Pastel Emilie, Pointud Jean-Christophe, Loubeau Gaëlle, Dani Christian, Slim Karem, Martin Gwenaëlle, Volat Fanny, Sahut-Barnola Isabelle, Val Pierre, Martinez Antoine, Lefrançois-Martinez Anne-Marie
Centre National de la Recherche Scientifique Unité Mixte de Recherche 6293 (E.P., J.-C.P., G.L., I.S.-B., P.V., A.M., A.-M.L.-M.), INSERM Unité 1103, Génétique Reproduction et Développement, Clermont Université, 63171 Aubière, France; iBV (C.D.), Institute of Biology Valrose, Université Nice Sophia Antipolis, 06189 Nice, France; Service de Chirurgie Digestive (K.S., G.M.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand, France; and INSERM Unité Mixte de Recherche 1048 (F.V.), Institute of Metabolic and Cardiovascular Diseases, Université Paul Sabatier, 31432 Toulouse, France.
Endocrinology. 2015 May;156(5):1671-84. doi: 10.1210/en.2014-1750. Epub 2015 Mar 2.
Aldose reductases (AKR1B) are widely expressed oxidoreductases whose physiological function remains elusive. Some isoforms are genuine prostaglandin F2α (PGF2α) synthases, suggesting they might influence adipose homeostasis because PGF2α inhibits adipogenesis. This was shown by Akr1b7 gene ablation in the mouse, which resulted in increased adiposity related to a lower PGF2α content in fat. Yet humans have no ortholog gene for Akr1b7, so the role of aldose reductases in human adipose homeostasis remains to be explored. We analyzed expression of genes encoding human and mouse aldose reductase isoforms in adipose tissues and differentiating adipocytes to assess conserved mechanisms regulating PGF2α synthesis and adipogenesis. The Akr1b3 gene encoded the most abundant isoform in mouse adipose tissue, whereas Akr1b7 encoded the only isoform enriched in the stromal vascular fraction. Most mouse aldose reductase gene expression peaked in early adipogenesis of 3T3-L1 cells and diminished with differentiation. In contrast with its mouse ortholog Akr1b3, AKR1B1 expression increased throughout differentiation of human multipotent adipose-derived stem cells, paralleling PGF2α release, whereas PGF2α receptor (FP) levels collapsed in early differentiation. Pharmacological inhibition of aldose reductase using Statil altered PGF2α production and enhanced human multipotent adipose-derived stem adipocyte differentiation. As expected, the adipogenic effects of Statil were counteracted by an FP agonist (cloprostenol). Thus, in both species aldose reductase-dependent PGF2α production could be important in early differentiation to restrict adipogenesis. PGF2α antiadipogenic signaling could then be toned down through the FP receptor or aldose reductases down-regulation in human and mouse cells, respectively. Our data suggest that aldose reductase inhibitors could have obesogenic potential.
醛糖还原酶（AKR1B）是广泛表达的氧化还原酶，其生理功能仍不清楚。一些同工型是真正的前列腺素F2α（PGF2α）合酶，这表明它们可能影响脂肪稳态，因为PGF2α抑制脂肪生成。小鼠中Akr1b7基因敲除证明了这一点，它导致肥胖增加，与脂肪中较低的PGF2α含量有关。然而，人类没有Akr1b7的直系同源基因，因此醛糖还原酶在人类脂肪稳态中的作用仍有待探索。我们分析了脂肪组织和分化中的脂肪细胞中编码人和小鼠醛糖还原酶同工型的基因表达，以评估调节PGF2α合成和脂肪生成的保守机制。Akr1b3基因编码小鼠脂肪组织中最丰富的同工型，而Akr1b7编码仅在基质血管部分富集的同工型。大多数小鼠醛糖还原酶基因表达在3T3-L1细胞早期脂肪生成中达到峰值，并随着分化而减少。与其小鼠直系同源基因Akr1b3相反，AKR1B1表达在人类多能脂肪来源干细胞的整个分化过程中增加，与PGF2α释放平行，而PGF2α受体（FP）水平在早期分化中下降。使用Statil对醛糖还原酶进行药理抑制改变了PGF2α的产生，并增强了人类多能脂肪来源干细胞的脂肪细胞分化。正如预期的那样，Statil的成脂作用被FP激动剂（氯前列醇）抵消。因此，在两个物种中，醛糖还原酶依赖性PGF2α产生在早期分化中对限制脂肪生成可能很重要。然后，PGF2α抗脂肪生成信号可能分别通过FP受体下调或醛糖还原酶下调在人和小鼠细胞中减弱。我们的数据表明醛糖还原酶抑制剂可能有致肥胖潜力。
