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.

Fatty acylation of proteins: The long and the short of it

“…However, studies in GOAT knockout mice have not mirrored the effects of the GOAT inhibitor. GOAT −/− mice grow at the same rate and achieve the same weight as wild type cohorts, even on a high fat diet[154, 155]. Of note, GOAT −/− mice exhibit reduced food intake and resistance to obesity when placed on a high-fat, high-sucrose diet[155].…”

“…GOAT −/− mice grow at the same rate and achieve the same weight as wild type cohorts, even on a high fat diet[154, 155]. Of note, GOAT −/− mice exhibit reduced food intake and resistance to obesity when placed on a high-fat, high-sucrose diet[155]. Complex interactions with other signaling axes that regulate appetite may complicate the ultimate in vivo use of GOAT inhibitors to control obesity and/or diabetes.…”

Therapeutic Potential of Targeting the Ghrelin Pathway

“…However, one study shows that ghrelin-deficient mice may be protected from diet-induced obesity if HFD-feeding is initiated before adulthood [252]. In another study, mice lacking the ghrelin-acylating enzyme GOAT showed no phenotypic difference from wildtype mice when fed a standard high-fat diet, but did exhibit reduced fat gain and glucose intolerance when fed a high-fat/high-sugar diet [253]. Deletion of the GHSR seems to have a more convincing effect of lowering body weight and susceptibility to obesity [254,255,256], although some investigators found that GHSR deletion had no effect on these parameters [251,257].…”

Effect of Aronia melanocarpa (Black Chokeberry) supplementation on the development of obesity in mice fed a high-fat diet

“…In addition, one of our obesogenic diets, LFHS, was high in sucrose. High sucrose diets have been used to induce obesity and diabetes in rodent models [43][44][45][46]. The high levels of sucrose in the LFHS diets could explain why we did not find large differences between LFHS and HF groups.…”