Novel Role of Glucagon as a Physiological Defender Against Catecholamine Surge Via Its Direct Action on Adrenomedullary Differentiation

The regulatory role of physiological glucagon (Gcg) in the cardiovascular system remains uncertain. Employing a mouse model harboring a functional deficiency of the preproglucagon gene (GCG-null), we found that lack of endogenous Gcg caused hypertension and systolic left ventricular (LV) dysfunction due to abnormal rise in circulating epinephrine (Ep) level, which was completely restored by the supplemental injection of Gcg (Sup-Gcg) or adrenergic β1-receptor blockers. More interestingly, GCG-null exhibited adrenal hypertrophy with the upregulation of phenylethanolamine N-methyltransferase (PNMT), a key enzyme that synthesizes Ep. Gcg directly facilitated mRNA decay via augmentation of enhancer of mRNA decapping protein 4 (EDC4) in a PKA-dependent fashion, thereby suppressing PNMT in adrenal chromaffin cells. Our data unveiled the novel action of Gcg like a circuit breaker against the Ep surge in the context of disease condition.