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 1

Homologous desensitization of the adipocyte β3-AR produces catecholamine resistance in vitro and in vivo.

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Homologous desensitization of the adipocyte β3-AR produces catecholamine...
(A) Adrb3 mRNA (n = 3 per group, repeated once) and (B) β3-AR were assessed in 3T3L1 adipocytes treated with 10 μM CL-316243 (n = 3 per group). (C) 3T3L1 adipocytes were pretreated for 48 hours with 10 μM CL-316243, then challenged with CL-316243 (1 μM–0.001 μM) or FSK (50 μM–0.05 μM) (representative n = 2 per group). (D) 3T3L1 adipocytes were pretreated for 48 hours with 10 μM CL-316243 and challenged with 1 μM CL-316243 or 50 μM FSK and FFA determined by absorbance (n = 3 per group). *Significance from vehicle-prevehicle challenge; #significance from vehicle–pre–CL-316243 challenge to CL-316243–pre–CL-316243 challenge; §significance from vehicle-pre-FSK challenge to CL-316243–pre–FSK challenge. (E) Oxygen consumption rate (OCR) after 18 hours pretreatment with 0.1 μM CL-316243 was determined by Seahorse in PPDIVs (n = 8 per group). *Significance from vehicle-prevehicle challenge in all groups. (F and G) Adrb3 mRNA (n = 7–8 per group) and β3-AR protein expression (n = 6 per group) were determined in mouse iWAT 12 hours after 0.5 mg/kg CL-316243 i.p. injection. (H and I) Mice were pretreated with 0.5 mg/kg CL-316243 and challenged with 0.1 mg/kg CL-316243 12 hours later (n = 10 per group). (H) Serum FFA, (I) lipolysis-dependent glucose lowering, and (J) pHSL in iWAT were assessed. *Significance equal to that of control unless otherwise specified. One-way ANOVA with Dunnett’s multiple comparison (A); 2-way ANOVA with Tukey’s multiple comparisons (D); 2-way mixed ANOVA (time × treatment) with Tukey’s post hoc tests (E); independent sample t tests (F, H, and I). All error bars represent SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. ####P < 0.0001. §§§P < 0.001.