A low protein diet drives short and long-term improvements in metabolic health in a mouse model of sleeve gastrectomy

Despite the largely beneficial impact of bariatric surgery on obesity and metabolic disease, many patients continue to suffer from obesity after surgery and weight recurrence is common. The success of bariatric surgery may be impacted by diet. While bariatric surgery guidelines recommend a high-protein diet following surgery based on the theory that this will preserve lean mass, emerging evidence suggests that both humans and mice are metabolically healthier when consuming low protein diets. Here, we assess the effect of varying dietary protein levels on post-surgical weight loss and weight regain in a mouse model of bariatric surgery, sleeve gastrectomy. We find that a low protein diet optimally drives post-surgical weight loss, boosting energy expenditure and improving blood glucose regulation. Using a multi-omics approach, we identified clusters of differentially expressed genes and metabolites that correlated with these phenotypes and find that diet heavily influences the molecular response of the liver to sleeve gastrectomy. These results suggest that current post-surgical dietary guidelines recommending a high protein diet may limit both the short and long-term benefits of surgery and lead us to conclude that a low protein diet may improve patient outcomes. Overall design: Five-week-old C57BL/6J male mice were fed a high-fat, high sucrose Western Diet for 12 weeks to induce obesity and glucose intolerance. They were then randomized into weight-matched groups to receive either Sleeve Gastrectomy or Sham operations. To examine the interaction between post-operative dietary protein consumption and metabolism following SG, both SG and Sham mice were further randomized following surgery to either continue consuming a WD, or to consume a lower-fat diet with either High protein (36% calories from protein), Medium (21% calories from protein), or Low protein (7% calories from protein). The three lower-fat diets were isocaloric, with 20% calories from fat and variable carbohydrate to replace any caloric deficit as previously reported. Given the critical role the liver plays in regulating metabolism, we conducted a detailed transcriptomic analysis of liver specimens from sham and SG mice across the three post-operative protein diets in response to feeding. Prior to euthanasia and tissue collection, mice were fasted for 16 hours followed by a 4-hour refeeding period with their respective diets.