The metabolic effects of mirabegron are mediated primarily by β3-adrenoceptors

Nodi Dehvari, Masaaki Sato, Muhammad Hamza Bokhari, Anastasia Kalinovich, Seungmin Ham, Jie Gao, Huong T.M. Nguyen, Lynda Whiting, Saori Mukaida, Jon Merlin, Ling Yeong Chia, Denise Wootten, Roger J. Summers, Bronwyn A. Evans, Tore Bengtsson, Dana S. Hutchinson

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4 Citations (Scopus)

Abstract

The β3-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 β-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, [3H]-2-deoxyglucose uptake, cellular glycolysis, and O2 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 β3-adrenoceptors as they were largely absent in adipocytes derived from β3-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 β3-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 β3-adrenoceptor.

Original languageEnglish
Article numbere00643
Number of pages16
JournalPharmacology Research & Perspectives
Volume8
Issue number5
DOIs
Publication statusPublished - 1 Oct 2020

Keywords

  • adipocyte
  • glucose
  • mirabegron
  • UCP1
  • β-adrenoceptor

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