醛糖还原酶通过诱导皮下脂肪组织衰老促进饮食诱导的肥胖。
Aldose reductase promotes diet-induced obesity via induction of senescence in subcutaneous adipose tissue.
机构信息
Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA.
Saha Cardiovascular Research Center, Department of Physiology, University of Kentucky, Lexington, Kentucky, USA.
出版信息
Obesity (Silver Spring). 2022 Aug;30(8):1647-1658. doi: 10.1002/oby.23496.
OBJECTIVE
Aldose reductase (AKR1B1 in humans; Akr1b3 in mice), a key enzyme of the polyol pathway, mediates lipid accumulation in the murine heart and liver. The study objective was to explore potential roles for AKR1B1/Akr1b3 in the pathogenesis of obesity and its complications.
METHODS
The study employed mice treated with an inhibitor of aldose reductase or mice devoid of Akr1b3 were used to determine their response to a high-fat diet. The study used subcutaneous adipose tissue-derived adipocytes to investigate mechanisms by which AKR1B1/Akr1b3 promotes diet-induced obesity.
RESULTS
Increased expression of aldose reductase and senescence in the adipose tissue of humans and mice with obesity were demonstrated. Genetic deletion of Akr1b3 or pharmacological blockade of AKRIB3 with zopolrestat reduced high-fat-diet-induced obesity, attenuated markers of adipose tissue senescence, and increased lipolysis.
CONCLUSIONS
AKR1B1/Akr1b3 modulation of senescence in subcutaneous adipose tissue contributes to aberrant metabolic responses to high-fat feeding. These data unveil new opportunities to target these pathways to combat obesity.
目的
醛糖还原酶（人类中的 AKR1B1；小鼠中的 Akr1b3）是多元醇途径的关键酶，介导了小鼠心脏和肝脏中的脂质积累。本研究的目的是探索 AKR1B1/Akr1b3 在肥胖及其并发症发病机制中的潜在作用。
方法
本研究采用醛糖还原酶抑制剂处理的小鼠或缺乏 Akr1b3 的小鼠，以确定它们对高脂肪饮食的反应。本研究还使用皮下脂肪组织来源的脂肪细胞来研究 AKR1B1/Akr1b3 促进饮食诱导肥胖的机制。
结果
研究表明，肥胖人群的脂肪组织中醛糖还原酶表达增加和衰老。Akr1b3 的基因缺失或 AKRIB3 的药理学阻断（用 zopolrestat）可减少高脂肪饮食诱导的肥胖，减轻脂肪组织衰老的标志物，并增加脂肪分解。
结论
AKR1B1/Akr1b3 对皮下脂肪组织衰老的调节导致对高脂肪喂养的异常代谢反应。这些数据揭示了靶向这些途径以对抗肥胖的新机会。
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