摘要：

AMP-activated protein kinase (AMPK), an evolutionarily conserved serine-threonine kinase that senses cellular energy status, is activated by stress and neurohumoral stimuli. We investigated the mechanisms by which adrenergic signaling alters AMPK activation in vivo. Brown adipose tissue (BAT) is highly enriched in sympathetic innervation which is critical for regulation of energy homeostasis. We performed unilateral denervation of BAT in wildtype (WT) mice to abolish neural input. Six days post-denervation, UCP-1 protein levels and AMPK α2 protein and activity were reduced by 45%. In β1,2,3-adrenergic receptor knockout (β-AR KO) mice, unilateral denervation led to a 25-45% decrease in AMPK activity, protein expression and Thr172 phosphorylation. In contrast, acute α- or β adrenergic blockade in WT mice resulted in increased AMPK α Thr172 phosphorylation and AMPK α1 and α2 activity in BAT. But short-term blockade of α-adrenergic signaling in β-AR KO mice resulted in decreased AMPK activity in BAT which strongly correlated with enhanced phosphorylation of AMPK on Ser485/491, a site associated with inhibition of AMPK activity. Both PKA and AKT inhibitors attenuated AMPK Ser485/491 phosphorylation resulting from α-adrenergic blockade and prevented decreases in AMPK activity. In vitro mechanistic studies in BAT explants showed that the effects of α-adrenergic blockade appeared to be secondary to inhibition of oxygen consumption. In conclusion, adrenergic pathways regulate AMPK activity in vivo acutely via alterations in Thr172 phosphorylation and chronically through changes in the α catalytic subunit protein levels. Furthermore, AMPK α Ser485/491 phosphorylation may be a novel mechanism to inhibit AMPK activity in vivo and alter its biological effects.

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