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.

Hypothermia has been observed during hypergravity load in mice and rats. This response is beneficial for maintaining blood glucose level, although food intake decreases. However, saving glucose is not enough to maintain blood glucose level during hypergravity load. In this study, we examined the contribution of humoral factors related to glycolysis in maintaining blood glucose level in a 2 G environment. Increased plasma corticosterone levels were observed in mice with intact peripheral vestibular organs, but not in mice with vestibular lesions. Plasma glucagon levels did not change, and decrease in plasma adrenaline levels was observed in mice with intact peripheral vestibular organs. Accordingly, it is possible that increase in plasma corticosterone level and hypothermia contribute to prevent hypoglycemia in a 2 G environment.

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.

Aim To clarify the effects of glucose‐dependent insulinotropic polypeptide (GIP) receptor agonists (GIPRAs) on feeding and body weight. Materials and Methods Acute and subchronic effects of subcutaneous GIPFA‐085, a long‐acting GIPRA, on blood glucose, food intake, body weight, respiratory exchange ratio and plasma leptin levels were measured in diet‐induced obese (DIO) mice and/or functional leptin‐deficient ob/ob mice. The effects of GIPFA‐085 on the hypothalamic arcuate nucleus (ARC) neurons from lean and DIO mice were studied by measuring cytosolic Ca2+ concentration ([Ca2+]i). Results Single bolus GIPFA‐085 (30, 300 nmol/kg) dose‐dependently reduced blood glucose in glucose tolerance tests, elevated plasma leptin levels at 0.5‐6 hours and inhibited food intake at 2‐24 hours after injection in DIO mice. Daily GIPFA‐085 (300 nmol/kg) inhibited food intake and increased fat utilization on day 1, and reduced body weight gain on days 3‐12 of treatment in DIO, but not ob/ob, mice. GIPFA‐085 increased [Ca2+]i in the ARC leptin‐responsive and proopiomelanocortin (POMC) neurons. GIPFA‐085 and leptin cooperated to increase [Ca2+]i in ARC neurons and inhibit food intake. Conclusions GIPFA‐085 acutely inhibits feeding and increases lipid utilization, and sustainedly lowers body weight in DIO mice via mechanisms involving rises in leptin and activation of ARC leptin‐responsive and POMC neurons. This study highlights the therapeutic potential of GIPRAs for treating obesity and diabetes.

Autonomic nerves, including the sympathetic and parasympathetic nerves, control the immune system along with their physiological functions. On the peripheral side, the interaction between the splenic sympathetic nerves and immune cells is important for the anti-inflammatory effects. However, the central mechanism underlying these anti-inflammatory effects remains unclear. C1 neurons respond to stressors and subsequently determine the outflow of the autonomic nervous system. We have previously shown that C1 neurons protect against acute kidney injury, and found a signaling connection between peripheral vestibular organs and C1 neurons. Thus, we hypothesized that hypergravity load or galvanic vestibular stimulation (GVS) might protect against acute lung injury. We showed that C1 neurons are histologically and functionally activated by stimulating the peripheral vestibular organs. Protection against acute lung injury that was induced by a 2 G load was disappeared due to vestibular lesions or the deletion of C1 neurons. This GVS-induced protective effect was also eliminated by the deletion of the C1 neurons. Furthermore, GVS increased splenic sympathetic nerve activity in conscious mice, and splenic sympathetic denervation abolished the GVS-induced protection against acute lung injury. Therefore, the activated pathway between C1 neurons and splenic sympathetic nerves is indispensable for the GVS-induced protection against acute lung injury.