α/β-Hydrolase Domain-6-Accessible Monoacylglycerol Controls Glucose-Stimulated Insulin Secretion

• Published in: Cell metabolism Vol. 19; no. 6; pp. 993 - 1007
• Main Authors: Zhao, Shangang, Mugabo, Yves, Iglesias, Jose, Xie, Li, Delghingaro-Augusto, Viviane, Lussier, Roxane, Peyot, Marie-Line, Joly, Erik, Taïb, Bouchra, Davis, Matthew A., Brown, J. Mark, Abousalham, Abdelkarim, Gaisano, Herbert, Madiraju, S.R. Murthy, Prentki, Marc
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-06-2014; Elsevier
• Subjects: Animals; Anti-Obesity Agents - pharmacology; Biochemistry; Biochemistry, Molecular Biology; Biphenyl Compounds - pharmacology; Carbamates - pharmacology; Cells, Cultured; Enzyme Inhibitors - pharmacology; Glucose - metabolism; Humans; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells; Lactones - pharmacology; Life Sciences; Lipase - antagonists & inhibitors; Lipid Metabolism; Lipolysis; Mice; Mice, Inbred C57BL; Mice, Knockout; Monoacylglycerol Lipases - antagonists & inhibitors; Monoacylglycerol Lipases - biosynthesis; Monoacylglycerol Lipases - genetics; Monoglycerides - biosynthesis; Monoglycerides - metabolism; Monoglycerides - pharmacology; Nerve Tissue Proteins - metabolism; Orlistat; Protein Binding; Rats; Rats, Wistar; Receptors, Cannabinoid - metabolism; RNA Interference; RNA, Small Interfering; Signal Transduction
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2014.04.003

Glucose metabolism in pancreatic β cells stimulates insulin granule exocytosis, and this process requires generation of a lipid signal. However, the signals involved in lipid amplification of glucose-stimulated insulin secretion (GSIS) are unknown. Here we show that in β cells, glucose stimulates production of lipolysis-derived long-chain saturated monoacylglycerols, which further increase upon inhibition of the membrane-bound monoacylglycerol lipase α/β-Hydrolase Domain-6 (ABHD6). ABHD6 expression in β cells is inversely proportional to GSIS. Exogenous monoacylglycerols stimulate β cell insulin secretion and restore GSIS suppressed by the pan-lipase inhibitor orlistat. Whole-body and β-cell-specific ABHD6-KO mice exhibit enhanced GSIS, and their islets show elevated monoacylglycerol production and insulin secretion in response to glucose. Inhibition of ABHD6 in diabetic mice restores GSIS and improves glucose tolerance. Monoacylglycerol binds and activates the vesicle priming protein Munc13-1, thereby inducing insulin exocytosis. We propose saturated monoacylglycerol as a signal for GSIS and ABHD6 as a negative modulator of insulin secretion.
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•Glucose increases monoacylglycerol (MAG) and insulin secretion in β cells•Suppression of the MAG hydrolase ABHD6 enhances GSIS•MAG binds to the exocytotic effector Munc13-1 and promotes insulin exocytosis•MAG is a coupling factor linking β cell glucose metabolism to insulin secretion
Glucose must be metabolized by pancreatic β cells to promote glucose-stimulated insulin secretion (GSIS). Zhao et al. found that saturated long-chain monoacylglycerol acts as metabolic coupling factor for GSIS, activating the exocytotic effector Munc13-1, and that the monoacylglycerol signal is controlled by α/β-Hydrolase Domain 6 (ABHD6).