β(3)-Adrenergic receptors regulate human brown/beige adipocyte lipolysis and thermogenesis

β(3)-Adrenergic receptors (β(3)-ARs) are the predominant regulators of rodent brown adipose tissue (BAT) thermogenesis. However, in humans, the physiological relevance of BAT and β(3)-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 β(3)-AR plays a critical role in regulating lipolysis, glycolysis, and thermogenesis. Silencing of the β(3)-AR compromised genes essential for thermogenesis, fatty acid metabolism, and mitochondrial mass. Functionally, reduction of β(3)-AR lowered agonist-mediated increases in intracellular cAMP, lipolysis, and lipolysis-activated, uncoupling protein 1–mediated thermogenic capacity. Furthermore, mirabegron, a selective human β(3)-AR agonist, stimulated BAT lipolysis and thermogenesis, and both processes were lost after silencing β(3)-AR expression. This study highlights that β(3)-ARs in human brown/beige adipocytes are required to maintain multiple components of the lipolytic and thermogenic cellular machinery and that β(3)-AR agonists could be used to achieve metabolic benefit in humans.