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

Department of Experimental Medicine, Sapienza University of Rome, Roma, Latium, Italy
Diabetes (Impact Factor: 8.47). 06/2007; 56(5):1468-74. DOI: 10.2337/db06-1389
Source: PubMed

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)beta 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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    • "Studies on AQP7 in human obesity are scarce and have shown differences according to the source of the adipose tissue. In this regard, lower AQP7 mRNA levels have been described in subcutaneous adipose tissue (SAT) samples from subjects with severe obesity than those obtained in lean subjects [6] [7] [8]. By contrast, higher AQP7 mRNA expression has been found in visceral adipose tissue (VAT) from massively obese subjects [9]. "
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    ABSTRACT: The trafficking of glycerol from adipose and hepatic tissue is mainly mediated by 2 aquaporin channel proteins: AQP7 and AQP9, respectively. In rodents, both aquaporins were found to act in a coordinated manner. The aim was to study the relationship between adipose AQP7 and hepatic AQP9 messenger RNA expression and the presence of glucose abnormalities simultaneously in morbid obesity. Adipose tissue (subcutaneous [SAT] and visceral [VAT]) and liver biopsies from the same patient were obtained during bariatric surgery in 30 (21 male and 9 female) morbidly obese subjects. Real-time quantification of AQP7 in SAT and VAT and hepatic AQP9 gene expression were performed. A 75-g oral glucose tolerance test was performed in all subjects. The homeostasis model assessment of insulin resistance and lipidic profile were also determined. Visceral adipose tissue AQP7 expression levels were significantly higher than SAT AQP7 (P = .009). Subcutaneous adipose tissue AQP7 positively correlated with both VAT AQP7 and hepatic AQP9 messenger RNA expression (r = 0.44, P = .013 and r = 0.45, P = .012, respectively). The correlation between SAT AQP7 and liver AQP9 was stronger in intolerant and type 2 diabetes mellitus subjects (r = 0.602, P = .011). We have found no differences in compartmental AQP7 adipose tissue distribution or AQP9 hepatic gene expression according to glucose tolerance classification. The present study provides, for the first time, evidence of coordinated regulation between adipose aquaglyceroporins, with a greater expression found in visceral fat, and between subcutaneous adipose AQP7 and hepatic AQP9 gene expression within the context of human morbid obesity.
    Metabolism: clinical and experimental 08/2009; 58(12):1762-8. DOI:10.1016/j.metabol.2009.06.004 · 3.61 Impact Factor
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    ABSTRACT: The family of water transport proteins known as aquaporins (AQPs) were first identified in the early 1990s. Functional investigation has since revealed physiological and pathological involvement in organs such as the eye, brain, heart and kidney, amongst others. Physiologically relevant function of AQPs described in the literature is balanced by several examples of expression not yet matched to a known purpose. AQPs expressed in the heart include AQP1, AQP4 and AQP7, although species differences suggest that function may not be highly conserved in all cases. Required physiological function or a causal role in pathology has not yet been demonstrated for cardiac AQPs. However, the field is young and much remains to be explored.
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    ABSTRACT: Context: Aquaporin-7 is required for efflux of glycerol from adipo- cytes and influences whole-body glucose homeostasis in animal studies. Objective: Our objective was to test the hypothesis that AQP7 gene expression levels may be affected by presence of obesity and type 2 diabetes in humans. Design: The obesity study cohort consisted of 12 lean, 22 nonseverely obese,and13severelyobesesubjects.Thetype2diabetesstudycohort consisted of 17 lean and 39 obese type 2 diabetic patients. Circulating levels of plasma soluble proteins monocyte chemoattractant pro- tein-1, TNF receptors 1 and 2, and IL-6 and glycerol were measured. The sc adipose tissue gene expression of AQP7, MCP-1, IL-6, TNF, PPAR, and SREBP1c genes was measured by real-time PCR. AQP7 gene mutation analysis was performed.
    Journal of Clinical Endocrinology &amp Metabolism 09/2007; 92(9):3640-3645. DOI:10.1210/jc.2007-0531 · 6.31 Impact Factor
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