Gastrointestinal Distension by Pectin-Containing Carbonated Solution Suppresses Food Intake and Enhances Glucose Tolerance via GLP-1 Secretion and Vagal Afferent Activation.

Kento Ohbayashi,Toshiki Asano,Toshihiko Yada,Yukiko Oyama,Chiharu Yamaguchi,Yusaku Iwasaki

doi:10.3389/fendo.2021.676869

Abstract

Diet-induced gastrointestinal distension is known to evoke satiation and suppress postprandial hyperglycemia; however, the underlying mechanisms remain poorly understood. This study explored how gastrointestinal distension regulates energy homeostasis by using inflating stomach formulation (ISF), the carbonated solution containing pectin that forms stable gel bubbles under acidic condition in the stomach. Here we show that, in mice, oral administration of ISF induced distension of stomach and proximal intestine temporarily, stimulated intestinal glucagon-like peptide-1 (GLP-1) secretion, and activated vagal afferents and brainstem. ISF suppressed food intake and improved glucose tolerance via enhancing insulin sensitivity. The anorexigenic effect was partially inhibited, and the beneficial glycemic effect was blunted by pharmacological GLP-1 receptor blockade and chemical denervation of capsaicin-sensitive sensory nerves. In HFD-fed obese mice showing arrhythmic feeding and obesity, subchronic ISF treatment at the light period (LP) onset for 10 days attenuated LP hyperphagia and visceral fat accumulation. These results demonstrate that gastrointestinal distension by ISF stimulates GLP-1 secretion and the vagal afferent signaling to the brain, thereby regulating feeding behavior and glucose tolerance. Furthermore, subchronic ISF treatment ameliorates HFD-induced visceral obesity. We propose the diet that induces gastrointestinal distension as a novel treatment of hyperphagic obesity and diabetes.

Highlights

Glucagon-like peptide-1 (GLP-1) is a peptide hormone produced primarily in the intestinal endocrine L cells and in the brainstem
inflating stomach formulation (ISF) increased expressions of lipid metabolism-related genes in epididymal WAT: peroxisome proliferator-activated receptor g (Pparg), adipose triglyceride lipase (Atgl), and hormone-sensitive lipase (Hsl) (Supplementary Figures 2A–C), while protein expression level of uncoupling protein-1 (UCP-1) in I-BAT was unaltered (Supplementary Figures 2D, E). These results indicate that subchronic ISF administration at light period (LP) onset corrects diurnal feeding rhythm and hyperphagia, which might contribute to improve insulin resistance and fat accumulation
We showed that temporary gastrointestinal distension by po administration of ISF stimulated intestinal GLP-1 secretion and activated “vagal afferents–brain” axis, thereby suppressing food intake and promoting glucose tolerance

Summary

Introduction

Glucagon-like peptide-1 (GLP-1) is a peptide hormone produced primarily in the intestinal endocrine L cells and in the brainstem. Secretion of intestinal GLP-1 is triggered by luminal macronutrient and plant polyphenols within 15–30 min after meal [1]. The meal-evoked GLP-1 secretion regulates postprandial functions such as satiation and blood glucose disposal [2]. GLP-1R agonists, unlike endogenous intestinal GLP-1, are stable and have a longer half-life in the circulation and act directly on pancreatic b cells [4] and hypothalamic neurons regulating glycemia and/or feeding [5, 6], thereby ameliorating hyperglycemia and overeating through direct action of GLP-1R agonists on target organs such as pancreatic b cells and central nerves [7, 8]. GLP-1R agonists elicit adverse effects including nausea and vomiting [9, 10], the effects possibly exerted by their passage through the blood–brain barrier to directly act on neurons in the brain [5, 6]

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Conclusion