Background & Aims Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) reduce weight and improve glucose metabolism in obese patients, although it is not clear if metabolic changes are independent of weight loss. We investigated alterations in glucose metabolism in rats following RYGB or VSG. Methods Rats underwent RYGB or VSG and were compared to sham-operated rats that were fed ad lib or pair-fed with animals that received RYGB. Intraperitoneal glucose tolerance and insulin sensitivity tests were performed to assess glycemic function, independent of the incretin response. A hyperinsulinemic euglycemic clamp was used to compare tissue-specific changes in insulin sensitivity following each procedure. A mixed-meal tolerance tests was used to assess the effect of each surgery on post-prandial release of GLP-1(7–36) and glucose tolerance, and were also performed in rats given the GLP-1 receptor antagonist exendin9–39. Results Following RYGB or VSG, glucose tolerance and insulin sensitivity improved, in proportion to weight loss. Hepatic insulin sensitivity was significantly better in rats that received RYGB or VSG, compared with rats fed ad lib or pair-fed, whereas glucose clearance was similar in all groups. During the mixed-meal tolerance test, plasma levels of GLP-1(7–36) and insulin were greatly and comparably increased in rats that received RYGB and VSG, compared with those that were pair-fed or fed ad lib. Administration of a GLP-1 receptor antagonist prevented improvements in glucose and insulin responses after a meal among rats that received RYGB or VSG. Conclusion In obese rats, VSG is as effective as RYGB at increasing secretion of GLP-1 and insulin secretion and at improving hepatic sensitivity to insulin; these effects are independent of weight loss.

Background & Aims-Surgical intervention produces sustainable weight loss and metabolic improvement in obese individuals. Vertical sleeve gastrectomy (VSG) produces dramatic, sustained weight loss; we investigated whether these changes result from improved sensitivity to leptin.

Despite considerable scientific progress on the biological systems that regulate energy balance, we have made precious little headway in providing new treatments to curb the obesity epidemic. Diet and exercise are the most popular treatment options for obesity, but rarely are they sufficient to produce long-term weight loss. Bariatric surgery, on the other hand, results in dramatic, sustained weight loss and for this reason has gained increasing popularity as a treatment modality for obesity. At least some surgical approaches also reduce obesity-related comorbidities including type 2 diabetes and hyperlipidemia. This success puts a premium on understanding how these surgeries exert their effects. This review focuses on the growing human and animal model literature addressing the underlying mechanisms. We compare three common procedures: Roux-en-Y Gastric Bypass (RYGB), vertical sleeve gastrectomy (VSG), and adjustable gastric banding (AGB). Although many would group together VSG and AGB as restrictive procedures of the stomach, VSG is more like RYGB than AGB in its effects on a host of endpoints including intake, food choice, glucose regulation, lipids and gut hormone secretion. Our strong belief is that to advance our understanding of these procedures, it is necessary to group bariatric procedures not on the basis of surgical similarity but rather on how they affect key physiological variables. This will allow for greater mechanistic insight into how bariatric surgery works, making it possible to help patients better choose the best possible procedure and to develop new therapeutic strategies that can help a larger portion of the obese population.

Unsuppressed hepatic glucose production (HGP) contributes significantly to glucose intolerance and diabetes, which can be modeled by genetic inactivation of hepatic insulin receptor substrate (Irs) 1 and Irs2 (LDKO-mice). We previously showed that glucose intolerance in LDKO-mice is resolved by hepatic inactivation of the transcription factor FoxO1 (i.e., LTKO-mice)—even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue (WAT) of LDKO-mice is also impaired, but is restored in LTKO-mice in conjunction with normal suppression of HGP by insulin. To establish the mechanism by which WAT insulin signaling and HGP were regulated by hepatic FoxO1, we identified putative hepatokines—including excess follistatin (Fst)—that were dysregulated in LDKO-mice but normalized in LTKO-mice. Knockdown of hepatic Fst in the LDKO-liver restored glucose tolerance, WAT insulin signaling, and the suppression of HGP by insulin; however, expression of Fst in the liver of healthy LTKO-mice had the opposite effect. Of potential clinical significance, knockdown of Fst also improved glucose tolerance in high-fat fed obese mice, and serum FST was reduced in parallel with glycated hemoglobin in obese individuals with diabetes who underwent therapeutic gastric bypass surgery. We conclude that follistatin is a pathological hepatokine that might be targeted for diabetes therapy during hepatic insulin resistance.