The role of acylated-ghrelin in the regulation of sucrose intake

Abstract

The octanoyl modification of ghrelin by ghrelin O-acyltransferase (GOAT) is essential for exerting its physiologic actions. Since exogenous acylated-ghrelin has shown to stimulate food intake in humans and rodents, GOAT has been regarded as a promising target for modulating appetite, thereby treating obesity and diabetes. However, GOAT-knockout (KO) mice have been reported to show no meaningful body weight reduction, when fed a high-fat diet. In this study, we sought to determine whether GOAT has a role in the regulation of body weight and food intake when fed a dietary sucrose. We found that GOAT KO mice showed significantly reduced food intake and marked resistance to obesity, when fed a high-fat + high-sucrose diet. In addition, GOAT KO mice fed a medium-chain triglyceride (MCT) + high-sucrose diet showed a marked resistance to obesity and reduced feed efficiency. These results suggest that blockade of acylated-ghrelin production offers therapeutic potential for obesity caused by overconsumption of palatable food.

High sucrose consumption decouples intrinsic and synaptic excitability of AgRP neurons without altering body weight

“…While other components typical of the western diet (carbohydrates, fats, and proteins) [69] remain to be investigated, we identify a link between sugar consumption with previous studies of sugar sweetened water diets [37][38][39], we did not identify significant changes in bodyweight or body composition in SucrW 12Wk mice. This is likely due to (1) decreases in NCD intake as mice attempt to regulate total caloric intake in response to increased SucrW intake, (2) robust sucrose preference, (3) gastric distention from liquid intake that prevents significant solid diet intake, or a combination of these factors [37][38][39][40]42]. While fat mass was unchanged in SucrW mice, lean was decreased; this decoupling between fat and lean mass has been described previously in studies examining the function of AgRP neurons and the ghrelin receptor (GHSR1) [70][71][72][73][74].…”

“…Separate circuitries regulate the homeostatic and hedonistic rewards associated with sugar consumption [40]. Regulation of Sucrose consumption by peripheral hormones, including ghrelin, leptin, and insulin, suggest that CNS and AgRP neuronal signal integration mechanisms coordinate homeostatic consumption of Sucrose diet [38,[41][42][43]. Further, 'motivated' (non-homeostatic or hedonistic) SucrW consumption demonstrates 'top-down' processing within the CNS and is associated with disrupted reward processing and diminished valence of the stimulus reward [44] likely linked to plasticity within the hypothalamus [45,46] but could also be regulated by taste receptors [47][48][49] or leptin and insulin signaling [43,50].…”

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“…The ME group had also significant higher acyl/desacyl ghrelin ratio (p<0.01) ( Figure 2A). Since medium-chain fatty acid (MCT) which is a component of the IMD is reported to promote ghrelin secretion, we also investigated the effect of MCT contained in the IMD on the plasma ghrelin level [12]. No significant difference was observed between these two groups neither in the acyl ghrelin levels nor desacyl ghrelin levels ( Figure 2B).…”

High Sucrose consumption decouples intrinsic and synaptic excitability of AgRP neurons without altering body weight

“…Separate circuitries regulate the homeostatic and hedonistic rewards associated with sugar consumption [40]. Regulation of Sucrose consumption by peripheral hormones, including ghrelin, leptin, and insulin, suggest that CNS and AgRP neuronal signal integration mechanisms coordinate homeostatic consumption of Sucrose diet [38,[41][42][43]. Further, 'motivated' (non-homeostatic or hedonistic) SucrW consumption demonstrates 'top-down' processing within the CNS and is associated with disrupted reward processing and diminished valence of the stimulus reward [44] likely linked to plasticity within the hypothalamus [45,46] but could also be regulated by taste receptors [47][48][49] or leptin and insulin signaling [42,50].…”