Abstract
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.
Highlights
Glucagon promotes hepatic gluconeogenesis and maintains whole-body glucose levels during fasting
In close agreement, when we examined livers of fasted high-fat diet (HFD)-fed mice, we observed a significant increase in p52 activation compared with those of chow-fed mice (Supplementary Fig. 1b)
We found that p52 knockdown lowered fasting blood glucose levels (Fig. 1b) and improved oral glucose tolerance (Supplementary Fig. 2a) in HFD-fed mice
Summary
Glucagon promotes hepatic gluconeogenesis and maintains whole-body glucose levels during fasting. P52 binds to phosphodiesterase 4B promoter to inhibit its transcription and promotes cAMP accumulation, augmenting the glucagon response through cAMP/PKA signaling. Insulin reduces postprandial hyperglycemia by promoting glucose disposal to target tissues, while glucagon stimulates hepatic gluconeogenesis to maintain blood glucose levels during fasting or starvation. By binding to the G-protein-coupled receptor, glucagon activates adenylyl cyclase signaling This leads to production of cAMP, which activates PKA and induces phosphorylation of cAMP-response element-binding protein (CREB). AMP-activated protein kinase (AMPK) and hypoxia-inducible factor 2α increase PDEs activity and antagonize hepatic glucagon-stimulated cAMP signaling[9,10]. Our work shows that p52 binds to PDE4B promoter to inhibit its transcription and promotes cAMP accumulation, augmenting the glucagon response through cAMP/PKA signaling. We show that metformin and ginsenoside Rb1 restrain hepatic glucagon response through a p52dependent manner
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