The role of beta 3 adrenergic receptor in white adipocyte adiponectin exocytosis

Abstract

In this thesis we define the physiological and underlying mechanisms involved in the white adipocyte adiponectin exocytosis, with a special focus on the beta 3 adrenergic receptor (β3AR) in health and metabolic disease. In paper I, we define the role of sympathetic innervation and purinergic signaling in the regulation of white adipocyte adiponectin release. We hypothesized that adiponectin exocytosis is regulated by sympathetic nerves, co-releasing noradrenaline and ATP within the white adipose tissue, acting on adrenergic and purinergic receptors, elevating cytosolic cAMP and Ca2+, respectively. A combination of electrophysiological recordings and secretion measurements confirmed that NA stimulate the release of adiponectin, whereas ATP augments it. This regulation is abrogated in adipocytes isolated from obese and diabetic mice, due to a reduction of protein expression of both receptors, and that this is associated with reduced circulating high molecular weight adiponectin. In paper II, we investigated the role of β3AR in white adipocyte adiponectin release and in metabolic health in more detail, using mice that are genetically ablated for β3AR (β3AR-KO). Our data show that the disturbed signaling mechanism in the KO mice results in abrogated adiponectin release and reduced serum levels of total and HMW adiponectin. Furthermore, fasting insulin and glucose indicate that KO mice have an improved insulin sensitivity and are metabolically healthy, despite the lower adiponectin levels. However, β3AR-KO mice become insulin resistant when challenged with high fat diet. Finally, in paper III, we show that an activation of β3AR rapidly triggers the release of HMW adiponectin, while insulin induces release of only smaller molecular forms of adiponectin. Adiponectin secretion is diminished in adipocyte isolated from obese individuals, connected to ~50% reduced abundance of β3ARs in adipocytes and lower circulating HMW adiponectin. Treatment with a β3AR agonist increased serum HMW adiponectin in both lean and obese mice.