Gamma-aminobutyric acid (GABA) is present in the mammalian brain as the main inhibitory neurotransmitter and in foods. It is widely used as a supplement that regulates brain function through stress-reducing and sleep-enhancing effects. However, its underlying mechanisms remain poorly understood, as it is reportedly unable to cross the blood–brain barrier. Here, we explored whether a single peroral administration of GABA affects feeding behavior as an evaluation of brain function and the involvement of vagal afferent nerves. Peroral GABA at 20 and 200 mg/kg immediately before refeeding suppressed short-term food intake without aversive behaviors in mice. However, GABA administration 30 min before refeeding demonstrated no effects. A rise in circulating GABA concentrations by the peroral administration of 200 mg/kg GABA was similar to that by the intraperitoneal injection of 20 mg/kg GABA, which did not alter feeding. The feeding suppression by peroral GABA was blunted by the denervation of vagal afferents. Unexpectedly, peroral GABA alone did not alter vagal afferent activities histologically. The coadministration of a liquid diet and GABA potentiated the postprandial activation of vagal afferents, thereby enhancing postprandial satiation. In conclusion, dietary GABA activates vagal afferents in collaboration with meals or meal-evoked factors and regulates brain function including feeding behavior.

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.

Obesity continues to increase worldwide. The primary cause of obesity is overeating, but the development of pharmacological treatments for obesity related to overeating has taken longer than expected. Recently, agonists of glucagon-like peptide-1 (GLP-1) receptor, designed based on the gut hormone GLP-1, have been developed as anti-obesity drugs and have demonstrated remarkable efficacy in treating both obesity and diabetes. Meanwhile, recent research using factors that promote GLP-1 secretion has highlighted the significance of endogenous GLP-1 function. This review provides an overview of the anorexigenic effects, adverse effects, and their underlying mechanisms of GLP-1 receptor agonists and endogenous gut-derived GLP-1. Furthermore, it discusses the potential anti-obesity effects of dual agonists targeting both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the GLP-1 receptor, which have gained attention in recent years. Finally, we compare the beneficial effects of GLP-1 receptor agonists and meal-induced gut GLP-1 secretion on overeating-induced obesity and discuss how combining these approaches may complement each other’s limitations and serve as a promising long-term strategy for preventing and treating obesity.

(1) Background: Proglucagon-derived peptides (PDGPs) including glucagon (Gcg), GLP-1, and GLP-2 regulate lipid metabolism in the liver, adipocytes, and intestine. However, the mechanism by which PGDPs participate in alterations in lipid metabolism induced by high-fat diet (HFD) feeding has not been elucidated. (2) Methods: Mice deficient in PGDP (GCGKO) and control mice were fed HFD for 7 days and analyzed, and differences in lipid metabolism in the liver, adipose tissue, and duodenum were investigated. (3) Results: GCGKO mice under HFD showed lower expression levels of the genes involved in free fatty acid (FFA) oxidation such as Hsl, Atgl, Cpt1a, Acox1 (p < 0.05), and Pparα (p = 0.05) mRNA in the liver than in control mice, and both FFA and triglycerides content in liver and adipose tissue weight were lower in the GCGKO mice. On the other hand, phosphorylation of hormone-sensitive lipase (HSL) in white adipose tissue did not differ between the two groups. GCGKO mice under HFD exhibited lower expression levels of Pparα and Cd36 mRNA in the duodenum as well as increased fecal cholesterol contents compared to HFD-controls. (4) Conclusions: GCGKO mice fed HFD exhibit a lesser increase in hepatic FFA and triglyceride contents and adipose tissue weight, despite reduced β-oxidation in the liver, than in control mice. Thus, the absence of PGDP prevents dietary-induced fatty liver development due to decreased lipid uptake in the intestinal tract.

Background/Objectives: Rare sugars, which naturally exist in small quantities, have gained attention as next-generation functional sugars due to their sweetness and low calorie content. Some of them have already been commercialized. Rare sugar-containing syrups, produced through alkaline isomerization of high-fructose corn syrup, are effective in preventing obesity and type 2 diabetes. However, the mechanisms underlying these effects remain incompletely understood. Recently, D-allulose has been found to improve hyperphagic obesity by stimulating the secretion of the intestinal hormone glucagon-like peptide-1 (GLP-1). The present study aimed to determine the comparative effects of aldohexoses (D-glucose, D-allose) and ketohexoses (D-fructose, D-allulose, D-tagatose, D-sorbose) on GLP-1 secretion and food intake in male mice. Method and Results: Single peroral administration of four ketohexoses at 1 and 3 g/kg, but not aldohexoses at 1 and 3 g/kg, significantly increased plasma GLP-1 concentrations with comparable efficacy. Moreover, these ketohexoses at 1 g/kg suppressed food intake in the short term, an effect blunted by GLP-1 receptor antagonism. In contrast, zero-calorie D-allose at 3 g/kg suppressed feeding without raising plasma GLP-1 levels. Conclusions: These results demonstrate that D-allulose, D-tagatose, and D-sorbose, which are low-calorie rare sugars classified as ketohexoses, suppress food intake through promoting GLP-1 secretion, showing their potential to prevent and/or ameliorate type 2 diabetes, obesity and related diseases.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) ameliorate hyperglycemia by directly stimulating insulin secretion from the pancreas. In contrast, the physiological role of short-lived endogenous GLP-1 remains unclear largely because of its limited access to pancreatic β-cells. Here, we used d-allulose, a nonmetabolizable noncaloric rare sugar, as a GLP-1 secretagogue. We show that d-allulose–induced intestinal GLP-1 secretion (AIGS) cooperates with insulin to reduce blood glucose levels by enhancing insulin action, rather than insulin secretion, in male mice. This cooperation and remote signaling require left-sided vagal afferents forming the common hepatic branch, but not right-sided afferents. AIGS-enhanced insulin action required both GLP-1Rs and insulin receptor substrate 2 in these neurons. Remarkably, in db/db mice exhibiting severe insulin resistance, AIGS improved insulin resistance and hyperglycemia more rapidly and potently than the GLP-1RA exendin-4. These findings reveal that a subclass of vagal afferent neurons synergistically activated by endogenous intestinal GLP-1 and insulin does not stimulate insulin secretion but augments insulin action to improve glucose tolerance. This novel extrapancreatic GLP-1 action mediated by vagal afferents provides a promising basis for innovative type 2 diabetes therapies. Article Highlights: Compared with glucagon-like peptide 1 (GLP-1) receptor agonists, the physiological roles and mechanisms of endogenous, short-lived GLP-1 in glucose metabolism remain poorly understood. We used the rare sugar d-allulose, a noncaloric GLP-1 secretagogue, as a tool to elucidate the physiological actions of endogenous GLP-1. d-Allulose–induced intestinal GLP-1 release cooperates with insulin to activate left-side vagal afferents, enhancing insulin action rather than insulin secretion and thereby regulating glycemic control. Because this acute mechanism improved hyperglycemia in type 2 diabetes to an extent comparable to that observed with GLP-1 receptor agonists, targeting GLP-1/insulin-vagal signaling may inform novel therapies and dietary or nutritional interventions for type 2 diabetes.