Lund Jenny, Krapf Solveig A, Sistek Medina, Bakke Hege G, Bartesaghi Stefano, Peng Xiao-Rong, Rustan Arild C, Thoresen G Hege, Kase Eili T
Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Norway.
Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Curr Res Pharmacol Drug Discov. 2021 Sep 25;2:100061. doi: 10.1016/j.crphar.2021.100061. eCollection 2021.
Sentrin-specific protease (SENP) 2 has been suggested as a possible novel drug target for the treatment of obesity and type 2 diabetes mellitus after observations of a palmitate-induced increase in SENP2 that lead to increased fatty acid oxidation and improved insulin sensitivity in skeletal muscle cells from mice. However, no precedent research has examined the role of SENP2 in human skeletal muscle cells. In the present work, we have investigated the impact of SENP2 on fatty acid and glucose metabolism as well as insulin sensitivity in human skeletal muscle using cultured primary human myotubes. Acute (4 h) oleic acid oxidation was reduced in SENP2-knockdown (SENP2-KD) cells compared to control cells, with no difference in uptake. After prelabeling (24 h) with oleic acid, total lipid content and incorporation into triacylglycerol was decreased, while incorporation into other lipids, as well as complete oxidation and β-oxidation was increased in SENP2-KD cells. Basal glucose uptake (i.e., not under insulin-stimulated conditions) was higher in SENP2-KD cells, whereas oxidation was similar to control myotubes. Further, basal glycogen synthesis was not different in SENP2-KD myotubes, but both insulin-stimulated glycogen synthesis and Akt phosphorylation was completely blunted in SENP2-KD cells. In conclusion, SENP2 plays an important role in fatty acid and glucose metabolism in human myotubes. Interestingly, it also appears to have a pivotal role in regulating myotube insulin sensitivity. Future studies should examine the role of SENP2 in regulation of insulin sensitivity in other tissues and , defining the potential for SENP2 as a drug target.
在观察到棕榈酸诱导的SENP2增加可导致小鼠骨骼肌细胞中脂肪酸氧化增加和胰岛素敏感性改善后，Sentrin特异性蛋白酶（SENP）2被认为是治疗肥胖症和2型糖尿病的一种可能的新型药物靶点。然而，此前尚无研究探讨SENP2在人骨骼肌细胞中的作用。在本研究中，我们使用培养的原代人肌管研究了SENP2对人骨骼肌中脂肪酸和葡萄糖代谢以及胰岛素敏感性的影响。与对照细胞相比，SENP2基因敲低（SENP2-KD）细胞中的急性（4小时）油酸氧化减少，摄取无差异。用油酸预标记（24小时）后，SENP2-KD细胞中的总脂质含量和掺入三酰甘油的量减少，而掺入其他脂质以及完全氧化和β氧化增加。SENP2-KD细胞中的基础葡萄糖摄取（即非胰岛素刺激条件下）较高，而氧化与对照肌管相似。此外，SENP2-KD肌管中的基础糖原合成没有差异，但SENP2-KD细胞中胰岛素刺激的糖原合成和Akt磷酸化均完全受到抑制。总之，SENP2在人肌管的脂肪酸和葡萄糖代谢中起重要作用。有趣的是，它似乎在调节肌管胰岛素敏感性方面也起着关键作用。未来的研究应探讨SENP2在其他组织中调节胰岛素敏感性的作用，并确定SENP2作为药物靶点的潜力。
