Adipose and endothelial dysfunction is tightly associated with
cardiovascular diseases in
obesity and
insulin resistance. Because perivascular adipose tissue (PVAT) surrounds vessels directly and influences vessel functions through paracrine effect, and
AMP-activated protein kinase (AMPK) and
sirtuin 1 (
SIRT1) show similarities in modulation of metabolic pathway, we hypothesized that activation of AMPK and
SIRT1 in PVAT might regulate the endothelial function in pathological settings. Thus, in this study, we focused on the regulation of AMPK and
SIRT1 activities implicated in
adipocytokine expression and endothelial homeostasis under inflammatory conditions by using
salicylate,
metformin,
AICA riboside (
AICAR) and
resveratrol as AMPK activating agents. We prepared
conditioned medium (CM) by stimulating PVAT with
palmitic acid (PA) and observed the effects of AMPK activating agents on
adipocytokine expression and vessel vasodilation in rats. Moreover, we explored the effects of
resveratrol and
metformin in
fructose-fed rats. We observed that PA stimulation induced
inflammation and dysregulation of
adipocytokine expression accompanied with reduced AMPK activity and
SIRT1 abundance in PVAT. AMPK activating agents inhibited NF-κB p65 phosphorylation and suppressed gene expression of pro-inflammatory
adipocytokines, and upregulated
adiponectin and PPARγ expression in PVAT in an AMPK/
SIRT1-interdependent manner. Meanwhile, CM stimulation impaired endothelium-dependent vasodilation in response to
acetylcholine (ACh). Pretreatment of CM with AMPK-activating agents enhanced eNOS phosphorylation in the aorta and restored the loss of endothelium-dependent vasodilation, whereas this action was abolished by co-treatment with
AMPK inhibitor compound C or
SIRT1 inhibitor
nicotinamide. Long-term
fructose-feeding in rats induced dysregulation of
adipocytokine expression in PVAT and the loss of endothelium-dependent vasodilation, whereas these alterations were reversed by
oral administration of
resveratrol and
metformin. Altogether, pharmacological activation of AMPK beneficially regulated
adipocytokine expression in PVAT and thus ameliorated endothelial dysfunction against inflammatory insult in an AMPK/
SIRT1-interdependent manner.