Aldose reductases influence prostaglandin F2α levels and adipocyte differentiation in male mouse and human species.
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.
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.
Emilie
E
Pastel
Jean-Christophe
JC
Pointud
Gaëlle
G
Loubeau
Christian
C
Dani
Karem
K
Slim
Gwenaëlle
G
Martin
Fanny
F
Volat
Isabelle
I
Sahut-Barnola
Pierre
P
Val
Antoine
A
Martinez
Anne-Marie
AM
Lefrançois-Martinez
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D003008:Cloprostenol / Q000494:pharmacology; D015237:Dinoprost / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008186:Luteolytic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D039902:Multipotent Stem Cells; D009765:Obesity / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D050507:Subcutaneous Fat, Abdominal / Q000378:metabolism
D004791:Enzyme Inhibitors; D008186:Luteolytic Agents; D010793:Phthalazines; D012333:RNA, Messenger; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; C042829:ponalrestat; D003008:Cloprostenol; D015237:Dinoprost; D006911:Hydroxyprostaglandin Dehydrogenases; C031051:prostaglandin-F synthase; C484670:AKR1B1 protein, human; C066498:Akr1b7 protein, mouse; D000449:Aldehyde Reductase