title: The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver.
abstract: 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.
authors.affiliation: 1] MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK [2].
authors.forename: Kashyap
authors.initials: K
authors.lastname: Patel
authors.affiliation: 1] INSERM, U1016, Institut Cochin, 75014 Paris, France [2] CNRS, UMR8104, 75014 Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France [4].
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: 1] INSERM, U1016, Institut Cochin, 75014 Paris, France [2] CNRS, UMR8104, 75014 Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Allison
authors.initials: A
authors.lastname: Marion
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: David G
authors.initials: DG
authors.lastname: Campbell
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Gourlay
authors.affiliation: 1] INSERM, U1016, Institut Cochin, 75014 Paris, France [2] CNRS, UMR8104, 75014 Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Boudaba
authors.affiliation: 1] INSERM, U1016, Institut Cochin, 75014 Paris, France [2] CNRS, UMR8104, 75014 Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Tournier
authors.affiliation: The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Titchenell
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Peggie
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Deak
authors.affiliation: The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wan
authors.affiliation: The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.affiliation: The Department of Experimental Medical Science, Lund University, BMC C11, 221 84 Lund, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Göransson
authors.affiliation: 1] INSERM, U1016, Institut Cochin, 75014 Paris, France [2] CNRS, UMR8104, 75014 Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.affiliation: Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Calum
authors.initials: C
authors.lastname: Sutherland
authors.affiliation: 1] MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK [2].
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D005215:Fasting; D005786:Gene Expression Regulation; D005934:Glucagon / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006943:Hyperglycemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C555318:CRTC3 protein, mouse; C504923:Crtc2 protein, mouse; C577044:HG-9-91-01; D007328:Insulin; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014157:Transcription Factors; D005934:Glucagon; C474808:salt-inducible kinase-2, mouse; D017346:Protein Serine-Threonine Kinases; C571369:SIK3 protein, mouse; C495376:Sik1 protein, mouse; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D005947:Glucose
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