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

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FEBS Letters 580 (2006) 4771–4776

Minireview Role of aquaporin-7 in the pathophysiological control of fat accumulation in mice

Amaia Rodrı´gueza, Victoria Catalańa, 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, Clıńica Universitaria de Navarra, University of Navarra, Avda. Pıó 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 glycerol, 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 Clıńica Universitaria de Navarra, University of Navarra, Avda. Pıó 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 to rodents has been shown to cose (Fig. 2) [23]. After feeding, plasma concentrations of insu- increase the expression of AQP7 in adipose tissue [15,17]. lin increase and this hormone inhibits the expression of AQP7 Despite the upregulation of AQP7 by TZDs, glycerol release in WAT and of AQP9 in liver through the negative IRE in the from adipocytes is not increased. This apparent paradox could promoter regions of these genes. Interestingly, the insulin- be understood when Lee et al. [17] reported that TZD also resistant obese db/db mice exhibit increased expression levels increase GK activity, favouring the recycling of glycerol for of the fat-specific AQP7 and the liver-specific AQP9, despite TG synthesis instead of stimulating the release of glycerol to their hyperinsulinemia [23]. The increase of these aquaglycero- bloodstream. The authors further observed that hepatic porins in the setting of insulin resistance may be caused by AQP9 expression was not affected by TZD treatment, proba- impaired IRS-1-mediated insulin signalling in adipocytes bly due to a lower expression of PPARc in the liver. Therefore, and reduced IRS-2-induced insulin signalling in hepatocytes the undesirable increase of adipose AQP7 expression in insu- [14,23]. Taken together, under physiological conditions, insulin-resistant states, which might lead to elevated plasma gly- lin-mediated regulation of AQP7 and AQP9 may account for cerol levels and, consequently, hepatic gluconeogenesis, can the increase or decrease of glycerol release from fat and gluco- be overcome through an increased glycerol recycling in adipo- neogenesis in liver, in order to regulate the glucose production cytes using TZDs. depending on the nutritional state. However, in the context Cathecolamines induce lipolysis, increasing the release of of insulin resistance, the overexpression of AQP7 and AQP9 FFA and glycerol from fat into the bloodstream [18]. This pro- leads to an increase of plasma glycerol and hepatic glucose cess has been suggested as one of the mechanisms by which production associated with elevated circulating glycerol con- cathecolamines may impair insulin sensitivity. Interestingly,

Fig. 2. AQP7 and AQP9 function in glucose homeostasis. Insulin constitutes a repressor of the expression of AQP7 in adipocytes and AQP9 in hepatocytes, through the negative IRE in their gene promoters. Plasma insulin concentrations change in accordance to the nutritional state and, therefore, AQP7 and AQP9 expression in fat cells and liver, respectively, increase or decrease in relation to the nutritional needs. However, in the setting of insulin resistance, AQP7 and AQP9 are overexpressed, despite the hyperinsulinemia. Consequently, glycerol output from fat cells and glycerol use for hepatic gluconeogenesis increase, enhancing the hyperglycemia. 4774 A. Rodrı´guez et al. / FEBS Letters 580 (2006) 4771–4776 isoproterenol, a b-adrenergic agonist, apparently represses into the C57BL/6N genetic background exhibit similar body AQP7 expression through activation of Gs-proteins and aden- weights to WT animals until 12 weeks of age, when AQP7-null ylyl cyclase in accordance with the classical induction of b- mice start to accumulate fat and become heavier, despite having adrenergic receptors [18]. Although the effect of isoproterenol the same food intake as WT mice [13,24]. The other line of on AQP7 expression has been observed in cultured 3T3-L1 AQP7 KO, generated in CD1 mice by Hara-Chikuma et al., adipocytes, the finding suggests that, under physiological cir- did not put on excess weight but exhibited a significantly in- cumstances, increased cAMP levels induced by cathecolamines creased whole body fat accumulation [22]. The differences in may not only enhance lipolysis but also repress AQP7 expres- body weight of the two lines of mice may be ascribed to the di- sion in adipocytes, thereby restricting to some extent glycerol verse genetic backgrounds [13]. Why do AQP7-deficient mice release from adipocytes. In an insulin-resistant state, the bal- become obese? A plausible mechanism is related to the fact of ance between stimulation of lipolysis and downregulation of a reduced energy expenditure in AQP7-KO mice since their the AQP7 gene induced by cathecolamines might be impaired. body temperature is lower than that of WT mice after 20 weeks However, observations made in isolated adipocytes or cell cul- of age [13]. A reduction in triglyceride/FFA cycling (Fig. 3) and tures do not necessarily reflect the processes taking place in the associated heat production may underlie the lower body whole-body regulation. In this sense, additional work is needed temperature observed in AQP7 knockout mice [11,12]. Alterna- to better clarify the true impact of adrenergic stimulation. tively, since the defence of the thermal set point is controlled in the hypothalamus, hypothermia would be also consistent with a central effect of AQP7 deficiency [12]. Nonetheless, additional 4. Aquaporin-7 deficiency leads to obesity and insulin resistance studies are needed to disentangle the exact mechanisms under- lying the effect of AQP7 deficiency on body temperature. To The suppression of the AQP7 gene in mice is associated with date, the main cause for the increased weight gain in adult adult-onset obesity [13,22,24]. The latest insights into AQP7 AQP7-null mice constitutes the excessive accumulation of tri- function regarding fat accumulation regulation stem from glycerides in subcutaneous and visceral fat pads [13,22,24]. This two different strains of mice, C57BL/6N and CD1, lacking excess of fat mass is not the result of either a decreased lipolysis the protein [13,22,24]. AQP7 knockout (KO) mice backcrossed or an increased adipogenesis, since the activity of HSL, a key

Fig. 3. AQP7 deletion effect on lipid and glucose homeostasis. The loss of glycerol release from adipocytes of AQP7-deficient mice causes an increase in intracellular glycerol, favouring the new biosynthesis of triglycerides. In addition, insulin fails to exert its antilipolytic action in adipocytes, due to impaired IRS-1-mediated insulin signalling, and its inhibition of hepatic gluconeogenesis, as a result of low IRS-2-associated PI3K activity. Consequently, AQP7-deficient mice exhibit a progressive fat accumulation and metabolic alterations, such as elevated FFA, hyperglycemia and insulin resistance. Striped arrows indicate inhibition; solid arrows indicate stimulation. A. Rodrı´guez et al. / FEBS Letters 580 (2006) 4771–4776 4775 regulator of the lipolytic process, and the expression of PPARc 2 fibres as well as of murine type 2 muscle fibres [10]. In this and C/EBPa, two important transcription factors involved in context, efforts aimed at elucidating the contribution of skele- adipogenesis, are not affected by AQP7 deletion. The major tal muscle AQP7 expression both under physiological circum- reason for the enlargement of adipose tissue in AQP7-deficient stances as well as in relation to potential changes related to mice is the progressive hypertrophy of adipocytes, character- different insulin resistance states deserve preferential consider- ised by larger sized lipid droplets [13,22]. AQP7 disruption ation. In addition, the tissue-specific invalidation of AQP7 in results in a reduced glycerol permeability of the plasma mem- adipose tissue, liver and skeletal muscle may prove useful to brane of adipocytes and, hence, in an intracellular glycerol decipher the relative impact of this glycerol channel to glucose accumulation. The increased enzymatic activity of GK in and energy homeostasis in well-known insulin-sensitive or- adipocytes from AQP7-null mice accelerates TG synthesis, gans. leading to a progressive fat accumulation (Fig. 3). Until now, results of AQP7 expression in humans are scarce. AQP7 deletion in mice is accompanied by an age-related Therefore, abusive extrapolation of rodent data to humans development of severe insulin resistance [13]. Young AQP7- should be avoided, until the contribution of AQP7 to the path- KO mice (10-week-old) present decreased fasting plasma gly- ophysiology of obesity and insulin resistance is specifically cerol and glucose concentrations. Glycerol secretion from addressed in these patients as well as in normal-weight, normo- adipocytes is not completely abolished in AQP7-KO mice, sug- glycaemic individuals. For instance, only a single human case gesting that other mechanisms, such as simple diffusion and/or of homozygous mutation in the coding region of the AQP7 other glycerol channels, are also probably involved in glycerol gene has been reported up to date [16]. Contrary to what secretion [24,25]. The fasting hypoglycemia of these young was observed in AQP7 deficient mice, this subject was neither mice may be related to a low glycerol transport to the liver to- obese nor diabetic. The only apparent consequence of this gether with an inefficient gluconeogenesis, despite an increased mutation was an impaired glycerol increase in response to PEPCK activity, a key liver enzyme that converts glucose from exercise. Moreover, a number of results in humans are limited pyruvate and/or glycerol, as well as due to the effect of coun- to mRNA determinations without functional studies on intact terregulatory hormones, like glucagon and corticosterone. adipocytes. In lean and obese individuals eating similar high- On the other hand, fasting plasma insulin concentrations and fat diets, a decreased expression of AQP7 was observed in sub- glucose tolerance tests of young AQP7-KO mice are similar cutaneous adipose tissue [26]. From a clinical point of view, it to age-matched WT mice. Insulin signalling also appears to would be interesting to discern whether the presence of insulin be functional in young AQP7-null mice, since insulin-stimu- resistance modifies AQP7 gene expression in WAT of lean and lated phosphorylation of Akt in WAT, liver and muscle is sim- obese subjects. Apparently, the coordinated regulation of ilar to that of WT mice [24]. However, adult AQP7-KO mice fat-specific AQP7 and liver-specific AQP9 expression might (20-week-old) show increased fasting plasma glucose and insu- be disrupted in human obesity and type 2 diabetes mellitus. lin concentrations, disturbed insulin-mediated suppression of However, additional studies related to gene expression and plasma glucose and impaired glucose tolerance [13]. Why do protein stability are needed to better establish a firm mechanis- AQP7 deficient mice become insulin-resistant? Insulin signal- tic basis for the involvement of AQP7 in the etiopathogenesis ling is impaired in insulin-sensitive tissues of adult AQP7 defi- of these metabolic disorders in humans. A deeper understand- cient mice [13]. Insulin stimulation of IRS-1-associated PI3K ing of the regulation of AQP7 together with that of AQP9 in activity in WAT and muscle, and IRS-2 associated PI3K activ- key metabolic organs might be useful to design drugs specifi- ity in liver and muscle, are markedly decreased in AQP7 KO cally targeting plasma membrane channels aimed at obesity mice (Fig. 3). Moreover, insulin-stimulated phosphorylation and/or type 2 diabetes mellitus control. of Akt in WAT, liver and muscle is significantly lower in AQP7 null mice. In addition, young AQP7 KO mice (8- Acknowledgements: This work was supported by the Instituto de Salud week-old) fed a high fat diet or sucrose during 4 weeks showed Carlos III, FIS RGTO (G03/028) and the Department of Health of the Gobierno de Navarra (20/2005), Spain. The PIUNA Foundation is higher plasma insulin and glucose concentrations, as well as also gratefully acknowledged. impaired insulin-mediated suppression of plasma glucose and impaired glucose tolerance. 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