Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor

Abstract

Synthetic agonists of the growth hormone secretagogue receptor (GHSR) rejuvenate the pulsatile pattern of GH-release in the elderly, and increase lean but not fat mass in obese subjects. Screening of tissue extracts in a cell line engineered to overexpress the GHSR led to the identification of a natural agonist called ghrelin. Paradoxically, this hormone was linked to obesity. However, it had not been directly shown that the GHSR is a physiologically relevant ghrelin receptor. Furthermore, ghrelin's structure is significantly different from the synthetic agonist (MK-0677) used to expression-clone the GHSR. To address whether the GHSR mediates ghrelin's stimulatory effects on GH release and appetite, we generated Ghsr-null mice. In contrast to wild-type mice, acute treatment of Ghsr-null mice with ghrelin stimulated neither GH release nor food intake, showing that the GHSR is a biologically relevant ghrelin receptor. Nevertheless, Ghsr-null mice are not dwarfs; their appetite and body composition are comparable to that of wild-type littermates. Furthermore, in contrast to suggestions that ghrelin regulates leptin and insulin secretion, fastinginduced changes in serum levels of leptin and insulin are identical in wild-type and null mice. Serum insulin-like growth factor 1 levels and body weights of mature Ghsr-null mice are modestly reduced compared to wild-type littermates, which is consistent with ghrelin's property as an amplifier of GH pulsatility and its speculated role in establishing an insulin-like growth factor 1 set-point for maintaining anabolic metabolism. Our results suggest that chronic treatment with ghrelin antagonists will have little effect on growth or appetite.

Sequence, genomic organization and expression of ghrelin receptor in grass carp, Ctenopharyngodon idellus

“…Several studies have also examined ghrelin's role in body weight homeostasis and as an important indicator of energy insufficiency (Kamegai et al, 2000;Tschop et al, 2000;Wisse et al, 2001;Wang et al, 2002;Asakawa et al, 2003;Yasuda et al, 2003). The central role of ghrelin in body weight homeostasis and the critical importance of GHS-R in transmitting ghrelin's energy balance and GH secretory messages are highlighted by recent studies on a GHS-R knockout mouse model (Sun et al, 2004(Sun et al, , 2008. In teleost, a goldfish that has four GHS-Ra that is divided into two types, 1a and 2a, and three of these four receptors (except 2a-2 receptor), were activated by goldfish ghrelin or GHS (Kaiya et al, 2010).…”

Cachexia in chronic obstructive pulmonary disease: new insights and therapeutic perspective

“…By binding to the growth hormone secretagogue receptor, ghrelin can induce secretion of growth hormone 234. This leads to modulation of the growth hormone/IGF1 axis, which is an important anabolic pathway in human skeletal muscle 235. Furthermore, ghrelin can induce food intake, mediated by stimulation of specific neurons in the food reward centre 217.…”

Ghrelin and reproductive disorders

“…In the dorsomedial hypothalamus, a region involved in the regulation of food intake (Halem et al, 2004), both ghrelin and BIM-28163 (a receptor antagonist) may regulate neurons involved in the modulation of ghrelin action on weight gain (Bluet-Pajot et al, 1998;Halem et al 2005), by still undefined receptors (Sun et al, 2004).…”