Salt-inducible Kinase Regulation of Adipose Tissue Metabolism

Salt-inducible kinases (SIKs) are a subfamily of the adenosine monophosphate-activated protein kinase-related kinase family. To be activated, SIKs require phosphorylation in the catalytic kinase domain by liver kinase B1. In response to extracellular stimulations, their activity can be further regulated through phosphorylation by protein kinase A (PKA), and Ca2+/calmodulin-dependent protein kinases. PKA-mediated SIK inhibition is a major link between G-protein coupled receptor activation and the target gene transcription program. All 3 SIK isoforms-SIK1, SIK2, and SIK3-are expressed in adipocytes, with SIK2 being the most abundant in both rodents and humans. SIKs play essential roles in maintaining adipose tissue homeostasis by regulating physiological processes involving insulin signaling, glucose uptake, lipogenesis, and thermogenesis. Each SIK isoform could play both redundant and unique roles in these physiological processes. Many of the substrates that mediate their physiological functions in adipocytes have been characterized, and downstream mechanisms of action have also been proposed. However, due to the functional redundancy of SIKs, a major challenge is to delineate their isoform-specific roles in adipose tissue in vivo using genetic mouse models. In addition, common genetic variants and rare mutations in the SIK genes have been identified to be associated with metabolic, cardiovascular, and developmental conditions, suggesting a translational implication for human disease that deserves investigation. Furthermore, small molecular SIK inhibitors have been developed and have shown therapeutic potential in multiple disease areas. Evaluation of their metabolic and cardiovascular effects will be required for future clinical development of SIK inhibitors.