Patel, KashyapForetz, MarcMarion, AllisonCampbell, David G.Gourlay, RobertBoudaba, NadiaTournier, EmilieTitchenell, PaulPeggie, MarkDeak, MariaWan, MinKaestner, Klaus H.Göransson, OlgaViollet, BenoitGray, NathanaelBirnbaum, Morris J.Sutherland, CalumSakamoto, Kei2014-10-012014Patel, K., M. Foretz, A. Marion, D. G. Campbell, R. Gourlay, N. Boudaba, E. Tournier, et al. 2014. “The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver.” Nature Communications 5 (1): 4535. doi:10.1038/ncomms5535. http://dx.doi.org/10.1038/ncomms5535.2041-1723http://nrs.harvard.edu/urn-3:HUL.InstRepos:12987233LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1–SIK pathway functions as a key gluconeogenic gatekeeper in the liver.en-USJournal Article2014-10-0110.1038/ncomms5535