Metabolic regulation by salt inducible kinases

Abstract

In fasting mammals, the liver is the primary source of glucose production for maintenance of normoglycemia. In this setting, circulating peptide hormones and catecholamines cause hepatic glucose output by stimulating glycogen breakdown as well as de novo glucose production through gluconeogenesis. Fasting gluconeogenesis is regulated by a complex transcriptional cascade culminating in elevated expression of hepatic enzymes that promote gluconeogenesis and glucose export to the blood. The cAMP response element binding protein CREB and its co-activator CRTC2 play crucial roles in signal-dependent transcriptional regulation of gluconeogenesis. Recent work has identified a family of serine/threonine kinases, the salt inducible kinases (SIKs), which are subject to hormonal control and constrain gluconeogenic and lipogenic gene expression in liver. As normal regulation of gluconeogenesis and lipogenesis is disrupted in diabetic states, SIK kinases are poised to serve as therapeutic targets to modulate metabolic disturbances in diabetic patients. The purpose of this review is to 1) describe the identification of CRTCs CREB co-activators and their regulation by SIKs, 2) discuss recent progress toward understanding regulation and function of SIKs in metabolism and 3) examine the potential clinical impact of therapeutics that target SIK kinase function.

Keywords

salt inducible kinases (SIKs) / cAMP response element binding protein (CREB) / CRTC / gluconeogenesis / lipogenesis / type 2 diabetes / transcription

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Acknowledgments

R. Berdeaux was supported by grants from the Muscular Dystrophy Association (MDA 68640), the American Heart Association (AHA 09BGIA2261362) and the University of Texas Health Science Center, Houston. I thank Randi Stewart for critical comments on the manuscript.

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