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

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.G hrelin is a 28-aa peptide produced predominantly in the stomach (1, 2) that has recently been identified as a ligand of the growth hormone (GH) secretogogue (GHS) receptor (GHS-R). Like other GHSs, activation of the receptor stimulates GH secretion from the pituitary gland (1). In addition to inducing GH release, administration of exogenous ghrelin also stimulates food intake and body weight gain (3-7), increases gastric motility and acid secretion (8, 9), and decreases lipid metabolism in mice and rats (3, 4). The effects of centrally administered ghrelin on food intake are independent of its ability to induce GH release and thought to result from its direct actions on the arcuate nucleus of the hypothalamus. Furthermore, recent studies have demonstrated that plasma ghrelin levels increase preceding meals and during fasting (10, 11). Thus, it has been suggested that ghrelin stimulates appetite and that inhibitors of endogenous ghrelin, therefore, could prove useful in reducing food intake and combating obesity (11).Supporting the possibility that ghrelin acts as a key regulator of appetite and food intake by actions on the hypothalamus, GHS-R is colocalized with neuropeptide Y (NPY)͞agouti-related protein (AgRP) neurons (12) in the arcuate nucleus, a region that is responsive to circulating peripheral nutrients and hormones and critically involved in the regulation of food intake (13). Indeed, ghrelin stimulates the spontaneous activity of these neurons (14), and central ghrelin administration increases NPY and AgRP gene expression (15). Moreover, ghrelin-immunoreactivity has been reported in the h...

The alcohol-induced locomotor stimulation and accumbal dopamine release is suppressed in ghrelin knockout mice

“…No differences in basal drinking between genotypes in ghrelin knockout mice were found here based on previous data showing no difference in spontaneous alcohol intake between genotypes in the GHS-R1A knockout mice (Jerlhag et al, 2009). It seems reasonable to suggest that this reflects the recruitment of compensatory mechanisms in these knockout mice, as suggested previously to explain why these mice are not lean and have normal spontaneous food intake (Sun et al, 2003;Wortley et al, 2004;De Smet et al, 2006). To expose a modest energy balance phenotype in the ghrelin knockout mice, it was necessary to expose the mice to a high fat diet from an early age (Wortley et al, 2004) or, for the food intake phenotype, alter their light/dark cycle (De Smet et al, 2006).…”

Body weight is regulated by the brain: a link between feeding and emotion

“…Deletion of ghrelin also affects metabolic responses to high-fat diet feeding in mice. 165 Like MC4-R mRNA, Y1-R mRNA is expressed in several brain sites critical for energy balance regulation in rodents, including the PVH and CeA. [166][167][168] Moreover, by using the MC4-R/GFP mice line, we identified MC4-R-positive cells coexpressing Y1-R mRNA in these forebrain sites that receive both NPY and melanocortinergic inputs.…”

Ghrelin and the growth hormone secretagogue receptor in growth and development

“…Deletion of the ghrelin gene does not affect litter size, birth weight and postnatal growth in mice despite a complete absence of tissue and plasma ghrelin. Random concentrations of GH 16 and insulin-like growth factor 1 17 (measured in adult animals) are similar in ghrl À/À and ghrl þ / þ animals.…”