Adipocyte lipolysis is tightly regulated to provide fatty acids when needed and this is suppressed postprandially by insulin. This regulation remains incompletely understood. We have identified the abhydrolase ABHD15 as a key player in this process together with the phosphodiesterase PDE3B. In the absence of either ABHD15 or PDE3B, insulin is not able to suppress lipolysis. ABHD15 and PDE3B form a complex and in response to insulin they are both phosphorylated by Akt and bind to the adaptor protein 14-3-3. Insertion of a constitutive 14-3-3 binding site into either ABHD15 or PDE3B results in complete suppression of lipolysis even under pro-lipolytic conditions. Notably, we have discovered that the kinase Akt interacts with ABHD15 and insulin and/or 14-3-3 binding to ABHD15 abolishes the interaction. In summary we propose a model where ABHD15 binds to and suppresses the phosphodiesterase activity of PDE3B in the absence of insulin thereby facilitating unrestrained lipolysis and supply of fatty acids during starvation or crisis. Akt directly interacts with the ABHD15/PDE3B complex leading to phosphorylation and 14-3-3 binding upon insulin stimulation, which activates a pool of PDE3B thus repressing PKA and the lipolytic drive.
J. Stoeckli: Research Support; Pfizer Inc. A. Zadoorian: None. G. Yang: None. D. E. James: Research Support; Eli Lilly and Company, Novo Nordisk, Pfizer Inc.