β3-Adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity

Valentine, Joseph M.; Ahmadian, Maryam; Keinan, Omer; Abu-Odeh, Mohammad; Zhao, Peng; Zhou, Xin; Keller, Mark P.; Gao, Hui; Yu, Ruth T.; Liddle, Christopher; Downes, Michael; Zhang, Jin; Lusis, Aldons J.; Attie, Alan D.; Evans, Ronald M.; Rydén, Mikael; Saltiel, Alan R.

doi:10.1172/jci153357

Cited by 51 publications

(37 citation statements)

References 86 publications

(117 reference statements)

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“…However, ADRβ3 and GIPR expression is markedly down-regulated in adipose tissue of obese human subjects in this study. This is consistent with other studies that have reported downregulation of these receptors in the adipose tissue of high fat-fed mice as well in human obese subjects (37)(38). Therefore, the approach to using agonists of these receptors to mitigate obesity and related disorders is unlikely to work.…”

Section: Discussionsupporting

confidence: 89%

Profiling of G-protein Coupled Receptors in Adipose Tissue and Differentiating Adipocytes Offers a Translational Resource for Obesity/Metabolic Research

Mahri¹,

Okla²,

Rashid³

et al. 2022

Preprint

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G protein-coupled receptors (GPCRs) are expressed essentially on all cells, facilitating cellular responses to external stimuli, and are involved in nearly every biological process. Several members of this family play significant roles in the regulation of adipogenesis and adipose me-tabolism. However, the expression and functional significance of a vast number of GPCRs in adipose tissue are unknown. We used a high-throughput RT-PCR panel to determine the expres-sion of the entire repertoire of non-sensory GPCRs in mouse white, and brown adipose tissue and assess changes in their expression during adipogenic differentiation of murine adipocyte cell line, 3T3-L1. In addition, the expression of GPCRs in subcutaneous adipose tissues from lean, obese, and diabetic human subjects was evaluated by re-analyzing RNA-sequencing data. We detected a total of 292 and 271 GPCRs in mouse white and brown adipose tissue, respectively. There is a significant overlap in the expression of GPCRs between the two adipose tissue depots but several GPCRs are specifically expressed in one of the two tissue types. Adipogenic differ-entiation of 3T3-L1 cells had a profound impact on the expression of several GPCRs. RNA se-quencing of subcutaneous adipose from healthy human subjects detected 255 GPCRs and obesity significantly changed the expression of several GPCRs in adipose tissue. Finally, we report sev-eral highly expressed GPCRs with no known role in adipose biology whose expression was sig-nificantly altered during adipogenic differentiation and/or in the diseased human subjects. These GPCRs could play an important role in adipose metabolism and serve as a valuable translational resource for obesity and metabolic research.

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Section: Discussionsupporting

confidence: 89%

Profiling of G-protein Coupled Receptors in Adipose Tissue and Differentiating Adipocytes Offers a Translational Resource for Obesity/Metabolic Research

Mahri¹,

Okla²,

Rashid³

et al. 2022

Preprint

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show abstract

“…β3-adrenergic receptor (β3-AR) is a seventransmembrane domain G-protein coupled receptor and its stimulation increases the production of cAMP [21], [24], [25]. β3-AR is expressed in many tissues including the reproductive system, urinary system, CNS, and adipose tissue [26], [27].…”

Section: Discussionmentioning

confidence: 99%

Impact of Targeting β3 Receptor on Male Sex Hormonal Balance

Ahmad

Saarti

Younes

2022

Open Access Maced J Med Sci

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BACKGROUND: Sympathetic stimulation has a significant impact on the physiology and pathology of the male reproductive system. β3 receptor is suspected to play a role in the regulation of fertility status in men. AIM: The study aims to investigate the role of the β3 receptor in regulating the fertility parameters (testosterone, estrogen, progesterone, and histology of testis) in male rats. MATERIALS AND METHODS: Male albino rats have been given either placebo (controls) or β3 agonist (Mirabegron). Testosterone, estrogen, and progesterone are measured before and after treatment for all cases and controls. Histology of testis is investigated for all the rats as well. RESULTS: β3 receptor activation caused a significant increase in testosterone plasma concentration and a significant reduction in estrogen plasma concentration. β3 agonist did not affect the progesterone plasma concentration. Histological sections showed that β3 activation resulted in degeneration of the spermatocytes and accumulation of edema between the seminiferous tubules in the testis. CONCLUSION: β3 receptor has a potentially important role in the fertility status of male rats via regulating sex hormonal profile and altering the histology of the testis.

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“…Using time-lapse total internal reflection fluorescence (TIRF) microscopy of GLUT4-GFP in primary adipocytes, GLUT4 near the plasma membrane was found either localised within relatively stationary clusters or in mobile structures thought to be GSCs adjacent to the plasma membrane 18 . High resolution imaging of surface-exposed GLUT4 inserted into the plasma membrane using antibodies directed against the exofacial HA epitope confirmed that GLUT4 distribution within the plasma membrane is inhomogeneous, being identified both in clustered domains and as a diffuse staining 18 , 19 . The authors identified two distinct modes of GLUT4-vesicle exocytosis.…”

Section: Introductionmentioning

confidence: 85%

GLUT4 translocation and dispersal operate in multiple cell types and are negatively correlated with cell size in adipocytes

Koester

Geiser

Bowman

et al. 2022

Sci Rep

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The regulated translocation of the glucose transporter, GLUT4, to the surface of adipocytes and muscle is a key action of insulin. This is underpinned by the delivery and fusion of GLUT4-containing vesicles with the plasma membrane. Recent studies have revealed that a further action of insulin is to mediate the dispersal of GLUT4 molecules away from the site of GLUT4 vesicle fusion with the plasma membrane. Although shown in adipocytes, whether insulin-stimulated dispersal occurs in other cells and/or is exhibited by other proteins remains a matter of debate. Here we show that insulin stimulates GLUT4 dispersal in the plasma membrane of adipocytes, induced pluripotent stem cell-derived cardiomyocytes and HeLa cells, suggesting that this phenomenon is specific to GLUT4 expressed in all cell types. By contrast, insulin-stimulated dispersal of TfR was not observed in HeLa cells, suggesting that the mechanism may be unique to GLUT4. Consistent with dispersal being an important physiological mechanism, we observed that insulin-stimulated GLUT4 dispersal is reduced under conditions of insulin resistance. Adipocytes of different sizes have been shown to exhibit distinct metabolic properties: larger adipocytes exhibit reduced insulin-stimulated glucose transport compared to smaller cells. Here we show that both GLUT4 delivery to the plasma membrane and GLUT4 dispersal are reduced in larger adipocytes, supporting the hypothesis that larger adipocytes are refractory to insulin challenge compared to their smaller counterparts, even within a supposedly homogeneous population of cells.

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β3-Adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity

Cited by 51 publications

References 86 publications

Profiling of G-protein Coupled Receptors in Adipose Tissue and Differentiating Adipocytes Offers a Translational Resource for Obesity/Metabolic Research

Profiling of G-protein Coupled Receptors in Adipose Tissue and Differentiating Adipocytes Offers a Translational Resource for Obesity/Metabolic Research

Impact of Targeting β3 Receptor on Male Sex Hormonal Balance

GLUT4 translocation and dispersal operate in multiple cell types and are negatively correlated with cell size in adipocytes

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