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: 8.1). 06/2007; 56(5):1468-74. DOI: 10.2337/db06-1389
Source: PubMed


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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Available from: Franco Folli, Aug 30, 2015
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    • "Indeed, AQP7 expression in adipose tissue is different in lean individuals compared with obese patients [31] and the delicate balance in AQP7 expression is perturbed in obese subjects [32]. Moreover, some patients with a mutated or parafunctional AQP7 gene are at increased risk of developing obesity and/or type 2 diabetes [33,34]. A downregulated AQP7 expression could then be involved in obesity susceptibility by reducing glycerol release and by promoting the accumulation of lipids in subcutaneous adipose tissue [31]. "
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    ABSTRACT: Background Adipocyte-secreted apelin contributes to decreased adiposity and to improved insulin resistance, but the mechanisms remain unknown. The present study aimed to assess if apelin-13 is an upstream signal regulation factor of aquaporin 7 (AQP7), a water-glycerol transporter present in the plasma membrane of adipocytes that plays a key role in the regulation of lipid accumulation. Material/Methods 3T3-L1 pre-adipocytes were induced to fully differentiated adipocytes; hypertrophic adipocytes were then induced using palmitate. The effects of apelin-13 on AQP7 expression in hypertrophic adipocytes were investigated before and after treatment with LY249002, a PI3K inhibitor. Accumulation of cytoplasmic triglycerides (TG) in hypertrophic adipocytes was also determined. Results We found that 0.1 mM of palmitate induced a model of hypertrophic adipocytes with a lower AQP7 expression (0.26±0.07 vs. 0.46±0.04, P<0.05). Apelin-13 100 nM or 1000 nM upregulated AQP7 mRNA expression (100 nM: 0.54±0.06 and 1000 nM: 0.58±0.09 vs. control: 0.33±0.04, both P<0.05), and decreased accumulation of cytoplasmic triglycerides in hypertrophic adipocytes. Pretreatment using 10 μM LY294002 prevented the increase in AQP7 expression observed when using apelin-13 alone (apelin-13 + LY49002: 0.38±0.03 vs. apelin-13: 0.54±0.06, P<0.05), as well as the decreased cytoplasmic TG accumulation (apelin-13 + LY294002: 3.79±0.04 μM per μg/ml vs. apelin-13: 3.32±0.08 μM per μg/ml, P<0.05). Conclusions Apelin-13 decreases lipid storage in hypertrophic adipocytes in vitro, possibly through the upregulation of AQP7 expression by the PI3K signaling pathway. Treatment using apelin-13 and AQP modulators might represent novel treatment strategies against obesity and its related complications.
    Medical science monitor: international medical journal of experimental and clinical research 08/2014; 20:1345-52. DOI:10.12659/MSM.890124 · 1.43 Impact Factor
    • "Further studies on AQP7 gene expression in human adipose tissue demonstrated a down-regulation in obese vs. lean subjects [17], [18]. Prudente et al. [19] identified a common polymorphism in the promoter region of the human AQP7 gene (A-953G SNP) that could be related to obesity and type 2 diabetes. Differently from mice, AQP7 involvement in human obesity is far from been clearly defined. "
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    ABSTRACT: Glycerol outflow from adipocytes has been considered for a decade to be mediated by aquaporin-7, an aquaglyceroporin highly expressed in the adipose tissue. Its involvement in glycerol metabolism has been widely studied also in humans. Recent studies in different aquaporin-7 KO mice models pose two different questions 1) the exact localization of aquaporin-7 in human white adipose tissue; 2) the existence of other aquaglyceroporins that work with aquaporin-7 to guarantee glycerol efflux and thus a normal adiposity in humans. To this purpose we investigated the expression, the localization and the functioning of aquaglyceroporin-10 in subcutaneous white adipose tissue, in isolated and cultured differentiated adipocytes. Aquaporin-7 and -10 were expressed in the white adipose tissue both at mRNA and at protein level. Immunofluorescence revealed aquaporin-7 and -10 labelling in the human adipose tissue both to the plasma membrane and to a thin rim of cytoplasm of adipocytes. Aquaporin-7, but not aquaporin-10, colocalized with the endothelial marker CD34. Human cultured differentiated adipocytes showed an aquaporin-7 and -10 labelling mainly in the cytoplasm and in the lipid droplets with insulin reinforcing the lipid droplets staining and isoproterenol inducing its translocation to the plasma membrane compartment. Water and glycerol permeability measurements using adipocytes and adipose membrane vesicles confirmed the presence of functioning aquaglyceroporins. Aquaporin-10 silencing in human differentiated adipocytes resulted in a 50% decrease of glycerol and osmotic water permeability. The results indicate that aquaporin-7, differently from mice, is present in both adipocyte and capillary plasma membranes of human adipose tissue. Aquaporin-10, on the contrary, is expressed exclusively in the adipocytes. The expression of two aquaglyceroporins in human adipose tissue is particularly important for the maintenance of normal or low glycerol contents inside the adipocyte, thus protecting humans from obesity.
    PLoS ONE 01/2013; 8(1):e54474. DOI:10.1371/journal.pone.0054474 · 3.23 Impact Factor
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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 · 3.89 Impact Factor
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