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.
Highlights
Body mass is governed by the balance between energy intake and expenditure, which are tightly coupled to ensure homeostasis even during periods of over- or under-nutrition [1,2,3,4]
We report here that pathways controlling the negative regulation of Adrb3 transcription by both homologous (b3-AR) and heterologous signals converge at the EPAC/RAP2A/PI-PLC pathway, which orchestrates a cascade of transcriptional events to repress Adrb3 gene expression through targeted degradation of CEBPa in adipocytes
The decrease in mRNA preceded that of b3-adrenergic receptor (b3-AR) protein expression (antibody and 10μM CL-316243 dose validated for specificity using b3-AR knockout adipocytes (Supplemental Figure 1A)), which was dramatically downregulated 12hrs after CL-316243 treatment (Figure 1B)
Summary
Body mass is governed by the balance between energy intake and expenditure, which are tightly coupled to ensure homeostasis even during periods of over- or under-nutrition [1,2,3,4]. Disruption of this balance leads to obesity, multi-hormone resistance and metabolic inflexibility [5]. Catecholamine resistance is a key feature of the obese state, and may even predict future weight gain in some patients [19, 20]
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