β3-Adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity
Joseph M. Valentine, … , Mikael Rydén, Alan R. Saltiel
Joseph M. Valentine, … , Mikael Rydén, Alan R. Saltiel
Published November 30, 2021
Citation Information: J Clin Invest. 2022;132(2):e153357. https://doi.org/10.1172/JCI153357.
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Research Article Cell biology Metabolism

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

Abstract

The dysregulation of energy homeostasis in obesity involves multihormone resistance. Although leptin and insulin resistance have been well characterized, catecholamine resistance remains largely unexplored. Murine β3-adrenergic receptor expression in adipocytes is orders of magnitude higher compared with that of other isoforms. While resistant to classical desensitization pathways, its mRNA (Adrb3) and protein expression are dramatically downregulated after ligand exposure (homologous desensitization). β3-Adrenergic receptor downregulation also occurs after high-fat diet feeding, concurrent with catecholamine resistance and elevated inflammation. This downregulation is recapitulated in vitro by TNF-α treatment (heterologous desensitization). Both homologous and heterologous desensitization of Adrb3 were triggered by induction of the pseudokinase TRIB1 downstream of the EPAC/RAP2A/PI-PLC pathway. TRIB1 in turn degraded the primary transcriptional activator of Adrb3, CEBPα. EPAC/RAP inhibition enhanced catecholamine-stimulated lipolysis and energy expenditure in obese mice. Moreover, adipose tissue expression of genes in this pathway correlated with body weight extremes in a cohort of genetically diverse mice and with BMI in 2 independent cohorts of humans. These data implicate a signaling axis that may explain reduced hormone-stimulated lipolysis in obesity and resistance to therapeutic interventions with β3-adrenergic receptor agonists.

Authors

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

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Figure 3

Heterologous desensitization of the adipocyte β3-AR occurs with obesity in mice and proinflammatory cytokine stimulation in vitro.

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Heterologous desensitization of the adipocyte β3-AR occurs with obesity ...
(A and B) Mice on HFD for 3 or 12 months (n = 3–6 per group) were challenged with 0.5 mg/kg CL-316243 and pHSL, with β3-AR expression and serum FFA normalized to baseline measured as before. §Significance compared with vehicle; *significance compared with ND-CL-316243. (C) RNA-Seq from isolated adipocytes of iWAT and eWAT in mice fed HFD for 16 weeks (n = 3 per group). *Significance between HFD and ND for the listed genes. (D and E) Mice were treated with 10 mg/kg LPS for 18 hours and gene expression assessed in eWAT (n = 5 per group). (F) Adrb3 (n = 3 per group repeated once) and (G) β3-AR were assessed as before with 17 ng/mL TNF-α treatment. n = 3 per group. (H) 3T3L1 adipocytes were pretreated and challenged as before then FFAs (n = 3 per group) measured as in Figure 1, D and E. (H) Experiments shown in part H had the same experimental design as in Figure 1D, except pretreatment was 17 ng/mL TNF-α. Significance symbols are as described for Figure 1, D and E. (I) Oxygen consumption rates after 18 hours pretreatment with 17 ng/mL TNF-α were determined by Seahorse using PPDIVs (n = 8 per group). *Significance compared with control unless otherwise specified. Controls in I were also used for Figure 1 for cognate experiments, as these assays were carried out simultaneously. Two-way ANOVA with Šidák’s (A) and Tukey’s (H) multiple comparisons; t tests and FDR applied to correct for multiple comparisons (C); independent samples t test (D and E); 1-way ANOVA with Dunnett’s post hoc test (F); 2-way mixed ANOVA (time × treatment) with Tukey’s post hoc test (I). Error bars represent SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. ####P < 0.0001. §§§§P < 0.001.