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 approximately 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 (-30%; 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 (-10%; p<0.01) and bone mass (-20%; 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.

Figure 1

Plasma concentrations of total and active (octanoylated) ghrelin. A single subcutaneous injection (arrow) of either 12 or 24 nmol of ghrelin to intact mice promptly raised plasma concentrations of total (A) and active (B) ghrelin (n = 6 in each group). Plasma concentrations of total and active ghrelin were low following gastrectomy (Gx) compared with sham operation in mice. Concentrations of total ghrelin (C) and active (D) ghrelin remained elevated 16 hours after injection of 12 nmol of ghrelin after sham operation or gastrectomy in mice. Values are means (SEM); n = 10–12. *p<0.05, **p<0.01, ***p<0.001.

Figure 2

Food intake after sham operation or gastrectomy (Gx) in mice receiving daily injections of either saline or ghrelin (12 nmol daily subcutaneously) for eight weeks. There was no statistically significant difference in daily food intake (g/animal) between the different groups at any time point (A) or in cumulative food intake (g/animal) over eight weeks between the groups (B). Values are means (SEM) (n = number of mice).

Figure 3

Body weight at different times before (time 0) and after sham operation or gastrectomy (Gx) (arrow indicates surgery). After nine weeks, mean body weight of Gx mice was 15% lower than that of sham operated mice. Values are means (SEM); n = 10–12. **p<0.01, ***p<0.001.

Figure 4

Body weight development after (A) sham operation or (B) gastrectomy (Gx) in mice receiving daily injections of saline or ghrelin (12 nmol subcutaneously) for eight weeks (starting at time 0). (A, B) Ghrelin increased body weight in Gx mice (8%) but not in sham operated mice. Ghrelin increased the cumulative weight gain in Gx mice (D) but not that of sham operated mice (C). Values are means (SEM); n = 10–12. Vertical bars are invisible at times because SEM values are small. *p<0.05, **p<0.01, ***p<0.001.

Figure 5

Effects of gastrectomy (Gx) and/or daily administration of ghrelin (12 nmol subcutaneously) for eight weeks on body composition. (A) Gx reduced the amount of fat (−30%); this effect was prevented by ghrelin. Administration of ghrelin also increased the amount of fat in sham operated mice (20%). (B) Gx reduced lean body mass (−10%) while administration of ghrelin reversed the effect. There was no statistically significant difference in lean body mass between the two groups of sham operated mice receiving either saline or ghrelin. (C) Gx reduced bone mineral density (BMD) (−20%); ghrelin treatment had no effect. (D) Gx reduced femur ash weight (−20%). Daily ghrelin administration did not affect the bone of either sham operated or Gx mice. Values are means (SEM); n = 10–12. *p<0.05, **p<0.01, ***p<0.001.