Article

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

CSS-Mendel Institute, Rome, Italy.
Diabetes (Impact Factor: 7.9). 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.

0 Bookmarks
 · 
124 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Obesity and secondary development of type 2 diabetes are major health care problems throughout the developed world. Accumulating evidence suggest that glycerol metabolism contributes to the pathophysiology of obesity and type 2 diabetes. Glycerol is a small metabolite that serves as an important intermediate between carbohydrate and lipid metabolism. It is stored primarily in adipose tissue as the backbone of triglyceride and during states of metabolic stress, such as fasting and diabetes, it is released for metabolism in other tissues. In the liver, glycerol serves a gluconeogenic precursor and it is used for the esterification of FFA into triglycerides. AQP7 in adipose tissue and AQP9 in the liver are transmembrane proteins that belong to the subset of aquaporins called aquaglyceroporins. AQP7 facilitates the efflux of glycerol from adipose tissue and AQP7 deficiency has been linked to triglyceride accumulation in adipose tissue, and adult onset obesity. On the other hand, AQP9 expressed in liver facilitates the hepatic uptake of glycerol and thereby the availability of glycerol for de novo synthesis of glucose and triglyceride that both are involved in the pathophysiology of diabetes. The aim of this review is to summarize the current knowledge on the role of the two glycerol channels in controlling glycerol metabolism in adipose tissue and liver.
    Journal of Molecular Endocrinology 01/2014; · 3.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Salivary glands and pancreas are involved in saliva secretion, pancreatic fluid secretion and insulin secretion. These functions are essential for proper oral, pancreatic and glucose homeostasis. Aquaporins are water-permeable transmembrane protein involved in the physiology of these secretory gland functions. This review gives an overview of the morphology of salivary glands and pancreas, the expression and localization of aquaporins, the secretion roles and mechanisms, the physiological roles of aquaporins, and the role of aquaporins in pathophysiological conditions. Several aquaporins are expressed in salivary glands and pancreas, and some play important physiological roles. Modulation of aquaporin expression and/or trafficking may contribute to the pathogenesis of diseases affecting salivary glands and pancreas glands such as xerostomic conditions, pancreatic insufficiencies and diabetes. Aquaporins are involved in physiological and pathophysiological processes in salivary glands and pancreas. They could represent therapeutic targets for the treatment of diseases affecting the salivary glands and pancreas. This article is part of a Special Issue entitled Aquaporins.
    Biochimica et Biophysica Acta 08/2013; · 4.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Membrane transporters enable efficient cellular metabolism, aid in nutrient sensing, and have been associated with various diseases, such as obesity and cancer. Genome-scale metabolic network reconstructions capture genomic, physiological, and biochemical knowledge of a target organism, along with a detailed representation of the cellular metabolite transport mechanisms. Since the first reconstruction of human metabolism, Recon 1, published in 2007, progress has been made in the field of metabolite transport. Recently, we published an updated reconstruction, Recon 2, which significantly improved the metabolic coverage and functionality. Human metabolic reconstructions have been used to investigate the role of metabolism in disease and to predict biomarkers and drug targets. Given the importance of cellular transport systems in understanding human metabolism in health and disease, we analyzed the coverage of transport systems for various metabolite classes in Recon 2. We will review the current knowledge on transporters (i.e., their preferred substrates, transport mechanisms, metabolic relevance, and disease association for each metabolite class). We will assess missing coverage and propose modifications and additions through a transport module that is functional when combined with Recon 2. This information will be valuable for further refinements. These data will also provide starting points for further experiments by highlighting areas of incomplete knowledge. This review represents the first comprehensive overview of the transporters involved in central metabolism and their transport mechanisms, thus serving as a compendium of metabolite transporters specific for human metabolic reconstructions.
    Frontiers in Physiology 01/2014; 5:91.