Session 11. EMBO and Poland: Metabolic Disorders: External and Internal Signaling Lectures L11.1 How to optimize pancreatic beta- cell function — is the regulation of lipid metabolism a golden tool?

Pancreatic beta cells exhibit a remarkable ability to tune their secretory functions in response to altered tissue insulin demands. Glucose, nutrients (amino acids and lipids), neurohormonal signals and lipid mediators (i.e. free fatty acids, diacylglycerol, phosphatidic acid) all efficaciously modulate insulin secretion. Recently, the presence of a functional endocannabinoid (eCB) system (that is, the enzymatic machinery to biosynthesize and degrade 2-arachidonoylglycerol (2-AG) and anandamide (AEA), as well as cannabinoid receptors) was identified in the endocrine pancreas. eCB signaling has been implicated in modulating insulin release from beta cells of the endocrine pancreas. However, the molecular cascade coupling cannabinoid receptor (CB R) activation to insulin release remains unknown. By combining molecular pharmacology and genetic tools, we recently showed that eCBs (AEA and 2-AG) activate CB1R to induce insulin hypersecretion. In doing so, CB1Rs recruit Akt/PKB and extracellular signal-regulated kinases 1/2 (ERK1/2) to phosphorylate focal adhesion kinase (FAK). FAK activation induces the formation of focal adhesion plaques, multimolecular platforms for secondphase insulin release. Inhibition of eCB synthesis or FAK activity precluded insulin release. Cytoskeletal remodeling induced by agonist-activation of CB1R was independent of extracellular calcium pool. Furthermore, eCBs-induced insulin secretion might also be associated with changes in lipid metabolism and activation of mitochondrial CB1Rs. We concluded that FAK downstream from CB1Rs mediates eCBs-induced insulin release by allowing cytoskeletal reorganization that is required for the exocytosis of secretory vesicles. The mechanism we identified suggests that acute CB1R activation may be critical for the adaptation of pancreatic beta cells to insulin resistance. Thus these findings show a mechanistic link between increased circulating and tissue eCB levels and hyperinsulinemia in type 2 diabetes. L11.2