Oea Signaling Pathways and the Metabolic Benefits of Vertical Sleeve Gastrectomy

Abstract

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.

Vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signaling

“…VSG mice also had improved oral glucose tolerance compared with sham surgery mice (Figure 1F). These data highlight that we have replicated our previous findings regarding the impact of VSG on BW, food intake, and glucose tolerance (19)(20)(21).…”

Glycemic effect of pancreatic preproglucagon in mouse sleeve gastrectomy

“…Intestinal GLP-1 is not necessary for the glycemic improvements after VSG. VSG produces reliable 3-to 4-fold increases in postprandial plasma GLP-1 levels in mice (26,27). We hypothesized that this large increase in postprandial GLP-1 comes from the intestine and that the degree of the increase would lead to a more prominent role for this source of GLP-1 in regulating glucose tolerance.…”

Targeting the GPR119/incretin axis: a promising new therapy for metabolic-associated fatty liver disease

“…Moran et al found that the gastric inhibitory effect produced by OEA may involve pancreatic polypeptide (PPY) [ 50 ]. OEA can trigger effects similar to those observed after bariatric surgery, including reduced food intake, reduced fat mass, increased GLP-1 release, and reduced lipid levels, which are undoubtedly beneficial to patients with MAFLD [ 69 ].…”