Published on January 25, 2024 Updated on February 13, 2024

J. M. Valentine, M. Ahmadian, O. Keinan, M. Abu-Odeh, P. Zhao, X. Zhou, M. P. Keller, H. Gao, R. T. Yu, C. Liddle, M. Downes, J. Zhang, A. J. Lusis, A. D. Attie, R. M. Evans, M. Rydén, A. R. Saltiel (2021)

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.
 
  • PMID: 34847077
  • DOI: https://doi.org/10.1172/JCI153357