The role of free fatty acids (FFAs) in glucagon secretion has not been well established, and the involvement of FFA receptor GPR40 and its downstream signaling pathways in regulating glucagon secretion are rarely demonstrated. In this study, it was found that linoleic acid (LA) acutely stimulated glucagon secretion from primary cultured rat pancreatic islets. LA at 20 and 40 μmol/l dose-dependently increased glucagon secretion both at 3 mmol/l glucose and at 15 mmol/l glucose, although 15 mmol/l glucose reduced basal glucagon levels. LA induced an increase in cytoplasmic free calcium concentrations ([Ca2 +]i) in identified rat α-cells, which is reflected by increased Fluo-3 intensity under confocal microscopy recording. The increase in [Ca2 +]i was partly inhibited by removal of extracellular Ca2 + and eliminated overall by further exhaustion of intracellular Ca2 + stores using thapsigargin treatment, suggesting that both Ca2 + release and Ca2 + influx contributed to the LA-stimulated increase in [Ca2 +]i in α-cells. Double immunocytochemical stainings showed that GPR40 was expressed in glucagon-positive α-cells. LA-stimulated increase in [Ca2 +]i was blocked by inhibition of GPR40 expression in α-cells after GPR40-specific antisense treatment. The inhibition of phospholipase C activity by U73122 also blocked the increase in [Ca2 +]i by LA. It is concluded that LA activates GPR40 and phospholipase C (and downstream signaling pathways) to increase Ca2 + release and associated Ca2 + influx through Ca2 + channels, resulting in increase in [Ca2 +]i and glucagon secretion.
Li Wang, Yufeng Zhao, Baosong Gui, Rongguo Fu, Feng Ma, Jun Yu, Ping Qu, Lei Dong and Chen Chen
Chunxia Yu, Sujuan Liu, Liqin Chen, Jun Shen, Yanmei Niu, Tianyi Wang, Wanqi Zhang and Li Fu
The composition and activity of the gut microbiota depend on the host genome, nutrition, and lifestyle. Exercise and sodium butyrate (NaB) exert metabolic benefits in both mice and humans. However, the underlying mechanisms have not been fully elucidated. This study aimed to examine the effect of exercise training and dietary supplementation of butyrate on the composition of gut microbiota and whether the altered gut microbiota can stimulate differential production of short-chain fatty acids (SCFAs), which promote the expression of SESN2 and CRTC2 to improve metabolic health and protect against obesity. C57BL/6J mice were used to study the effect of exercise and high-fat diet (HFD) with or without NaB on gut microbiota. Bacterial communities were assayed in fecal samples using pyrosequencing of 16S rRNA gene amplicons. Western blot was performed using relevant antibodies to detect the protein expressions in liver and HepG2 cell extracts. Exercise and butyrate administration significantly reversed metabolic dysfunctions induced by HFD (P < 0.05). The number of Firmicutes and the proportion of Firmicutes to Bacteroidetes order were predominant in all HFD groups (P = 0.001). Exercise and butyrate supplementation significantly inhibited the relative abundance of lipopolysaccharide-producing phyla (P = 0.001). SESN2 and CRTC2 expression in the liver of mice were significantly increased after exercise (P < 0.05) and/or supplementation of butyrate (P < 0.05). Exercise enhances butyrate-producing fecal bacteria and increases butyrate production and consequently improves lipid metabolism through the butyrate-SESN2/CRTC2 pathway. Excess butyrate may reduce the proportion of probiotics and reverse the metabolic effects.