Central and Peripheral Roles of Salt-inducible Kinases in Metabolic Regulation

Abstract Salt-inducible kinases (SIKs), a member of the serine/threonine protein kinase family, have recently garnered considerable research interest as one of the emerging key regulators of metabolism. The 3 SIK isoforms—SIK1, SIK2, and SIK3—exhibit diverse roles both in central and peripheral physiological processes. While early studies focused on their role in inflammation, spurring the development of SIK inhibitors for chronic inflammatory diseases currently in clinical trials, emerging evidence highlights their broader functions in metabolism. In this review, we will summarize the current state of research on the central roles of SIKs in the brain, particularly in regulating energy balance and glucose homeostasis, alongside their peripheral functions in critical metabolic tissues such as the liver, adipose tissue, and pancreas. By integrating insights into their central and peripheral roles, this review underscores the importance of SIKs in maintaining metabolic homeostasis and highlights their therapeutic potential as novel targets for metabolic disease.