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 2

Desensitization of β3-AR depends on EPAC/RAP2A/PLC pathway activation.

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Desensitization of β3-AR depends on EPAC/RAP2A/PLC pathway activation. (...
(A) 3T3L1 adipocytes were pretreated with 10 μM ESI09 for 1 hour, then challenged with 10 μM CL-316243 for 3 hours (n = 3 per group, 3 independent experiments). (B) Active (GTP bound) RAP2 was determined by pulldown followed by Western blotting with RAP2 antibody (n = 2 per group). (C and D) FLAG-tagged RAP2A WT or constitutively active RAP2A (V12) was electroporated into 3T3L1 adipocytes (n = 1–2 per group, repeated once). (E and F) 3T3L1 adipocytes were pretreated for 1 hour with 10 μM U73122 or 50 μM BAPTA-AM, followed by 3 hours challenge with 10 μM CL-316243 (n = 3 per group, 3 independent experiments). (G) 3T3L1 adipocytes were pretreated with 10 μM ESI09 for 1 hour, challenged with 10 μM CL-316243, and calcium flux assessed in live cells using Fura2-AM (91 randomly chosen cells from 4 experiments [blue] and 101 from 3 experiments [gray]). Graph represents the subpopulation of cells that responded to CL-316243 (~20%). *Significance compared with control or GFP in all experiments. One-way ANOVA with Tukey’s post hoc comparisons (A, C, E, and F); independent samples t test (G). All error bars represent SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.