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<p>Brown adipose tissue (BAT) is responsible for energy homeostasis and adaptive thermogenesis. SUMO-specific protease 2 (SENP2) plays an essential role in adipogenesis; however, the role of SENP2 in BAT metabolism has not been explored. Here we investigated the role of SENP2 in mature brown adipocytes with a brown adipocyte-specific SENP2 knockout (<i>Senp2</i>-BKO) mouse model generated using the uncoupling protein 1 (<i>Ucp1</i>)-Cre. High-fat diet-induced insulin resistance was aggravated in <i>Senp2</i>-BKO mice compared with control mice. In <i>Senp2</i>-BKO mice, adaptive thermogenesis upon acute cold exposure was impaired and UCP1 expression was barely induced upon cold or β-adrenergic stimulation. SENP2-mediated deSUMOylation of estrogen-related receptor alpha (ERRα) significantly enhanced <i>Ucp1</i> promoter activity through activation of the ERRα/PGC1α complex. The absence of SENP2 inhibited formation of ERRα, cAMP-response element-binding protein (CREB) and RNA Polymerase II transcriptional complex at the <i>Ucp1</i> promoter following β3-adrenergic stimulation. In addition, SUMOylation of ERRα severely interfered with binding of ERRα to its DNA-binding site (ERRE) in the promoter of <i>Ucp1</i>. Our findings revealed that SENP2 plays a role in the metabolic flexibility and thermogenic efficiency of BAT, particularly in response to β3-adrenergic activation.</p>

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SENP2 regulates UCP1-dependent thermogenesis in brown adipocytes via deSUMOylation of ERRα

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月27日

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  • Hun Jee Choe,
  • Ji Seon Lee,
  • Jong Yoen Park,
  • Seung-Ah Lee,
  • Young Joo Park,
  • Sung Soo Chung,
  • Kyong Soo Park

摘要

Brown adipose tissue (BAT) is responsible for energy homeostasis and adaptive thermogenesis. SUMO-specific protease 2 (SENP2) plays an essential role in adipogenesis; however, the role of SENP2 in BAT metabolism has not been explored. Here we investigated the role of SENP2 in mature brown adipocytes with a brown adipocyte-specific SENP2 knockout (Senp2-BKO) mouse model generated using the uncoupling protein 1 (Ucp1)-Cre. High-fat diet-induced insulin resistance was aggravated in Senp2-BKO mice compared with control mice. In Senp2-BKO mice, adaptive thermogenesis upon acute cold exposure was impaired and UCP1 expression was barely induced upon cold or β-adrenergic stimulation. SENP2-mediated deSUMOylation of estrogen-related receptor alpha (ERRα) significantly enhanced Ucp1 promoter activity through activation of the ERRα/PGC1α complex. The absence of SENP2 inhibited formation of ERRα, cAMP-response element-binding protein (CREB) and RNA Polymerase II transcriptional complex at the Ucp1 promoter following β3-adrenergic stimulation. In addition, SUMOylation of ERRα severely interfered with binding of ERRα to its DNA-binding site (ERRE) in the promoter of Ucp1. Our findings revealed that SENP2 plays a role in the metabolic flexibility and thermogenic efficiency of BAT, particularly in response to β3-adrenergic activation.