1970-P: Epinephrine and Insulin Stimulates White Adipocyte Secretion of Diverse Adiponectin Forms

Abstract

The white adipocyte hormone adiponectin is released in different molecular forms and a reduction of high-molecular weight (HMW) adiponectin has specifically been associated with the development of metabolic disease. We have recently shown that adiponectin is released via cAMP/epinephrine-stimulated exocytosis, involving activation of beta 3 adrenergic receptors (beta3ARs). However, a number of studies have, seemingly incompatible with the catecholamine-triggered release, reported that insulin (lowers cAMP) increases adiponectin secretion. Here we have pinpointed the differences between insulin- and catecholamine-stimulated short-term adiponectin secretion. Using a combination of biophysical and biochemical techniques applied to mouse and human adipocytes as well as whole animal studies, we show that catecholamines specifically stimulate the rapid exocytosis of high-molecular weight (HMW) adiponectin. In contrast, insulin induces secretion of smaller adiponectin forms only, with slower time kinetics. The catecholamine-stimulated secretion of HMW adiponectin is blunted in adipocytes isolated from obese and diabetic mice (8 weeks high-fat diet) and this secretory defect is paralleled by a ∼50% reduction of serum HMW adiponectin. The insulin-induced release of smaller adiponectin forms is also abrogated i adipocytes from obese/diabetic mice. However, the total serum adiponectin level remains unaltered, likely due to enhanced basal (unstimulated) release of smaller adiponectin forms. Our findings suggest that insulin and catecholamines have entirely different roles in the regulation of adiponectin secretion and demonstrate a previously unknown role of beta3ARs for human white adipocyte physiology. We propose that the reduced levels of HMW adiponectin observed in diabetic individuals, and that have been linked to the development of metabolic disease, is a result of a secretory disturbance largely depending on disrupted adrenergic signaling. Disclosure S. Musovic: None. A.M. Komai: None. E. Banke Nordbeck: None. U.A. Noor: None. I. Wernstedt Asterholm: None. C.S. Olofsson: None. Funding Swedish Diabetes Foundation; Knut and Alice Wallenberg Foundation; Swedish Medical Research Council