SUMO 特异性蛋白酶 2 在瘦素诱导的白色脂肪细胞脂肪酸代谢中的作用。

Role of SUMO-Specific Protease 2 in Leptin-Induced Fatty Acid Metabolism in White Adipocytes.

机构信息

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.

出版信息

Diabetes Metab J. 2023 May;47(3):382-393. doi: 10.4093/dmj.2022.0156. Epub 2023 Mar 6.

DOI:10.4093/dmj.2022.0156

PMID:36872063

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10244199/

Abstract

BACKGROUND

Leptin is a 16-kDa fat-derived hormone with a primary role in controlling adipose tissue levels. Leptin increases fatty acid oxidation (FAO) acutely through adenosine monophosphate-activated protein kinase (AMPK) and on delay through the SUMO-specific protease 2 (SENP2)-peroxisome proliferator-activated receptor δ/γ (PPARδ/γ) pathway in skeletal muscle. Leptin also directly increases FAO and decreases lipogenesis in adipocytes; however, the mechanism behind these effects remains unknown. Here, we investigated the role of SENP2 in the regulation of fatty acid metabolism by leptin in adipocytes and white adipose tissues.

METHODS

The effects of leptin mediated by SENP2 on fatty acid metabolism were tested by siRNA-mediated knockdown in 3T3-L1 adipocytes. The role of SENP2 was confirmed in vivo using adipocyte-specific Senp2 knockout (Senp2-aKO) mice. We revealed the molecular mechanism involved in the leptin-induced transcriptional regulation of carnitine palmitoyl transferase 1b (Cpt1b) and long-chain acyl-coenzyme A synthetase 1 (Acsl1) using transfection/reporter assays and chromatin immunoprecipitation.

RESULTS

SENP2 mediated the increased expression of FAO-associated enzymes, CPT1b and ACSL1, which peaked 24 hours after leptin treatment in adipocytes. In contrast, leptin stimulated FAO through AMPK during the initial several hours after treatment. In white adipose tissues, FAO and mRNA levels of Cpt1b and Acsl1 were increased by 2-fold 24 hours after leptin injection in control mice but not in Senp2-aKO mice. Leptin increased PPARα binding to the Cpt1b and Acsl1 promoters in adipocytes through SENP2.

CONCLUSION

These results suggest that the SENP2-PPARα pathway plays an important role in leptin-induced FAO in white adipocytes.

摘要

背景

瘦素是一种 16kDa 的脂肪衍生激素，主要作用是控制脂肪组织水平。瘦素通过单磷酸腺苷激活的蛋白激酶（AMPK）急性增加脂肪酸氧化（FAO），并通过 SUMO 特异性蛋白酶 2（SENP2）-过氧化物酶体增殖物激活受体 δ/γ（PPARδ/γ）途径延迟在骨骼肌中。瘦素还直接增加脂肪细胞中的 FAO 并减少脂肪生成；然而，这些作用的机制尚不清楚。在这里，我们研究了 SENP2 在脂肪细胞中瘦素调节脂肪酸代谢中的作用。

方法

通过 3T3-L1 脂肪细胞中的 siRNA 介导的敲低测试瘦素介导的 SENP2 对脂肪酸代谢的影响。使用脂肪细胞特异性 Senp2 敲除（Senp2-aKO）小鼠在体内证实了 SENP2 的作用。我们通过转染/报告基因测定和染色质免疫沉淀揭示了瘦素诱导的肉碱棕榈酰转移酶 1b（Cpt1b）和长链酰基辅酶 A 合成酶 1（Acsl1）转录调节中涉及的分子机制。

结果

SENP2 介导了 FAO 相关酶，Cpt1b 和 ACSL1 的表达增加，这在脂肪细胞中瘦素处理 24 小时后达到峰值。相比之下，瘦素在治疗后的最初几个小时内通过 AMPK 刺激 FAO。在白色脂肪组织中，瘦素注射后 24 小时，对照小鼠的 FAO 和 Cpt1b 和 Acsl1 的 mRNA 水平增加了 2 倍，但 Senp2-aKO 小鼠则没有。瘦素通过 SENP2 增加了 PPARα 与 Cpt1b 和 Acsl1 启动子的结合。