Diet-dependent sex differences in the response to vertical sleeve gastrectomy.

Nearly 80% of patients that receive bariatric surgery are women, yet mechanistic preclinical studies have focused on males. The goal of this study was to determine the metabolic impact of diet- and surgery-induced weight loss in males, females, and ovariectomized females. All mice were fed a 60% high-fat diet (HFD) before undergoing either vertical sleeve gastrectomy (VSG) or sham surgery. Mice either remained on an HFD or were switched to a standard chow diet postsurgically. When maintained on an HFD, males and females decreased fat mass and improved oral glucose tolerance after VSG. After dietary intervention, additional adiposity was lost in both surgical groups. Ovariectomized females showed a blunted decrease in fat mass on an HFD, but lost significant adiposity after dietary intervention. Energy expenditure was impacted by dietary and not surgical intervention across all groups. Males decreased hepatic triglyceride levels after VSG, which was further decreased after dietary intervention. Intact and ovariectomized females had a blunted decrease in hepatic triglycerides after VSG, but a significant decrease after dietary intervention. The more pronounced effect of VSG on hepatic lipids in males is strongly associated with changes in hepatic expression of genes and microRNAs previously linked to hepatic lipid regulation and systemic energy homeostasis. These data highlight the importance of postsurgical diet on metabolic outcomes across sexes. Furthermore, these data suggest the impact of VSG on hepatic triglycerides is diet-dependent in females and support the hypothesis that males and females achieve similar metabolic outcome, at least within the liver, via distinct mechanisms.NEW & NOTEWORTHY These data highlight the interaction of postsurgical diet after bariatric surgery on metabolic outcomes across sexes. These data suggest the impact of VSG on hepatic triglycerides is diet-dependent in females and support the hypothesis that males and females achieve similar metabolic outcome, at least within the liver, via distinct mechanisms.

Oea Signaling Pathways and the Metabolic Benefits of Vertical Sleeve Gastrectomy.

OBJECTIVE: The aim of this study was to determine whether downstream [peroxisome proliferator-activated-receptor alpha (PPARα) and the G-protein coupled receptor, GPR119] and upstream (a fatty acid translocase, CD36) signaling targets of N-oleoylethanolamide (OEA) were necessary for weight loss, metabolic improvements, and diet preference following vertical sleeve gastrectomy (VSG). SUMMARY BACKGROUND DATA: OEA is an anorectic N-acylethanolamine produced from dietary fats within the intestinal lumen that can modulate lipid metabolism, insulin secretion, and energy expenditure by activating targets such as PPARα and GPR119. METHODS: Diet-induced obese mice, including wild-type or whole body knockout (KO) of PPARα, GPR119, and CD36, were stratified to either VSG or sham surgery before body weight, body composition, diet preference, and glucose and lipid metabolic endpoints were assessed. RESULTS: We found increased duodenal production of OEA and expression of both GPR119 and CD36 were upregulated in wild-type mice after VSG. However, weight loss and glucose tolerance were improved in response to VSG in PPARαKO, GPR119KO, and CD36KO mice. In fact, VSG corrected hepatic triglyceride dysregulation in CD36KO mice, and circulating triglyceride and cholesterol levels in PPARαKO mice. Lastly, we found PPARα-mediated signaling contributes to macronutrient preference independent of VSG, while removal of CD36 signaling blunts the VSG-induced shift toward carbohydrate preference. CONCLUSIONS: In the search for more effective and less invasive therapies to help reverse the global acceleration of obesity and obesity-related disease OEA is a promising candidate; however, our data indicate that it is not an underlying mechanism of the effectiveness of VSG.

Glycemic effect of pancreatic preproglucagon in mouse sleeve gastrectomy.

Intestinally derived glucagon-like peptide-1 (GLP-1), encoded by the preproglucagon (Gcg) gene, is believed to function as an incretin. However, our previous work questioned this dogma and demonstrated that pancreatic peptides rather than intestinal Gcg peptides, including GLP-1, are a primary regulator of glucose homeostasis in normal mice. The objective of these experiments was to determine whether changes in nutrition or alteration of gut hormone secretion by bariatric surgery would result in a larger role for intestinal GLP-1 in the regulation of insulin secretion and glucose homeostasis. Multiple transgenic models, including mouse models with intestine- or pancreas tissue-specific Gcg expression and a whole-body Gcg-null mouse model, were generated to study the role of organ-specific GLP-1 production on glucose homeostasis under dietary-induced obesity and after weight loss from bariatric surgery (vertical sleeve gastrectomy; VSG). Our findings indicated that the intestine is a major source of circulating GLP-1 after various nutrient and surgical stimuli. However, even with the 4-fold increase in intestinally derived GLP-1 with VSG, it is pancreatic peptides, not intestinal Gcg peptides, that are necessary for surgery-induced improvements in glucose homeostasis.

The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in mice.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two peptides that function to promote insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase the bioavailability of both GLP-1 and GIP but the dogma continues to be that it is the increase in GLP-1 that contributes to the improved glucose homeostasis. We have previously demonstrated that pancreatic rather than intestinal GLP-1 is necessary for improvements in glucose homeostasis in mice. Therefore, we hypothesise that a combination of pancreatic GLP-1 and GIP is necessary for the full effect of DPP-4 inhibitors on glucose homeostasis. METHODS: We have genetically engineered mouse lines in which the preproglucagon gene (Gcg) is absent in the entire body (GcgRAΔNull) or is expressed exclusively in the intestine (GcgRAΔVilCre) or pancreas and duodenum (GcgRAΔPDX1Cre). These mice were used to examine oral glucose tolerance and GLP-1 and GIP responses to a DPP-4 inhibitor alone, or in combination with incretin receptor antagonists. RESULTS: Administration of the DPP-4 inhibitor, linagliptin, improved glucose tolerance in GcgRAΔNull mice and control littermates and in GcgRAΔVilCre and GcgRAΔPDX1Cre mice. The potent GLP-1 receptor antagonist, exendin-[9-39] (Ex9), blunted improvements in glucose tolerance in linagliptin-treated control mice and in GcgRAΔPDX1Cre mice. Ex9 had no effect on glucose tolerance in linagliptin-treated GcgRAΔNull or in GcgRAΔVilCre mice. In addition to GLP-1, linagliptin also increased postprandial plasma levels of GIP to a similar degree in all genotypes. When linagliptin was co-administered with a GIP-antagonising antibody, the impact of linagliptin was partially blunted in wild-type mice and was fully blocked in GcgRAΔNull mice. CONCLUSIONS/INTERPRETATION: Taken together, these data suggest that increases in pancreatic GLP-1 and GIP are necessary for the full effect of DPP-4 inhibitors on glucose tolerance.

G-CSF partially mediates effects of sleeve gastrectomy on the bone marrow niche.

Bariatric surgeries are integral to the management of obesity and its metabolic complications. However, these surgeries cause bone loss and increase fracture risk through poorly understood mechanisms. In a mouse model, vertical sleeve gastrectomy (VSG) caused trabecular and cortical bone loss that was independent of sex, body weight, and diet, and this loss was characterized by impaired osteoid mineralization and bone formation. VSG had a profound effect on the bone marrow niche, with rapid loss of marrow adipose tissue, and expansion of myeloid cellularity, leading to increased circulating neutrophils. Following VSG, circulating granulocyte-colony stimulating factor (G-CSF) was increased in mice, and was transiently elevated in a longitudinal study of humans. Elevation of G-CSF was found to recapitulate many effects of VSG on bone and the marrow niche. In addition to stimulatory effects of G-CSF on myelopoiesis, endogenous G-CSF suppressed development of marrow adipocytes and hindered accrual of peak cortical and trabecular bone. Effects of VSG on induction of neutrophils and depletion of marrow adiposity were reduced in mice deficient for G-CSF; however, bone mass was not influenced. Although not a primary mechanism for bone loss with VSG, G-CSF plays an intermediary role for effects of VSG on the bone marrow niche.

Inflammatory responses to dietary and surgical weight loss in male and female mice.

BACKGROUND: Weight loss by surgery or lifestyle changes is strongly recommended for obese individuals to improve metabolic health, but the underlying impairments that persist from a history of obesity remain unclear. Recent investigations demonstrate a persistent inflammatory state with weight loss and bariatric surgery, but the mechanism and impact are not fully understood. Additionally, these studies have not been performed in females although women are the majority of individuals undergoing weight loss interventions. METHODS: The goal of this study was to determine the sex differences in metabolically induced inflammation after dietary weight loss (WL) or bariatric surgery. Following a 60% high-fat diet (HFD) for 12 weeks, C57Bl/6j mice underwent either a dietary switch to normal chow for WL or vertical sleeve gastrectomy (VSG) and were evaluated 8 weeks after intervention. WL effects on myelopoiesis were further evaluated with bone marrow chimeras. RESULTS: Both sexes had a decrease in adiposity and total weight following WL or VSG intervention. With HFD, females had very little inflammation and no further increase with WL, but males had persistent inflammation even after WL despite metabolic improvement. Interestingly, after VSG, myeloid inflammation was increased in the livers of males and to a lesser extent in females. CONCLUSIONS: These studies demonstrate that regardless of sex, it is critical to assess an individuals' history of obesity rather than just rely on current weight status in medical decision-making. There are long-lasting effects on tissue inflammation in both sexes especially with surgical weight loss. Dietary change is overall most effective to improve meta-inflammation in obese males on its own or in combination with surgical weight loss.

The Role of GLP-1 in the Metabolic Success of Bariatric Surgery.

Two of the most popular bariatric procedures, vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB), are commonly considered metabolic surgeries because they are thought to affect metabolism in a weight loss-independent manner. In support of this classification, improvements in glucose homeostasis, insulin sensitivity, and even discontinuation of type 2 diabetes mellitus (T2DM) medication can occur before substantial postoperative weight loss. The mechanisms that underlie this effect are unknown. However, one of the common findings after VSG and RYGB in both animal models and humans is the sharp postprandial rise in several gut peptides, including the incretin and satiety peptide glucagonlike peptide-1 (GLP-1). The increase in endogenous GLP-1 signaling has been considered a primary pathway leading to postsurgical weight loss and improvements in glucose metabolism. However, the degree to which GLP-1 and other gut peptides are responsible for the metabolic successes after bariatric surgery is continually debated. In this review we discuss the mechanisms underlying the increase in GLP-1 and its potential role in the metabolic improvements after bariatric surgery, including remission of T2DM. Understanding the role of changes in gut peptides, or lack thereof, will be crucial in understanding the critical factors necessary for the metabolic success of bariatric surgery.

Physiological and molecular responses to bariatric surgery: markers or mechanisms underlying T2DM resolution?

Bariatric surgery is currently the most effective treatment for obesity and associated comorbidities, including rapid resolution of type 2 diabetes mellitus (T2DM). Although the weight loss itself has substantial impact, bariatric surgery also has weight loss-independent effects on T2DM. Several variations of bariatric surgery exist, including the widely studied Roux-en-Y gastric bypass and vertical sleeve gastrectomy. The success of both of these bariatric surgeries was originally attributed to restrictive and malabsorptive modes of action; however, mounting evidence from both human and animal studies implicates mechanisms beyond surgery-induced mechanical changes to the gastrointestinal (GI) system. In fact, with bariatric surgery comes a spectrum of physiological responses, including postprandial enhancement of gut peptide and bile acids levels, restructuring of microbial composition, and changes in GI function and morphology. Although many of these processes are also essential for glucoregulation, the independent role of each in the success of surgery is still an open question. In this review, we explore whether these changes are necessary for the improvements in body mass and glucose homeostasis or whether they are simply markers of the physiological effect of surgery.