Impact of adipocyte lipolysis on beta cell function

Type 2 diabetes is a major global health problem and strongly associated with severe metabolic comorbidities such as stroke, heart or kidney failure. The progression of diabetes is characterized by the inability to meet insulin requirement because of increased peripheral insulin resistance and impaired insulin secretion from pancreatic beta cells. Therapeutic approaches to counteract diabetes are amongst others the improvement of beta cell growth to maintain sufficient insulin secretion. Insulin secretion is primarily regulated by the uptake of glucose, but also lipids such as fatty acids are crucial to modulate insulin secretory response. Adipose tissue is the main organ that stores fat in form of triglycerides. The enzymatic breakdown of triglycerides (lipolysis) results in the release of fatty acids, and is primarily catalyzed by Adipose Triglyceride Lipase (ATGL) and Hormone-sensitive Lipase (HSL). Our preliminary data demonstrate that reduced adipocyte lipolysis directly affects beta cell function and growth. Inhibition of ATGL-mediated adipocyte lipolysis reduces glucose-stimulated insulin secretion in vivo and impairs insulin synthesis and storage ability within pancreatic islets resulting in reduced beta cell mass. The CENTRAL AIM of this proposal is to determine the contribution of adipocyte lipolysis and the released lipid metabolites to insulin secretory response and beta cell growth. For this purpose, we have generated mouse models with adipocyte-specific targeted-deletion of ATGL and HSL. We will evaluate the impact of each lipase on in vivo insulin secretory response and peripheral insulin sensitivity as well as studying metabolic mechanisms within pancreatic beta cells that regulate insulin secretion and/or beta cell growth. Finally, we will determine lipid profiles in our knockout mouse models to link alterations in beta cell function and growth to the presence of specific lipid species. Overall, these studies will promote the understanding of adipocyte lipolysis and its impact on beta cell function and growth, thereby providing new insights into the development and treatment of diabetes.

Impact of adipocyte lipolysis on beta cell function Type 2 diabetes is a major global health problem and strongly associated with severe metabolic comorbidities such as stroke, heart, or kidney failure. The progression of diabetes is characterized by the inability to meet insulin requirement because of increased peripheral insulin resistance and impaired insulin secretion from pancreatic beta cells. Therapeutic approaches to counteract diabetes are amongst others the improvement of beta cell function to maintain sufficient insulin secretion. Insulin secretion is primarily regulated by the uptake of glucose, but also lipids such as fatty acids are critical to modulate insulin secretory response. Adipose tissue is the main organ that stores fat in form of triglycerides. The enzymatic breakdown of triglycerides (also known as lipolysis) results in the release of fatty acids and is primarily catalyzed by Adipose Triglyceride Lipase (ATGL) and Hormone-sensitive Lipase (HSL). Within the framework of this project, we used adipocyte-specific ATGL and HSL knockout (AAKO and AHKO) mice to demonstrate that both adipocyte lipases are essential to regulate insulin secretion in vivo. The loss of ATGL or HSL and the accompanied reduced fatty acids release results in a significant decline in insulin secretion in vivo upon fasting. In contrast, pancreatic islets derived from KO mice have a sufficient insulin secretory response, suggesting that these islets are metabolic active and that AAKO and AHKO mice are missing an insulinotropic trigger in vivo. The impaired insulin secretory response is accompanied by reduced levels of beta cell-specific neutral lipids including triglycerides and monoglycerides. Especially, insulinotropic monoglycerides are significantly reduced in beta cells, indicating that adipocyte-derived fatty acids are a critical exogenous source to generate beta cell-specific lipids that mediate insulin exocytosis. Thus, the findings of our study provide new insights into the importance of adipocyte lipolysis to beta cell function, which might eventually help to counteract the development of diabetes. Within the scope of the project, a number of collaborations with national and international research groups in the field of lipid metabolism and diabetes have been carried out. In total, nine scientific papers and one review article were published.