Glucagon regulates gluconeogenesis through KAT2B- and WDR5-mediated epigenetic effects
Kim Ravnskjaer, … , Jerrold Olefsky, Marc Montminy
Kim Ravnskjaer, … , Jerrold Olefsky, Marc Montminy
Published September 24, 2013
Citation Information: J Clin Invest. 2013;123(10):4318-4328. https://doi.org/10.1172/JCI69035.
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Research Article Metabolism

Glucagon regulates gluconeogenesis through KAT2B- and WDR5-mediated epigenetic effects

Abstract

Circulating pancreatic glucagon is increased during fasting and maintains glucose balance by stimulating hepatic gluconeogenesis. Glucagon triggering of the cAMP pathway upregulates the gluconeogenic program through the phosphorylation of cAMP response element–binding protein (CREB) and the dephosphorylation of the CREB coactivator CRTC2. Hormonal and nutrient signals are also thought to modulate gluconeogenic gene expression by promoting epigenetic changes that facilitate assembly of the transcriptional machinery. However, the nature of these modifications is unclear. Using mouse models and in vitro assays, we show that histone H3 acetylation at Lys 9 (H3K9Ac) was elevated over gluconeogenic genes and contributed to increased hepatic glucose production during fasting and in diabetes. Dephosphorylation of CRTC2 promoted increased H3K9Ac through recruitment of the lysine acetyltransferase 2B (KAT2B) and WD repeat–containing protein 5 (WDR5), a core subunit of histone methyltransferase (HMT) complexes. KAT2B and WDR5 stimulated the gluconeogenic program through a self-reinforcing cycle, whereby increases in H3K9Ac further potentiated CRTC2 occupancy at CREB binding sites. Depletion of KAT2B or WDR5 decreased gluconeogenic gene expression, consequently breaking the cycle. Administration of a small-molecule KAT2B antagonist lowered circulating blood glucose concentrations in insulin resistance, suggesting that this enzyme may be a useful target for diabetes treatment.

Authors

Kim Ravnskjaer, Meghan F. Hogan, Denise Lackey, Laszlo Tora, Sharon Y.R. Dent, Jerrold Olefsky, Marc Montminy

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Figure 5

Inhibiting hepatic KAT2B activity lowers blood glucose concentrations in diabetes.

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Inhibiting hepatic KAT2B activity lowers blood glucose concentrations in...
(A) Effect of hepatic Kat2b depletion on gluconeogenic gene expression and blood glucose concentrations in lean db/+ and diabetic db/db mice fasted for 12 hours. (B) Effects of acute knockdown of Wdr5 on fasting blood glucose in livers of 12-hour fasted, lean, HFD-fed (DIO), or diabetic db/db mice. (C) Effect of AA (Anac.) and chemically related derivative SPV-106 on mRNA amounts (left), CRE-Luc activity, and H3K9Ac over gluconeogenic genes (right) in hepatocytes exposed to glucagon (Glu). (D) Fasting blood glucose and hepatic CRE-Luc activity in lean and DIO Cre-Luc transgenic mice injected i.p. for 5 consecutive days with AA (15 mg/kg), SPV-106, or vehicle. (E) Epigenetic regulation of the gluconeogenic program during fasting and in diabetes. Increases in circulating glucagon trigger the dephosphorylation and nuclear translocation of CRTC2, which associates with and mediates the recruitment of KAT2B and WDR5 to CREB binding sites on gluconeogenic promoters. In turn, KAT2B and WDR5 upregulate gluconeogenic genes through a self-reinforcing cycle in which increases in H3K9 acetylation further enhance CREB and CRTC2 occupancy (*P < 0.05 relative to lean mice; n = 4).