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 7

Inflammation drives EPAC/RAP-dependent catecholamine resistance in obesity.

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Inflammation drives EPAC/RAP-dependent catecholamine resistance in obesi...
(A) eWAT of male and female mice with highest and lowest body weights (n = 10 per group, body weights in Supplemental Figure 7) in diversity outbred mice (n = 10 per group). (B) Starting body weights for mice fed HFD for 18 weeks before ESI-09 or vehicle treatment. (C) Body weight change in these mice during ESI-09 (10 mg/kg) or vehicle treatment (n = 17–18 per group). (D) β3-AR and pHSL from eWAT of mice in C; 24 hours after ESI09 treatment cessation, mice were challenged with 0.1 mg/kg CL-316243 or saline for 20 minutes (n = 6 per group). (E) Whole body oxygen consumption (VO2) and carbon dioxide production (VCO2) measured in a second cohort of mice fed HFD for 16 weeks with or without ESI-09 (10 mg/kg) for 1 week (n = 7–8 per group). Two-way ANOVA and Šidák’s post hoc comparison(A); independent samples t test (B); 2-way mixed ANOVA (day repeated measure and drug independent) with Šidák’s post hoc comparisons (C); 2-way mixed model (drug × time) and Fisher’s LSD post hoc test (E). *Significance compared with control unless otherwise specified. Error bars represent SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.