2487-PUB: Purinergic Regulation of Adiponectin Exocytosis and the Role of Sympathetic Innervation for Adiponectin Secretion

The white adipocyte hormone adiponectin improves insulin sensitivity and has a protective role in the development of type 2 diabetes. The rapid incidence of obesity-associated disorders emphasizes the importance of understanding the regulation of adiponectin secretion. Hormones are typically secreted via regulated exocytosis but the mechanisms controlling adiponectin release remains inadequately investigated. We have previously demonstrated that catecholamines/cAMP trigger adiponectin exocytosis via activation of adrenergic beta-3-receptors (β3ARs) and Epac1, while elevations of intracellular Ca2+ potentiate the exocytotic process. White adipose tissue is highly innervated by sympathetic nerves, co-releasing norepinephrine (NE) and ATP, thus suggesting a role of the sympathetic nervous system in regulation of adiponectin secretion. Here we have studied the role of sympathetic innervation and purinergic signaling in adiponectin release. Extracellular NE triggered adipocyte exocytosis, whereas extracellular ATP potentiated NE-triggered adipocyte exocytosis. Short-term adiponectin secretion was stimulated by NE while ATP augmented the catecholamine-stimulated release. The effect of ATP was abolished in adipocytes pre-treated with a P2Y2-receptor antagonist. In adipocytes isolated from obese/diabetic mice, ATP-induced adiponectin release was abrogated together with a reduced gene expression of the P2Y2-receptor. Moreover, white adipose tissue content of NE and tyrosine hydroxylase was reduced in obese/diabetic mice. We propose that the physiological stimulatory pathway for adiponectin exocytosis is via sympathetic innervation, co-releasing NE and ATP which activates β3ARs (elevates cAMP) and P2Y2Rs (increases Ca2+). We also suggest that decreased NE and ATP release within the adipose tissue together with disrupted adipocyte purinergic signaling results in disturbed adiponectin release in diabetic/obese conditions.