It has long been thought that long-chain free fatty acids (FFAs) stimulate insulin secretion via mechanisms involving their metabolism in pancreatic β-cells. Recently, it was reported that FFAs function as endogenous ligands for GPR40, a G protein-coupled receptor, to amplify glucose-stimulated insulin secretion in an insulinoma cell line and rat islets. However, signal transduction mechanisms for GPR40 in β-cells are little known. The present study was aimed at elucidating GPR40-linked Ca²⁺signaling mechanisms in rat pancreatic β-cells. We employed oleic acid (OA), an FFA that has a high affinity for the rat GPR40, and examined its effect on cytosolic Ca²⁺concentration ([Ca²⁺]_i) in single β-cells by fura 2 fluorescence imaging. OA at 1–10 μM concentration-dependently increased [Ca²⁺]_iin the presence of 5.6, 8.3, and 11.2 mM, but not 2.8 mM, glucose. OA-induced [Ca²⁺]_iincreases at 11.2 mM glucose were inhibited in β-cells transfected with small interfering RNA targeted to rat GPR40 mRNA. OA-induced [Ca²⁺]_iincreases were also inhibited by phospholipase C (PLC) inhibitors, U73122 and neomycin, Ca²⁺-free conditions, and an L-type Ca²⁺channel blocker, nitrendipine. Furthermore, OA increased insulin release from isolated islets at 8.3 mM glucose, and it was markedly attenuated by PLC and L-type Ca²⁺channel inhibitors. These results demonstrate that OA interacts with GPR40 to increase [Ca²⁺]_ivia PLC- and L-type Ca²⁺channel-mediated pathway in rat islet β-cells, which may be link to insulin release.

Recent studies suggest that oxytocin (Oxt) is implicated in energy metabolism. We aimed to explore acute and sub-chronic effects of peripheral Oxt treatment via different routes on food intake and energy balance. Intraperitoneal (ip) injection of Oxt concentration-dependently decreased food intake in mice. Ip Oxt injection induced c-Fos expression in the hypothalamus and brain stem including arcuate nucleus (ARC), paraventricular nucleus (PVN) and nucleus tractus solitarius (NTS). Subcutaneous (sc) injection of Oxt suppressed food intake in normal and high fat diet-induced obese (DIO) mice. Daily sc injection of Oxt for 17 days in DIO mice reduced food intake for 6 days and body weight for the entire treatment period and additional 9 days after terminating Oxt. Oxt infusion by sc implanted osmotic minipumps for 13 days in DIO mice reduced food intake, body weight, and visceral fat mass and adipocyte size. Oxt infusion also decreased respiratory quotient specifically in light phase, ameliorated fatty liver and glucose intolerance, without affecting normal blood pressure in DIO mice. These results demonstrate that peripheral Oxt treatment reduces food intake and visceral fat mass, and ameliorates obesity, fatty liver and glucose intolerance. Peripheral Oxt treatment provides a new therapeutic avenue for treating obesity and hyperphagia.

Overeating and arrhythmic feeding promote obesity and diabetes. Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective anti-obesity drugs but their use is limited by side effects. Here we show that oral administration of the non-calorie sweetener, rare sugar d-allulose (d-psicose), induces GLP-1 release, activates vagal afferent signaling, reduces food intake and promotes glucose tolerance in healthy and obese-diabetic animal models. Subchronic d-allulose administered at the light period (LP) onset ameliorates LP-specific hyperphagia, visceral obesity, and glucose intolerance. These effects are blunted by vagotomy or pharmacological GLP-1R blockade, and by genetic inactivation of GLP-1R signaling in whole body or selectively in vagal afferents. Our results identify d-allulose as prominent GLP-1 releaser that acts via vagal afferents to restrict feeding and hyperglycemia. Furthermore, when administered in a time-specific manner, chronic d-allulose corrects arrhythmic overeating, obesity and diabetes, suggesting that chronotherapeutic modulation of vagal afferent GLP-1R signaling may aid in treating metabolic disorders.