Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30, Göteborg, Sweden.
Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30, Göteborg, Sweden.
Mol Cell Endocrinol. 2022 Jun 1;549:111619. doi: 10.1016/j.mce.2022.111619. Epub 2022 Mar 22.
White adipocyte adiponectin exocytosis is triggered by cAMP and a concomitant increase of cytosolic Ca potentiates its release. White adipose tissue is richly innervated by sympathetic nerves co-releasing noradrenaline (NA) and ATP, which may act on receptors in the adipocyte plasma membrane to increase cAMP via adrenergic receptors and Ca via purinergic receptors. Here we determine the importance of NA and ATP for the regulation of white adipocyte adiponectin exocytosis, at the cellular and molecular level, and we specifically detail the ATP signalling pathway. We demonstrate that tyrosine hydroxylase (enzyme involved in catecholamine synthesis) is dramatically reduced in inguinal white adipose tissue (IWAT) isolated from mice with diet-induced obesity; this is associated with diminished levels of NA in IWAT and with a reduced ratio of high-molecular-weight (HMW) to total adiponectin in serum. Adiponectin exocytosis (measured as an increase in plasma membrane capacitance and as secreted product) is triggered by NA or ATP alone in cultured and primary mouse IWAT adipocytes, and enhanced by a combination of the two secretagogues. The ATP-induced adiponectin exocytosis is largely Ca-dependent and activated via purinergic P2Y2 receptors (P2Y2Rs) and the Gq11/PLC pathway. Adiponectin release induced by the nucleotide is abrogated in adipocytes isolated from obese and insulin-resistant mice, and this is associated with ∼70% reduced abundance of P2Y2Rs. The NA-triggered adiponectin exocytosis is likewise abolished in "obese adipocytes", concomitant with a 50% lower gene expression of beta 3 adrenergic receptors (βARs). An increase in intracellular Ca is not required for the NA-stimulated adiponectin secretion. Collectively, our data suggest that sympathetic innervation is a principal regulator of adiponectin exocytosis and that disruptions of this control are associated with the obesity-associated reduction of circulating levels of HMW/total adiponectin.
白色脂肪细胞脂联素的胞吐作用是由 cAMP 触发的，细胞溶质 Ca 的增加会增强其释放。白色脂肪组织富含交感神经，交感神经共同释放去甲肾上腺素（NA）和 ATP，这些神经递质可能作用于脂肪细胞膜上的受体，通过肾上腺素能受体增加 cAMP，通过嘌呤能受体增加 Ca。在这里，我们在细胞和分子水平上确定了 NA 和 ATP 对白色脂肪细胞脂联素胞吐作用的调节作用的重要性，并特别详细说明了 ATP 信号通路。我们证明，饮食诱导肥胖的小鼠腹股沟白色脂肪组织（IWAT）中酪氨酸羟化酶（儿茶酚胺合成酶）显著减少；这与 IWAT 中 NA 水平降低以及血清中高分子量（HMW）与总脂联素的比例降低有关。单独用 NA 或 ATP 可在培养的和原代的小鼠 IWAT 脂肪细胞中触发脂联素的胞吐作用（通过增加质膜电容和分泌产物来测量），并且两种分泌剂的组合可增强其作用。ATP 诱导的脂联素胞吐作用在很大程度上依赖于 Ca，通过嘌呤能 P2Y2 受体（P2Y2R）和 Gq11/PLC 途径激活。从肥胖和胰岛素抵抗的小鼠分离的脂肪细胞中，核苷酸诱导的脂联素释放被阻断，这与 P2Y2R 的丰度降低约 70%有关。同样，在“肥胖脂肪细胞”中，NA 触发的脂联素胞吐作用也被废除，同时β3 肾上腺素能受体（βAR）的基因表达降低 50%。细胞内 Ca 的增加不是 NA 刺激的脂联素分泌所必需的。总的来说，我们的数据表明，交感神经支配是脂联素胞吐作用的主要调节因子，这种调节的破坏与肥胖相关的循环 HMW/总脂联素水平降低有关。
