The metabolic effects of mirabegron are mediated primarily by β3-adrenoceptors
The metabolic effects of mirabegron are mediated primarily by β3-adrenoceptors
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DOI：
10.1002/prp2.643
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发表时间：
2020-10-01
影响因子：
2.6
通讯作者：
Hutchinson, Dana S.
中科院分区：
文献类型：
--
作者：
Dehvari, Nodi;Sato, Masaaki;Hutchinson, Dana S.
β（3）-肾上腺素受体激动剂米拉贝隆被批准用于膀胱过度活动症，并据称可用于治疗人类肥胖相关代谢疾病，包括涉及葡萄糖稳态紊乱的疾病。我们研究了米拉贝隆在体外和体内模型中对葡萄糖稳态的影响，重点是其对β-肾上腺素受体的选择性，导致白色脂肪细胞布朗宁的能力，以及UCP 1在葡萄糖稳态中的作用。在小鼠棕色、白色和棕色脂肪细胞中，研究了米拉贝隆介导的对cAMP、UCP 1 mRNA、[H-3]-2-脱氧葡萄糖摄取、细胞糖酵解和O（2）消耗的影响。Mirabegron增加棕色脂肪细胞中的环AMP水平、UCP 1 mRNA含量、葡萄糖摄取和细胞糖酵解，而这些作用在白色脂肪细胞中不存在或减少。在brite脂肪细胞中，mirabegron增加环AMP水平和UCP 1 mRNA含量，导致UCP 1介导的耗氧量、葡萄糖摄取和细胞糖酵解增加。米拉贝隆在棕色和棕色脂肪细胞中的代谢效应主要是由于对β（3）-肾上腺素受体的作用，因为它们在β（3）-肾上腺素受体敲除小鼠的脂肪细胞中基本上不存在。在体内，米拉贝隆增加全身耗氧量、棕色和腹股沟白色脂肪组织对葡萄糖的摄取，并改善葡萄糖耐量，所有这些作用都需要β 3肾上腺素受体的存在。此外，在UCP 1基因敲除小鼠中，米拉贝隆对葡萄糖耐量的影响减弱。因此，米拉贝隆对脂肪细胞的细胞代谢有影响，改善体内葡萄糖处理，主要是由于对β（3）-肾上腺素受体的作用。
The beta(3)-adrenoceptor agonist mirabegron is approved for use for overactive bladder and has been purported to be useful in the treatment of obesity-related metabolic diseases in humans, including those involving disturbances of glucose homeostasis. We investigated the effect of mirabegron on glucose homeostasis with in vitro and in vivo models, focusing on its selectivity at beta-adrenoceptors, ability to cause browning of white adipocytes, and the role of UCP1 in glucose homeostasis. In mouse brown, white, and brite adipocytes, mirabegron-mediated effects were examined on cyclic AMP, UCP1 mRNA, [H-3]-2-deoxyglucose uptake, cellular glycolysis, and O(2)consumption. Mirabegron increased cyclic AMP levels, UCP1 mRNA content, glucose uptake, and cellular glycolysis in brown adipocytes, and these effects were either absent or reduced in white adipocytes. In brite adipocytes, mirabegron increased cyclic AMP levels and UCP1 mRNA content resulting in increased UCP1-mediated oxygen consumption, glucose uptake, and cellular glycolysis. The metabolic effects of mirabegron in both brown and brite adipocytes were primarily due to actions at beta(3)-adrenoceptors as they were largely absent in adipocytes derived from beta(3)-adrenoceptor knockout mice. In vivo, mirabegron increased whole body oxygen consumption, glucose uptake into brown and inguinal white adipose tissue, and improved glucose tolerance, all effects that required the presence of the beta(3)-adrenoceptor. Furthermore, in UCP1 knockout mice, the effects of mirabegron on glucose tolerance were attenuated. Thus, mirabegron had effects on cellular metabolism in adipocytes that improved glucose handling in vivo, and were primarily due to actions at the beta(3)-adrenoceptor.