Ghrelin treatment reverses the reduction in weight gain and body fat in gastrectomised mice

Abstract

Background and aims: The gastric hormone ghrelin has been reported to stimulate food intake, increase weight gain, and cause obesity but its precise physiological role remains unclear. We investigated the long term effects of gastrectomy evoked ghrelin deficiency and of daily ghrelin injections on daily food intake, body weight, fat mass, lean body mass, and bone mass in mice. Methods: Ghrelin was given by subcutaneous injections (12 nmol/mouse once daily) for eight weeks to young female mice subjected to gastrectomy or sham operation one week previously. Results: Gastrectomy reduced plasma concentrations of total ghrelin (octanoylated and des-octanoylated) and active (octanoylated) ghrelin by ,80%. Immediately after injection of ghrelin, the plasma concentration was supraphysiological and was still elevated 16 hours later. Daily food intake was not affected by either gastrectomy or ghrelin treatment. The effect of ghrelin on meal initiation was not studied. At the end point of the study, mean body weight was 15% lower in gastrectomised mice than in sham operated mice (p,0.001); daily ghrelin injections for eight weeks partially prevented this weight loss. In sham operated mice, ghrelin had no effect on body weight. The weight of fat was reduced in gastrectomised mice (230%; p,0.01). This effect was reversed by ghrelin, enhancing the weight of fat in sham operated mice also (+20%; p,0.05). Gastrectomy reduced lean body mass (210%; p,0.01) and bone mass (220%; p,0.001) compared with sham operated mice. Ghrelin replacement prevented the gastrectomy induced decrease in lean body mass but did not affect bone. In sham operated mice, ghrelin affected neither of these two parameters. Conclusions: Ghrelin replacement partially reversed the gastrectomy induced reduction in body weight, lean body mass, and body fat but not in bone mass. In sham operated mice, ghrelin only increased fat mass. Our results suggest that ghrelin is mainly concerned with the control of fat metabolism and that ghrelin replacement therapy may alleviate the weight loss associated with gastrectomy.

Long-term changes in gut hormones, appetite and food intake 1 year after subtotal gastrectomy with normal body weight

“…Therefore, it seems unlikely that compensatory ghrelin production remains so in the long-term, although it can occur transiently. Ghrelin is known to enhance appetite and increase food intake in the short term and maintain body fat in the long term (Dornonville de la Cour et al, 2005). In this study, appetite did not change 1 year after subtotal gastrectomy, but body fat decreased significantly compared to before surgery, which is considered to be closely related to reduced ghrelin concentrations.…”

The role of the central ghrelin system in reward from food and chemical drugs

“…Indeed, it has been proposed that ghrelin decreases fat utilization (Theander-Carrillo et al 2006;Tschöp et al 2000), implying that the CNS circuits mediating ghrelin's acute orexigenic effects differ, at least in part, from those involved in fat accumulation. We noticed previously that ghrelin's orexigenic effects decline after a few days of repeated peripheral ghrelin injection (Dornonville de la Cour et al 2005). However, in another chronic study, in which rats received a 2 week infusion of ghrelin into the brain ventricles, we were surprised to detect a clear orexigenic response (Salomé et al 2009), suggesting that under certain experimental/physiological conditions, the orexigenic ghrelin-responsive networks remain ghrelin-sensitive during chronic exposure.…”

“…Thus, as reviewed elsewhere (Egecioglu et al 2011;Skibicka and Dickson 2011), GHS-R1A provides a potential target for the treatment of problematic over-eating. Indeed, it will be important to establish how the ghrelin-responsive circuits adapt during the development of diet-induced obesity (Lindqvist et al 2005;Briggs et al 2010), and whether GHS-R1A antagonists could provide an effective therapy for this disease area.…”

Role of ghrelin in reproduction

“…Considering that the major stimulant for testicular expression of ghrelin is pituitary LH, it is tempting to speculate that ghrelin might operate as a local regulator in the fine-tuning of the steroidogenic actions of LH, which might participate in the autolimitation of testicular testosterone response to gonadotropic stimulation . Alternatively, such an inhibitory effect upon testosterone secretion might be conducted by the systemic, gut-derived ghrelin, whose plasma levels are inversely correlated with body mass index (Dornonville et al 2005). Thereby, elevated ghrelin levels (as those observed in energy insufficiency) might contribute to the suppression of male reproductive axis in situations of negative energy balance, such as starvation.…”