Role of Adipose Triglyceride Lipase and Lipolysis in the Regulation of Insulin Secretion: Study in β-Cell-Specific ATGL-Deficient Mice

Abstract

Previous studies have suggested that lipolysis-derived lipid signalling molecules play a role in the regulation of glucose-stimulated insulin secretion. To directly assess the role of lipolysis of β-cell endogenous lipid stores in glucose signalling for insulin secretion, β-cell-specific adipose triglyceride lipase (ATGL)-deficient mice (KO) were generated. β-cell-specific tamoxifen-inducible ATGL deletion in MIP-Cre-ER/ATGL-LoxP mice (KO) was compared to tamoxifen-injected-MIP-Cre-ER and -ATGL-LoxP mice (controls). Two weeks after tamoxifen treatment in 8-week-old mice, ATGL protein level was dramatically decreased in KO islets from both sexes. KO male mice showed a decrease in body weight gain compared to the controls, which became significant 6 weeks after tamoxifen injection. Fasting plasma levels of free fatty acids and triglycerides were unchanged in KO mice of both sexes. Male KO mice showed a 60% decrease in insulinemia without altered glycemia in fed and fasted states. They also showed a 70% reduction in plasma insulin levels in response to a glucose challenge and a trend toward glucose intolerance. However, despite similar ATGL deletion in female KO mice, none of these changes in glucose homeostasis and insulin secretory response were observed. These results demonstrate that lipolysis via ATGL is involved in glucose-stimulated insulin secretion, at least in male mice. Female mice are often protected from diabetes in various animal models due to estrogens and a number of compensatory processes. We are currently studying the compensatory mechanisms that occur in KO female mice as they may reveal signalling and compensatory pathways involved in insulin secretion.