Depressed Levels of Prostaglandin F in Mice Lacking Akr1b7 Increase Basal Adiposity and Predispose to Diet-Induced Obesity

  1. Antoine Martinez1
  1. 1Centre 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
  2. 2Institut National de la Recherche Agronomique Unité Mixte de Recherche 1019, Centre de Recherche en Nutrition Humaine Auvergne, Clermont-Ferrand, France
  3. 3EA975, Biologie de la Reproduction, Faculté de Médecine, Université d’Auvergne, Clermont-Ferrand, France
  4. 4Plate-Forme de Recombinaison Homologue, Institut Cochin, Paris, France
  5. 5Institut National de la Santé et de la Recherche Médicale U870, Institut National de la Recherche Agronomique 1235, INSA-Lyon, RMND/Institut Multidisciplinaire de Biochimie des Lipides, Université de Lyon 1, Villeurbanne, France
  1. Corresponding author: Antoine Martinez, antoine.martinez{at}univ-bpclermont.fr.
  1. F.E.V. and J.-C.P. contributed equally to this work. A.-M.L.-M. and A.M. should be regarded as joint last authors.

Abstract

Negative regulators of white adipose tissue (WAT) expansion are poorly documented in vivo. Prostaglandin F (PGF) 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 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 WAT contents. Cloprostenol (PGF 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-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.

Footnotes

  • Received September 21, 2011.
  • Accepted May 8, 2012.

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  1. Diabetes vol. 61 no. 11 2796-2806
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