Abstract
The hormone adiponectin is secreted by white adipocytes and has been put forward as a key mediator of obesity-linked insulin resistance and the metabolic syndrome. Although adiponectin was discovered two decades ago, the knowledge about the molecular and cellular regulation of its secretion is incomplete. Here we have investigated the adrenergic regulation of adiponectin secretion in primary visceral (gonadal) adipocytes isolated from lean or obese/diabetic mice. We show that visceral adipocyte adiponectin release is triggered by cAMP/catecholamines via signalling pathways involving adrenergic beta-3-receptors (β3ARs) and Exchange Protein directly Activated by cAMP, isoform 1 (Epac1). The adrenergically stimulated adiponectin secretion is blunted in visceral adipocytes isolated from obese and diabetic mice and our results suggest the existence of a secretory defect. We have previously shown that adiponectin secretion in subcutaneous adipocytes is abolished in the obese/diabetic state due to reduced abundance of β3ARs and Epac1. However, here we show that protein levels of β3ARs and Epac1 are maintained in visceral adipocytes from obese/diabetic mice proposing that other molecular defects underlie the blunted adiponectin release. Gene expression analysis indicate diabesity-associated disturbances of the signalling downstream of Epac1 and/or the exocytotic process itself. Our study proposes that visceral adipocytes partake in the regulated secretion of adiponectin and may thus influence circulating levels of the hormone, in health and in metabolic disease.
Highlights
The hormone adiponectin, secreted by white adipocytes, has been proposed as an important mediator of the crosstalk between the adipose tissue and other organs involved in regulation of whole body metabolism
We have demonstrated that catecholamines stimulate acute adiponectin release from subcutaneous adipocytes via activation of adrenergic beta-3-receptors (β3ARs) and Exchange Protein directly Activated by cAMP, isoform 1 (Epac1)
In order to study if visceral adipocyte short-term adiponectin secretion can be stimulated via cAMP/adrenergic signalling, mouse gonadal white adipose tissue (GWAT) adipocytes were incubated with forskolin (FSK;[10] μM) in combination with IBMX (200 μM; FSK/IBMX), adrenaline (ADR; 5 μM) or the β3AR agonist CL316243 (CL; 1 μM) respectively during 30 minutes
Summary
The hormone adiponectin, secreted by white adipocytes, has been proposed as an important mediator of the crosstalk between the adipose tissue and other organs involved in regulation of whole body metabolism. Individuals with increased VAT are at greater risk of developing obesity-related disorders, such as type 2 diabetes and cardiovascular disease This is likely in part due to the anatomical position of VAT, with direct portal drainage to the liver through the portal vein;[14] free fatty acids and hormones released from VAT can directly affect glucose and liver metabolism. We have demonstrated that catecholamines stimulate acute adiponectin release from subcutaneous adipocytes (isolated from inguinal white adipose tissue; IWAT) via activation of adrenergic beta-3-receptors (β3ARs) and Exchange Protein directly Activated by cAMP, isoform 1 (Epac[1]). Adiponectin has been suggested to be released from visceral adipose tissue depots (perivascular adipocytes), via β3AR-dependent pathways and to act as a vasorelaxant factor[24], the detailed regulation of visceral adipocyte adiponectin secretion has never been investigated. The stimulated adiponectin secretion is blunted in diabesity but the mechanisms underlying the abrogated release differ from those characterised in IWAT adipocytes
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