Journal
NATURE COMMUNICATIONS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms5535
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Funding
- British MRC
- Region Ile-de-France (CORDDIM)
- Societe Francophone du Diabete (SFD)
- Division of Signal Transduction Therapy Unit
- AstraZeneca
- Boehringer-Ingelheim
- GlaxoSmithKline
- Merck KgaA
- Janssen Pharmaceutica
- Pfizer
- Wellcome Trust [093991/Z/10/Z]
- NIHR [RO1DK56886]
- Wellcome Trust [093991/Z/10/Z] Funding Source: Wellcome Trust
- Diabetes UK [10/0004131] Funding Source: researchfish
- Novo Nordisk Fonden [NNF13OC0005033] Funding Source: researchfish
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LKB1 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.
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