Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference

TLDR

Ghrelin, a growth hormone secretagogue, stimulates food intake, increases adiposity, and reduces fat utilization in mice, acting via orexigenic neurons independently of GH release, and its inhibition has been proposed as an anti‑obesity strategy. The study aimed to determine the role of endogenous ghrelin in appetite and body weight regulation. The authors generated ghrelin‑deficient (ghrl⁻/⁻) mice by replacing the ghrelin gene with a lacZ reporter gene. The ghrl⁻/⁻ mice were viable, grew normally, maintained typical food intake and neuropeptide levels, and did not exhibit fasting‑induced hyperphagia, indicating endogenous ghrelin is not essential for appetite regulation, though it influences metabolic fuel preference, especially under high‑fat conditions.

Abstract

Ghrelin is a recently identified growth hormone (GH) secretogogue whose administration not only induces GH release but also stimulates food intake, increases adiposity, and reduces fat utilization in mice. The effect on food intake appears to be independent of GH release and instead due to direct activation of orexigenic neurons in the arcuate nucleus of the hypothalamus. The effects of ghrelin administration on food intake have led to the suggestion that inhibitors of endogenous ghrelin could be useful in curbing appetite and combating obesity. To further study the role of endogenous ghrelin in appetite and body weight regulation, we generated ghrelin-deficient (ghrl(-/-)) mice, in which the ghrelin gene was precisely replaced with a lacZ reporter gene. ghrl(-/-) mice were viable and exhibited normal growth rates as well as normal spontaneous food intake patterns, normal basal levels of hypothalamic orexigenic and anorexigenic neuropeptides, and no impairment of reflexive hyperphagia after fasting. These results indicate that endogenous ghrelin is not an essential regulator of food intake and has, at most, a redundant role in the regulation of appetite. However, analyses of ghrl(-/-) mice demonstrate that endogenous ghrelin plays a prominent role in determining the type of metabolic substrate (i.e., fat vs. carbohydrate) that is used for maintenance of energy balance, particularly under conditions of high fat intake.