title: Depressed levels of prostaglandin F2α in mice lacking Akr1b7 increase basal adiposity and predispose to diet-induced obesity.
abstract: Negative regulators of white adipose tissue (WAT) expansion are poorly documented in vivo. Prostaglandin F(2α) (PGF(2α)) is a potent antiadipogenic factor in cultured preadipocytes, but evidence for its involvement in physiological context is lacking. We previously reported that Akr1b7, an aldo-keto reductase enriched in adipose stromal vascular fraction but absent from mature adipocytes, has antiadipogenic properties possibly supported by PGF(2α) synthase activity. To test whether lack of Akr1b7 could influence WAT homeostasis in vivo, we generated Akr1b7(-/-) mice in 129/Sv background. Akr1b7(-/-) mice displayed excessive basal adiposity resulting from adipocyte hyperplasia/hypertrophy and exhibited greater sensitivity to diet-induced obesity. Following adipose enlargement and irrespective of the diet, they developed liver steatosis and progressive insulin resistance. Akr1b7 loss was associated with decreased PGF(2α) WAT contents. Cloprostenol (PGF(2α) agonist) administration to Akr1b7(-/-) mice normalized WAT expansion by affecting both de novo adipocyte differentiation and size. Treatment of 3T3-L1 adipocytes and Akr1b7(-/-) mice with cloprostenol suggested that decreased adipocyte size resulted from inhibition of lipogenic gene expression. Hence, Akr1b7 is a major regulator of WAT development through at least two PGF(2α)-dependent mechanisms: inhibition of adipogenesis and lipogenesis. These findings provide molecular rationale to explore the status of aldo-keto reductases in dysregulations of adipose tissue homeostasis.
authors.affiliation: Centre National de la Recherche Scientifique Unité Mixte de Recherche 6293/Institut National de la Santé et de la Recherche Médicale U1103–Génétique, Reproduction et Développement, Clermont Université, Aubière, France.
authors.forename: Fanny E
authors.initials: FE
authors.lastname: Volat
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Pointud
authors.forename: Emilie
authors.initials: E
authors.lastname: Pastel
authors.forename: Béatrice
authors.initials: B
authors.lastname: Morio
authors.forename: Benoit
authors.initials: B
authors.lastname: Sion
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Hamard
authors.forename: Michel
authors.initials: M
authors.lastname: Guichardant
authors.forename: Romain
authors.initials: R
authors.lastname: Colas
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lefrançois-Martinez
authors.forename: Antoine
authors.initials: A
authors.lastname: Martinez
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050154:Adiposity / Q000187:drug effects; D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology / Q000627:therapeutic use; D048429:Cell Size / Q000187:drug effects; D003008:Cloprostenol / Q000494:pharmacology / Q000627:therapeutic use; D003433:Crosses, Genetic; D059305:Diet, High-Fat / Q000009:adverse effects*; D015237:Dinoprost / Q000819:agonists / Q000378:metabolism*; D004198:Disease Susceptibility; D015536:Down-Regulation / Q000187:drug effects; D007333:Insulin Resistance; D050155:Lipogenesis / Q000187:drug effects; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009765:Obesity / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology
chemical_list: D019440:Anti-Obesity Agents; D003008:Cloprostenol; D015237:Dinoprost; C066498:Akr1b7 protein, mouse; D000449:Aldehyde Reductase