Functional Characterization of the Obesity-Linked Variant of the β3-Adrenergic Receptor

Abstract

Adrenergic receptor β3 (ADRβ3) is a member of the rhodopsin-like G protein-coupled receptor family. The binding of the ligand to ADRβ3 activates adenylate cyclase and increases cAMP in the cells. ADRβ3 is highly expressed in white and brown adipocytes and controls key regulatory pathways of lipid metabolism. Trp64Arg (W64R) polymorphism in the ADRβ3 is associated with the early development of type 2 diabetes mellitus, lower resting metabolic rate, abdominal obesity, and insulin resistance. It is unclear how the substitution of W64R affects the functioning of ADRβ3. This study was initiated to functionally characterize this obesity-linked variant of ADRβ3. We evaluated in detail the expression, subcellular distribution, and post-activation behavior of the WT and W64R ADRβ3 using single cell quantitative fluorescence microscopy. When expressed in HEK 293 cells, ADRβ3 shows a typical distribution displayed by other GPCRs with a predominant localization at the cell surface. Unlike adrenergic receptor β2 (ADRβ2), agonist-induced desensitization of ADRβ3 does not involve loss of cell surface expression. WT and W64R variant of ADRβ3 displayed comparable biochemical properties, and there was no significant impact of the substitution of tryptophan with arginine on the expression, cellular distribution, signaling, and post-activation behavior of ADRβ3. The obesity-linked W64R variant of ADRβ3 is indistinguishable from the WT ADRβ3 in terms of expression, cellular distribution, signaling, and post-activation behavior.

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“…The adrenergic system plays an important role in regulating energy balance through heat production and lipid mobilisation, and it has been con rmed that adrenergic receptors (β1-AR, β2-AR, and β3-Ar) are involved in the regulation of obesity [36]. It is well-known that the synergistic effect between 3-Ar and uncoupling protein 1(UCP1) is related to weight gain and anti-weight loss, and is highly expressed in white and brown adipocytes and controls the key regulatory pathway of lipid metabolism [36][37][38]. However, adrenergic stimulation and lipolysis of UCP1 in human brown fat may be mainly mediated by ADRB1 [39].…”

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“…ADRβ2, existing in bronchi and blood vessels, relaxes various smooth muscles, such as the bronchial smooth muscle, vascular smooth muscles (muscle and liver), and the uterine smooth muscle, as well as controls glucose metabolism [46][47][48][49][50][51][52]. ADRβ3 is present in adipocytes, the gastrointestinal tract, liver, and skeletal muscles and is expected to be present in the postsynaptic membrane of adrenergic nerves [53][54][55][56]; it is also known to affect basal metabolism [57].…”

Special Issue: “G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0”

“…In their original report, Haji and colleagues [ 9 ] analyzed the impact of the nonsynonymous polymorphism of amino acid 64, where tryptophan can exist in place of arginine (W64R), on the expression, cellular distribution, and post-activation of the β3-adrenergic receptor (β3AR). Notably, this βAR isoform, similar to β1 and β2AR, has been reported to elicit a prominent role in the cardiovascular system, mainly in the myocardium, endothelium, and adipose tissue, modulating the cardiac function, angiogenesis, and metabolism, respectively [ 10 , 11 ].…”

“…In this regard, previous studies conducted in vitro demonstrated that W64R mutation generated a β3AR that was less responsive to catecholamine stimulation [ 11 ]. Therefore, several reports suggested an association between this variant and certain pathophysiological conditions (i.e., obesity) [ 9 , 11 ]. However, in this study, Haji et al demonstrated that, in HEK293 cells, the WT or W64R β3AR displayed comparable biochemical properties.…”