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A functional variant of the adipocyte glycerol channel Aquaporin 7 gene is associated with obesity and related metabolic abnormalities

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

Correspondence: s.prudente{at}css-mendel.it

Correspondence: vincenzo.trischitta{at}uniroma1.it

Key Words: type 2 diabetes • elevated FFA levels • insulin resistance • multifactorial diseases

Aquaporin 7 (AQP7), the gateway protein controlling glycerol release, has recently emerged as a modulator of adipocyte metabolism and AQP7 knock out mice develop obesity and hyperglycaemia. The contribution of AQP7 to these abnormalities in humans is unknown. We examined whether common single nucleotide polymorphisms (SNP) in AQP7 gene modulate the risk of obesity and related abnormalities. Among several SNPs we identified, the A-953G in AQP7 promoter was associated with type 2 diabetes (T2D) in 977 (530F/447M) Caucasians: OR for XG (i.e. AG+GG) vs. AA individuals=1.36, 95% CI=1.01-1.84, p=0.04. This finding was entirely due to the association among females (OR=1.8, 95% CI=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 females) for morbid obesity (OR=1.66, 95% CI=1.01-2.74, p=0.04). Luciferase and mobility shift assays showed that, as compared to the --953A, --953G promoter had reduced transcriptional activity (p=0.001) and impaired ability to bind C/EBPß 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 down-regulation is pathogenic for obesity and/or T2D.

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