high-sucrose diet.
abstract: Ghrelin is an appetite-stimulating hormone secreted from stomach. Since the discovery that acylation of the serine-3 residue by ghrelin O-acyltransferase (GOAT) is essential for exerting its functions, GOAT has been regarded as an therapeutic target for attenuating appetite, and thus for the treatment of obesity and diabetes. However, contrary to the expectations, GOAT-knockout (KO) mice have not shown meaningful body weight reduction, under high-fat diet. Here, in this study, we sought to determine whether GOAT has a role in body weight regulation and glucose metabolism with a focus on dietary sucrose, because macronutrient composition of diet is important for appetite regulation. We found that peripherally administered acylated-ghrelin, but not unacylated one, stimulated sucrose consumption in a two-bottle-drinking test. The role of acylated-ghrelin in sucrose preference was further supported by the finding that GOAT KO mice consumed less sucrose solution compared with WT littermates. Then, we investigated the effect of dietary composition of sucrose on food intake and body weight in GOAT KO and WT mice. As a result, when fed on high-fat diet, food intake and body weight were similar between GOAT KO and WT mice. However, when fed on high-fat, high-sucrose diet, GOAT KO mice showed significantly reduced food intake and marked resistance to obesity, leading to amelioration of glucose metabolism. These results suggest that blockade of acylated-ghrelin production offers therapeutic potential for obesity and metabolic disorders caused by overeating of palatable food.
authors.affiliation: Discovery Research Laboratory for Innovative Frontier MedicinesShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDiscovery Research Laboratory for Core Therapeutic AreasShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDepartment of Biological ChemistryHuman Health Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan Discovery Research Laboratory for Innovative Frontier MedicinesShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDiscovery Research Laboratory for Core Therapeutic AreasShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDepartment of Biological ChemistryHuman Health Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan tetsuya.kouno@shionogi.co.jp.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kouno
authors.affiliation: Discovery Research Laboratory for Innovative Frontier MedicinesShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDiscovery Research Laboratory for Core Therapeutic AreasShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDepartment of Biological ChemistryHuman Health Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Nobuteru
authors.initials: N
authors.lastname: Akiyama
authors.affiliation: Discovery Research Laboratory for Innovative Frontier MedicinesShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDiscovery Research Laboratory for Core Therapeutic AreasShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDepartment of Biological ChemistryHuman Health Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Ito
authors.affiliation: Discovery Research Laboratory for Innovative Frontier MedicinesShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDiscovery Research Laboratory for Core Therapeutic AreasShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDepartment of Biological ChemistryHuman Health Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Okuda
authors.affiliation: Discovery Research Laboratory for Innovative Frontier MedicinesShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDiscovery Research Laboratory for Core Therapeutic AreasShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDepartment of Biological ChemistryHuman Health Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Nanchi
authors.affiliation: Discovery Research Laboratory for Innovative Frontier MedicinesShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDiscovery Research Laboratory for Core Therapeutic AreasShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDepartment of Biological ChemistryHuman Health Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Notoya
authors.affiliation: Discovery Research Laboratory for Innovative Frontier MedicinesShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDiscovery Research Laboratory for Core Therapeutic AreasShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDepartment of Biological ChemistryHuman Health Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Oka
authors.affiliation: Discovery Research Laboratory for Innovative Frontier MedicinesShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDiscovery Research Laboratory for Core Therapeutic AreasShionogi and Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, JapanDepartment of Biological ChemistryHuman Health Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yukioka
mesh_terms: D000215:Acylation; D000217:Acyltransferases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001066:Appetite / Q000502:physiology; D001069:Appetite Regulation / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D059305:Diet, High-Fat; D019422:Dietary Sucrose / Q000008:administration & dosage*; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism; D054439:Ghrelin / Q000737:chemistry / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D006963:Hyperphagia / Q000188:drug therapy; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000201:enzymology*
chemical_list: D019422:Dietary Sucrose; D054439:Ghrelin; D008565:Membrane Proteins; D000217:Acyltransferases; C526983:Mboat4 protein, mouse; D005947:Glucose
keywords: body weight; food intake; ghrelin; insulin sensitivity; sucrose