Elsevier

Molecular Metabolism

Volume 4, Issue 12, December 2015, Pages 940-950
Molecular Metabolism

Original article
α/β-Hydrolase domain-6 and saturated long chain monoacylglycerol regulate insulin secretion promoted by both fuel and non-fuel stimuli

https://doi.org/10.1016/j.molmet.2015.09.012Get rights and content
Under a Creative Commons license
open access

Highlights

  • ABHD6 is the major monoacylglycerol (MAG) hydrolase in pancreatic β cells.

  • 1-MAG level is elevated in islets from β cell specific ABHD6-KO mice (BKO).

  • BKO islets show enhanced fuel and non-fuel induced insulin secretion.

  • ABHD6 accessible 1-MAG synergizes with other signals for insulin secretion.

Abstract

Objective

α/β-Hydrolase domain-6 (ABHD6) is a newly identified monoacylglycerol (MAG) lipase. We recently reported that it negatively regulates glucose stimulated insulin secretion (GSIS) in the β cells by hydrolyzing lipolysis-derived MAG that acts as a metabolic coupling factor and signaling molecule via exocytotic regulator Munc13-1. Whether ABHD6 and MAG play a role in response to all classes of insulin secretagogues, in particular various fuel and non-fuel stimuli, is unknown.

Methods

Insulin secretion in response to various classes of secretagogues, exogenous MAG and pharmacological agents was measured in islets of mice deficient in ABHD6 specifically in the β cell (BKO). Islet perifusion experiments and determinations of glucose and fatty acid metabolism, cytosolic Ca2+ and MAG species levels were carried out.

Results

Deletion of ABHD6 potentiated insulin secretion in response to the fuels glutamine plus leucine and α-ketoisocaproate and to the non-fuel stimuli glucagon-like peptide 1, carbamylcholine and elevated KCl. Fatty acids amplified GSIS in control and BKO mice to the same extent. Exogenous 1-MAG amplified insulin secretion in response to fuel and non-fuel stimuli. MAG hydrolysis activity was greatly reduced in BKO islets without changes in total diacylglycerol and triacylglycerol lipase activity. ABHD6 deletion induced insulin secretion independently from KATP channels and did not alter the glucose induced rise in intracellular Ca2+. Perifusion studies showed elevated insulin secretion during second phase of GSIS in BKO islets that was not due to altered cytosolic Ca2+ signaling or because of changes in glucose and fatty acid metabolism. Glucose increased islet saturated long chain 1-MAG species and ABHD6 deletion caused accumulation of these 1-MAG species at both low and elevated glucose.

Conclusion

ABHD6 regulates insulin secretion in response to fuel stimuli at large and some non-fuel stimuli by controlling long chain saturated 1-MAG levels that synergize with other signaling pathways for secretion.

Keywords

α/β-Hydrolase domain-6
Monoacylglycerol
Insulin secretion
Pancreatic islets
Cytosolic Ca2+

Abbreviations

ABHD6
α/β-hydrolase domain-6
ATGL
adipose triglyceride lipase
BKO
β cell specific ABHD6-knockout
Carb
carbamylcholine
DAG
diacylglycerol
FFA
free fatty acid
Flox
flox/flox
GL/FFA
glycerolipid/ free fatty acid
GLP1
glucagon-like peptide 1
GPCR
G-protein coupled receptor
GSIS
glucose stimulated insulin secretion
HSL
hormone sensitive lipase
Kic
α-ketoisocaproate
KO
knockout
MAG
monoacylglycerol
OGTT
oral glucose tolerance test
ROS
reactive oxygen species
TG
triacylglycerol
WT
wild type
1-OG
1-oleoylglycerol
1-PG
1-palmitoylglycerol
1-SG
1-stearoylglycerol

Cited by (0)

1

Shangang Zhao and Pegah Poursharifi equally contributed to this project.

2

Current address: Departamento de Nutricion y Bioquímica, Pontificia Universidad Javeriana, Cra 7, No. 43–82, Edf. Carlos Ortiz., Bogotá, Colombia.