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.

中文翻译：

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肥胖症中β3-肾上腺素受体下调导致脂肪细胞儿茶酚胺抵抗

肥胖症中能量稳态的失调涉及多激素抵抗。尽管瘦素和胰岛素抵抗已得到很好的表征，但儿茶酚胺抵抗在很大程度上仍未得到探索。与其他亚型相比，脂肪细胞中的鼠β3-肾上腺素能受体表达要高出几个数量级。虽然对经典脱敏途径有抵抗力，但其 mRNA ( Adrb3 ) 和蛋白质表达在配体暴露后显着下调（同源脱敏）。高脂肪饮食喂养后，β 3-肾上腺素受体下调也会发生，同时伴有儿茶酚胺抵抗和炎症升高。通过 TNF- α治疗（异源脱敏）可在体外重现这种下调。Adrb3的同源和异源脱敏都是通过诱导 EPAC/RAP2A/PI-PLC 途径下游的假激酶 TRIB1 来触发的。TRIB1 反过来降解Adrb3的主要转录激活因子CEBP α。EPAC/RAP 抑制增强了肥胖小鼠儿茶酚胺刺激的脂肪分解和能量消耗。此外，该通路中基因的脂肪组织表达与一组遗传多样性小鼠的体重极端值以及两个独立的人类组的BMI相关。这些数据暗示了一个信号轴，可以解释肥胖症中激素刺激的脂肪分解减少以及对β 3-肾上腺素能受体激动剂治疗干预的抵抗。