Inactivation of NF-κB2 (p52) restrains hepatic glucagon response via preserving PDE4B induction

Nat Commun. 2019 Sep 20;10(1):4303. doi: 10.1038/s41467-019-12351-x.


Glucagon promotes hepatic gluconeogenesis and maintains whole-body glucose levels during fasting. The regulatory factors that are involved in fasting glucagon response are not well understood. Here we report a role of p52, a key activator of the noncanonical nuclear factor-kappaB signaling, in hepatic glucagon response. We show that p52 is activated in livers of HFD-fed and glucagon-challenged mice. Knockdown of p52 lowers glucagon-stimulated hyperglycemia, while p52 overexpression augments glucagon response. Mechanistically, p52 binds to phosphodiesterase 4B promoter to inhibit its transcription and promotes cAMP accumulation, thus augmenting the glucagon response through cAMP/PKA signaling. The anti-diabetic drug metformin and ginsenoside Rb1 lower blood glucose at least in part by inhibiting p52 activation. Our findings reveal that p52 mediates glucagon-triggered hepatic gluconeogenesis and suggests that pharmacological intervention to prevent p52 processing is a potential therapeutic strategy for diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose
  • Cyclic AMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Fasting / metabolism
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Ginsenosides
  • Glucagon / metabolism*
  • Gluconeogenesis
  • Glucose / metabolism
  • Hep G2 Cells
  • Humans
  • Liver / metabolism*
  • Male
  • Metabolic Diseases / genetics
  • Metabolic Diseases / metabolism
  • Metformin / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B p52 Subunit / antagonists & inhibitors
  • NF-kappa B p52 Subunit / genetics
  • NF-kappa B p52 Subunit / metabolism*
  • Promoter Regions, Genetic
  • Signal Transduction


  • Blood Glucose
  • Ginsenosides
  • NF-kappa B p52 Subunit
  • ginsenoside Rb1
  • Glucagon
  • Metformin
  • Cyclic AMP
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4B protein, mouse
  • Glucose