A Functional Variant of the Adipocyte Glycerol Channel Aquaporin 7 Gene Is Associated With Obesity and Related Metabolic Abnormalities

  1. Sabrina Prudente12,
  2. Elisabetta Flex3,
  3. Eleonora Morini14,
  4. Federica Turchi1,
  5. Daria Capponi4,
  6. Salvatore De Cosmo2,
  7. Vittorio Tassi2,
  8. Valentina Guida1,
  9. Angelo Avogaro5,
  10. Franco Folli6,
  11. Francesca Maiani4,
  12. Lucia Frittitta7,
  13. Bruno Dallapiccola18 and
  14. Vincenzo Trischitta124
  1. 1CSS-Mendel Institute, Rome, Italy
  2. 2Research Laboratory of Diabetes and Endocrinology, CSS Scientific Institute, San Giovanni, Rotondo, Italy
  3. 3Department of Cellular Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy
  4. 4Department of Clinical Sciences, University “La Sapienza,” Rome, Italy
  5. 5Unit of Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
  6. 6Department of Medicine, Diabetes Division, University of Texas Health Science Center, San Antonio, Texas
  7. 7Division of Endocrinology, Department of Internal and Specialist Medicine, University of Catania Medical School, Garibaldi Hospital, Catania, Italy
  8. 8Department of Experimental Medicine and Pathology, University “La Sapienza,” Rome, Italy
  1. Address correspondence and reprint requests to Sabrina Prudente, PhD, or Vincenzo Trischitta, MD, CSS-Mendel Institute, Viale Regina Margherita 261, 00198 Rome, Italy. E-mail: s.prudente{at}css-mendel.it (S.P.) or vincenzo.trischitta{at}uniroma1.it (V.T.)

Abstract

Aquaporin 7 (AQP7), the gateway protein controlling glycerol release, has recently emerged as a modulator of adipocyte metabolism. AQP7 knockout mice develop obesity and hyperglycemia. The contribution of AQP7 to these abnormalities in humans is unknown. We examined whether common single nucleotide polymorphisms (SNPs) in the AQP7 gene modulate the risk of obesity and related abnormalities. Among several SNPs we identified, A-953G in the AQP7 promoter was associated with type 2 diabetes in 977 (530 female/447 male) Caucasians: odds ratio for XG (i.e., AG+GG) versus AA individuals was 1.36 (95% CI 1.01–1.84), P = 0.04. This finding was entirely due to the association among females (1.8 [1.2–2.6], P = 0.004), which was no longer significant when adjusted for BMI. In fact, BMI was higher in XG than in AA females (30.8 ± 6.6 vs. 28.9 ± 5.2, P = 0.002). This association was confirmed in independent case-control study (n = 299 female subjects) for morbid obesity (1.66 [1.01–2.74], P = 0.04). Luciferase and mobility shift assays showed that, compared with −953A, the −953G promoter had reduced transcriptional activity (P = 0.001) and impaired ability to bind CCAAT/enhancer binding protein (C/EBP)β transcription factor (P = 0.01). Finally, AQP7 expression in adipose tissue decreased from AA to AG to GG individuals (P = 0.036). These data strongly suggest that AQP7 downregulation is pathogenic for obesity and/or type 2 diabetes.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 9 March 2007. DOI: 10.2337/db06-1389.

  • Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1389.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted January 21, 2007.
    • Received October 1, 2006.
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  1. Published online before print March 9, 2007, doi: 10.2337/db06-1389 Diabetes May 2007 vol. 56 no. 5 1468-1474
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