Regulation of lipid metabolism in rat and 3T3-L1 adipocytes; Cross-talk between Insulin, the neuro-peptides PACAP/VIP and with B1-integrins

Sammanfattning: Type 2 Diabetes is a disorder that increases globally, but mainly in the western world. One of the hallmarks of Type 2 diabetes is insulin resistance in the target tissues of insulin action (adipose tissue, liver and skeletal muscle). In addition, most patients with Type 2 diabetes are obese. Increased release of free fatty acids from the enlarged and/or dysfunctional adipose tissue is suggested to be a direct cause of insulin resistance. Understanding regulation of adipocyte metabolism and intracellular signaling is therefore of great importance for further understanding of the development and treatment of insulin resistance and Type 2 diabetes. Results presented in this thesis demonstrate that the neuro-peptide pituitary adenylate cyclase-activating polypeptide (PACAP) is able to act directly on adipocytes in dual manners, depending on the presence or absence of insulin. In the absence of insulin, PACAP is able to efficiently stimulate lipolysis in a protein kinase A (PKA)-dependent manner. However, when insulin is present, PACAP-induced lipolysis is abolished and PACAP switches to potentiate insulin-induced lipogenesis. Furthermore, the lipolytic effects mediated by PACAP and the related vasoactive intestinal polypeptide (VIP) were shown to be mediated by VPAC2-R, one of three PACAP/VIP receptors expressed on rat adipocytes. However, activation of VPAC1-R and VPAC2-R resulted in activation of PKA, although only VPAC2-R stimulation resulted in lipolysis. It is conceivable to hypothesize that lipolysis and lipogenesis might be mediated via different PACAP-receptors and that PACAP signaling pathways are able to stimulate independent pools of cAMP and PKA. The potential impact of ?1-integrin activation on insulin signaling was also studied in this thesis. Most cells cannot survive unless they are properly connected to the extracellular matrix. It has been hypothesized that insulin and growth factor signaling is closely integrated. The preliminary results presented in this thesis indicate that ?1-integrins may act to potentiate phosphorylation of insulin signaling components in 3T3-L1 adipocytes, but not in primary adipocytes. However, further studies in this matter are needed. Taken together, this thesis has contributed to further understanding of PACAP/VIP effects and the signaling mechanisms whereby these peptides exert their effects in adipocytes. Furthermore, the importance of cross-talk between the insulin signaling pathways and those elicited by G-protein coupled receptors (GPCRs) and integrins has been emphasized.