Changes in serum ghrelin predict weight loss after Roux-en-Y gastric bypass in rats

Background: Although Roux-en-Y gastric bypass (RYGB) is an effective and widely used therapy for severe obesity, the mechanisms by which it induces weight loss are not well understood. Several studies have shown that RYGB in human patients causes a decrease in circulating levels of ghrelin, a gastric hormone that strongly stimulates food intake. Substantial variation in the effect of RYGB on serum ghrelin has been reported in different studies and among individual patients, suggesting that regulation of this hormone is complex and subject to genetic and other patient-specific factors. To control for these factors and to enable more detailed study of physiologic mechanisms, we have recently developed a clinically relevant rat model of RYGB. In this study, we used this model to examine the effect of RYGB on serum ghrelin levels. Methods: Fifteen Sprague-Dawley rats that had received a high-fat diet to induce moderate obesity underwent RYGB. The operation closely resembled the procedure in humans. Serum samples were collected I month before and 3 months after RYGB, and serum ghrelin levels were measured. The primary outcomes of the study were the changes in body weight, food intake, and circulating ghrelin levels after RYGB. A multiple linear regression model was developed to examine the relationship between ghrelin levels and weight change after RYGB. Results: Three months after the procedure, RYGB-treated rats weighed 20 +/- 5% less than they would have, had they not undergone the procedure. Despite the weight loss, serum ghrelin levels were 38 +/- 6% lower than before surgery. There was appreciable variation in the weight loss in individual animals, and preoperative weight and pre- and postoperative ghrelin levels were the best predictors of postoperative weight loss. Thus, the animals who had the greatest weight loss were those that were heaviest before surgery. These rats had the highest preoperative and lowest postoperative ghrelin levels. Conclusions: Using our recently developed rat model of RYGB, we found that postoperative weight loss is correlated with the magnitude of the decrease in circulating ghrelin levels. This correlation provides the strongest evidence to date that altered ghrelin signaling contributes to weight loss after this operation. The lower level of circulating ghrelin after RYGB likely blunts the appetitive drive, leading to decreased food intake in these animals.