Cdkn2a/p16Ink4a regulates fasting-induced hepatic gluconeogenesis through the PKA-CREB-PGC1α pathway.
Type 2 diabetes (T2D) is hallmarked by insulin resistance, impaired insulin secretion, and increased hepatic glucose production. The worldwide increasing prevalence of T2D calls for efforts to understand its pathogenesis in order to improve disease prevention and management. Recent genome-wide association studies have revealed strong associations between the CDKN2A/B locus and T2D risk. The CDKN2A/B locus contains genes encoding cell cycle inhibitors, including p16(Ink4a), which have not yet been implicated in the control of hepatic glucose homeostasis. Here, we show that p16(Ink4a) deficiency enhances fasting-induced hepatic glucose production in vivo by increasing the expression of key gluconeogenic genes. p16(Ink4a) downregulation leads to an activation of PKA-CREB-PGC1α signaling through increased phosphorylation of PKA regulatory subunits. Taken together, these results provide evidence that p16(Ink4a) controls fasting glucose homeostasis and could as such be involved in T2D development.
Université Lille 2, Lille, France INSERM, U1011, Lille, France European Genomic Institute for Diabetes, Lille, France Institut Pasteur de Lille, Lille, France.
Kadiombo
K
Bantubungi
Université Lille 2, Lille, France INSERM, U1011, Lille, France European Genomic Institute for Diabetes, Lille, France Institut Pasteur de Lille, Lille, France.
Sarah-Anissa
SA
Hannou
Université Lille 2, Lille, France INSERM, U1011, Lille, France European Genomic Institute for Diabetes, Lille, France Institut Pasteur de Lille, Lille, France.
Sandrine
S
Caron-Houde
Université Lille 2, Lille, France INSERM, U1011, Lille, France European Genomic Institute for Diabetes, Lille, France Institut Pasteur de Lille, Lille, France.
Emmanuelle
E
Vallez
Université Lille 2, Lille, France INSERM, U1011, Lille, France European Genomic Institute for Diabetes, Lille, France Institut Pasteur de Lille, Lille, France.
Morgane
M
Baron
Université Lille 2, Lille, France INSERM, U1011, Lille, France European Genomic Institute for Diabetes, Lille, France Institut Pasteur de Lille, Lille, France.
Anthony
A
Lucas
Université Lille 2, Lille, France INSERM, U1011, Lille, France European Genomic Institute for Diabetes, Lille, France Institut Pasteur de Lille, Lille, France.
Emmanuel
E
Bouchaert
Université Lille 2, Lille, France INSERM, U1011, Lille, France European Genomic Institute for Diabetes, Lille, France Institut Pasteur de Lille, Lille, France.
Réjane
R
Paumelle
Université Lille 2, Lille, France INSERM, U1011, Lille, France European Genomic Institute for Diabetes, Lille, France Institut Pasteur de Lille, Lille, France.
Anne
A
Tailleux
Université Lille 2, Lille, France INSERM, U1011, Lille, France European Genomic Institute for Diabetes, Lille, France Institut Pasteur de Lille, Lille, France bart.staels@pasteur-lille.fr.
Bart
B
Staels
D000818:Animals; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D005215:Fasting / Q000378:metabolism*; D005943:Gluconeogenesis / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D017868:Cyclic AMP-Dependent Protein Kinases