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Role of Aquaporin-7 in the Pathophysiological Control of Fat Accumulation in Mice

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Role of Aquaporin-7 in the Pathophysiological Control of Fat Accumulation in Mice View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 580 (2006) 4771–4776 Minireview Role of aquaporin-7 in the pathophysiological control of fat accumulation in mice Amaia Rodrı´gueza, Victoria Catala´na, Javier Go´mez-Ambrosia, Gema Fru¨hbecka,b,* a Metabolic Research Laboratory, Clinica Universitaria de Navarra, University of Navarra, Pamplona, Spain b Department of Endocrinology, Clı´nica Universitaria de Navarra, University of Navarra, Avda. Pı´o XII, 36. 31008 Pamplona, Spain Received 6 June 2006; revised 28 July 2006; accepted 31 July 2006 Available online 8 August 2006 Edited by Robert Barouki groups on the basis of their permeability characteristics: Abstract Aquaporins are channels that allow the movement of water across the cell membrane. Some members of the aquaporin aquaporins (pure water channels) and aquaglyceroporins family, the aquaglyceroporins, also allow the transport of gly- (channels permeated by water and small solutes, such as gly- cerol, which is involved in the biosynthesis of triglycerides and cerol). Aquaporin-7 (AQP7), together with AQP3, AQP9 the maintenance of fasting glucose levels. Aquaporin-7 (AQP7) and AQP10, belongs to the aquaglyceroporin subfamily [2]. is a glycerol channel mainly expressed in adipocytes. The dele- The human AQP7 gene, mapped to chromosome 9p13, was tion of AQP7 gene in mice leads to obesity and type 2 diabetes. cloned from adipose tissue in 1997 (originally named AQPap) AQP7 modulates adipocyte glycerol permeability thereby con- [3,4]. Despite its initial description as an adipose-specific gly- trolling triglyceride accumulation and fat cell size. Furthermore, cerol channel, this pore has been shown to be also expressed the coordinated regulation of fat-specific AQP7 and liver- in kidney, testis, ovary, heart, gastrointestinal tract, and skeletal specific AQP9 may be key to determine glucose metabolism in muscle [5–10]. AQP7 facilitates the secretion of glycerol from insulin resistance. Ó 2006 Federation of European Biochemical Societies. Pub- adipocytes. Glycerol constitutes a key metabolite in the control lished by Elsevier B.V. All rights reserved. of fat accumulation (as the carbon backbone of triglycerides (TG)) and glucose metabolism (as the major substrate for hepa- Keywords: Aquaporin-7; Adipocyte; Glycerol; Obesity; tic gluconeogenesis during fasting) [11,12]. Since mice lacking Diabetes the AQP7 gene develop adult-onset obesity and type 2 diabetes mellitus, it was proposed that the glycerol channel AQP7 plays a pivotal role in adipose tissue enlargement and function as well as in glucose homeostasis [13]. The expression of AQP7 is posi- tively up-regulated by fasting and peroxisome proliferator-acti- 1. Aquaporin-7 vated receptor c (PPARc) agonists [14–17], whereas refeeding, insulin, dexamethasone and tumour necrosis factor-a (TNF-a) Aquaporins (AQP) are channel-forming integral membrane suppress the expression of this glycerol channel [14,18]. Thus, proteins that allow the movement of water through cell mem- the regulation of AQP7 expression in adipose tissue might be branes [1]. These selective channels belong to the broad super- one of the determining factors for the control of fat accumula- family of the major intrinsic protein (MIP) transmembrane tion and whole body glucose homeostasis [19,20]. channels, which are found in eubacteria, archaea, fungi, proto- zoa, plants, and animals. To date, 13 different aquaporins (AQP0-12) have been found in diverse human tissues. The im- 2. Control of adipogenesis and adipocyte function paired function of aquaporins has been associated with several human diseases, such as congenital cataracts or nephrogenic Adipocyte differentiation is a highly controlled process, diabetes insipidus [1]. Aquaporins assemble as tetramers in where the expression of adipose-specific genes is crucial for the plasma membrane, with each monomer containing a chan- determining phenotypic characteristics of adipocytes. The nel [1]. The aquaporin family can be divided into two sub- transcription factors that regulate this process include PPARc, CCAAT enhancer binding protein (C/EBP) and sterol-regula- tory element binding proteins (SREBP) [14]. The human AQP7 *Corresponding author. Address: Department of Endocrinology, gene promoter presents binding sites for these transcription Clı´nica Universitaria de Navarra, University of Navarra, Avda. Pı´o factors, suggesting that this glycerol channel is involved in adi- XII, 36. 31008 Pamplona, Spain. Fax: +34 948 29 65 00. pocyte differentiation. In this sense, it has been shown that the E-mail address: [email protected] (G. Fru¨hbeck). expression of AQP7 in undifferentiated 3T3-L1 preadipocytes Abbreviations: AQP, aquaporin; BAT, brown adipose tissue; FABP, is almost negligible, while AQP7 becomes markedly expressed fatty acid binding protein; FATP, fatty acid transporter protein; FFA, during the late adipogenesis in a process mediated by PPARc, free fatty acids; GK, glycerol kinase; HSL, hormone-sensitive lipase; the master adipogenic transcription factor [12,15]. IRE, insulin response element; IRS, insulin receptor substrate; PEP- CK, phosphoenolpyruvate carboxykinase; PPARc, peroxisome prolif- In differentiated adipocytes, TG synthesis and hydrolysis are erator-activated receptor c; TG, triglycerides; TZD, thiazolidinediones; stimulated according to the energetic status [20]. During peri- WAT, white adipose tissue ods of caloric excess, adipocytes take up free fatty acids (FFA), 0014-5793/$32.00 Ó 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2006.07.080 4772 A. Rodrı´guez et al. / FEBS Letters 580 (2006) 4771–4776 Fig. 1. Role of AQP7 in adipocyte formation and function. During fasting or exercise, triglycerides are hydrolysed to glycerol and FFA and released to the bloodstream. Glycerol is secreted from the adipose tissue through AQP7, a glycerol channel mainly expressed in adipocytes during late adipogenesis. which are stored as TG. The other metabolite required for TG to glycerol-3-phosphate [21]. Thus, a defective glycerol exit re- biosynthesis, glycerol-3-phosphate, proceeds from three meta- sults in intracellular glycerol accumulation, which induces the bolic sources: (i) glucose; (ii) glycerol derived from lipolysis, enzymatic activity of GK. The consequent increase in glycerol- which is phosphorylated by glycerol kinase (GK); or (iii) 3-phosphate concentrations promotes the biosynthesis of TG, pyruvate, which is converted to glycerol by the activity of resulting in a progressive adipocyte hypertrophy [22]. phosphoenolpyruvate carboxykinase (PEPCK) (Fig. 1). In The expression of AQP7 and the molecules that contribute to circumstances of negative energy balance, such as fasting the efflux of FFA from adipocytes are tightly regulated by the or exercise, TG are hydrolysed to glycerol and FFA by the nutritional state. Fasting increases the levels of AQP7 and hormone-sensitive lipase (HSL) and released into the blood- FATP1 (a FFA transport protein) in adipose tissue, whereas stream. Several membrane proteins, including fatty acid bind- refeeding suppresses the expression of these proteins [14,15]. ing protein (FABP), fatty acid translocase (FAT, CD36) or In addition, insulin decreases AQP7 and FATP1 expression fatty acid transporter protein (FATP), facilitate the FFA in WAT, since their gene promoters present a negative insulin transport across the membrane [14]. About 30–40% of FFA response element (IRE) [14,15]. Therefore, a coordinated regu- are recycled back to TG in white adipose tissue (WAT) [11]. lation of the expression levels of AQP7 and FATP1 by insulin is However, the recycling of FFA also occurs in other peripheral programmed to work as an efficient mechanism for supplying tissues, such as liver, skeletal muscle, heart, pancreas or brown energy in accordance with nutritional needs. adipose tissue (BAT), where FFA are oxidized or re-esterified to TG. On the other hand, AQP7 appears to be one of the main channels for glycerol release from adipocytes, a process 3. Glucose homeostasis that contributes to the regulation of fat accumulation. In this sense, it has been shown that adipocytes of AQP7-deficient Glycerol is one of the major factors that determine plasma mice exhibit a higher intracellular glycerol content than those glucose [11]. During fasting and post-absorptive states, hepatic of wild type (WT) mice [13]. A recent study has reported that glucose output is the main source of plasma glucose in rodents, glycerol induces conformational changes and enzymatic activ- and plasma glycerol becomes the major substrate for hepatic ity of GK, which is a key enzyme in the conversion of glycerol gluconeogenesis [11,12]. Adipose tissue constitutes the most A. Rodrı´guez et al. / FEBS Letters 580 (2006) 4771–4776 4773 important source of plasma glycerol. AQP7, the adipose-spe- centrations, a circumstance that further aggravates the hyper- cific glycerol channel, represents a gateway for the delivery glycemia. of fat-derived glycerol into plasma. This plasma glycerol is Thiazolidinediones (TZD), e.g. pioglitazone and rosig- introduced into hepatocytes by the liver-specific aquaglycero- litazone, are oral antidiabetic agents that increase insulin- porin AQP9, where it is converted into glycerol-3-phosphate sensitivity via the stimulation of PPARc. Pioglitazone and by the enzymatic activity of GK for de novo synthesis of glu- rosiglitazone administration
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