β3-Adrenergic receptors regulate human brown/beige adipocyte lipolysis and thermogenesis.

Cheryl Cero,Farnaz Shamsi,Kenneth Y Zhu,Yu-Hua Tseng,Aaron M Cypess,Hannah J Lea

doi:10.1172/jci.insight.139160

Abstract

β3-Adrenergic receptors (β3-ARs) are the predominant regulators of rodent brown adipose tissue (BAT) thermogenesis. However, in humans, the physiological relevance of BAT and β3-AR remains controversial. Herein, using primary human adipocytes from supraclavicular neck fat and immortalized brown/beige adipocytes from deep neck fat from 2 subjects, we demonstrate that the β3-AR plays a critical role in regulating lipolysis, glycolysis, and thermogenesis. Silencing of the β3-AR compromised genes essential for thermogenesis, fatty acid metabolism, and mitochondrial mass. Functionally, reduction of β3-AR lowered agonist-mediated increases in intracellular cAMP, lipolysis, and lipolysis-activated, uncoupling protein 1–mediated thermogenic capacity. Furthermore, mirabegron, a selective human β3-AR agonist, stimulated BAT lipolysis and thermogenesis, and both processes were lost after silencing β3-AR expression. This study highlights that β3-ARs in human brown/beige adipocytes are required to maintain multiple components of the lipolytic and thermogenic cellular machinery and that β3-AR agonists could be used to achieve metabolic benefit in humans.

Highlights

Brown adipose tissue (BAT) is the principal thermogenic organ in mammals with the purpose of increasing energy expenditure in response to cold or nutritional overload [1, 2]
IBAT β3-Adrenergic receptors (β3-ARs) are the principal mediators of lipolysis and thermogenesis [1,2,3]
Clarifying the picture has been hampered by the difficulty in accessing human BAT, the lower BAT β3-AR receptor levels compared with mice, and differences in murine versus human β3-AR ligand affinities

Summary

Introduction

Brown adipose tissue (BAT) is the principal thermogenic organ in mammals with the purpose of increasing energy expenditure in response to cold (nonshivering thermogenesis) or nutritional overload (diet-induced thermogenesis) [1, 2]. BAT is primarily located in the interscapular region (iBAT), and its activation leads to improvement in obesity, glucose metabolism, and atherosclerosis [3, 4]. The physiological roles of BAT in rodents have grown with the identification of various classes of mediators that affect at least liver and muscle lipid and glucose metabolism [5,6,7,8]. Activation of BAT by cold exposure is associated with increased insulin sensitivity [16]. Given these potential effects on glucose and lipid metabolism, investigating the physiological and metabolic relevance of human BAT is of great interest

Methods

Results

Conclusion