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

¹ CSS-Mendel Institute, Rome, Italy
² Research Laboratory of Diabetes and Endocrinology, CSS Scientific Institute, San Giovanni, Rotondo, Italy
³ Department of Cellular Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy
⁴ Department of Clinical Sciences, University "La Sapienza," Rome, Italy
⁵ Unit of Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy
⁶ Department of Medicine, Diabetes Division, University of Texas Health Science Center, San Antonio, Texas
⁷ Division of Endocrinology, Department of Internal and Specialist Medicine, University of Catania Medical School, Garibaldi Hospital, Catania, Italy
⁸ Department of Experimental Medicine and Pathology, University "La Sapienza," Rome, Italy

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.)

Abbreviations: AQP7, aquaporin 7; C/EBP, CCAAT/enhancer binding protein; FFA, free fatty acid; HWE, Hardy-Weinberg equilibrium; LD, linkage disequilibrium; MAF, minor allele frequency; PPAR, peroxisome proliferator–activated receptor; RXR, retinoid X receptor; SNP, single nucleotide polymorphism; UTR, untranslated region

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)ß 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.

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