FEBS Letters 580 (2006) 4771–4776

Minireview

Role of aquaporin-7 in the pathophysiological control of fataccumulation in mice

Amaia Rodrıgueza, Victoria Catalana, Javier Gomez-Ambrosia, Gema Fruhbecka,b,*

a Metabolic Research Laboratory, Clinica Universitaria de Navarra, University of Navarra, Pamplona, Spainb Department of Endocrinology, Clınica Universitaria de Navarra, University of Navarra, Avda. Pıo 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

Abstract Aquaporins are channels that allow the movement ofwater across the cell membrane. Some members of the aquaporinfamily, the aquaglyceroporins, also allow the transport of gly-cerol, which is involved in the biosynthesis of triglycerides andthe maintenance of fasting glucose levels. Aquaporin-7 (AQP7)is a glycerol channel mainly expressed in adipocytes. The dele-tion of AQP7 gene in mice leads to obesity and type 2 diabetes.AQP7 modulates adipocyte glycerol permeability thereby con-trolling triglyceride accumulation and fat cell size. Furthermore,the coordinated regulation of fat-specific AQP7 and liver-specific AQP9 may be key to determine glucose metabolism ininsulin resistance.� 2006 Federation of European Biochemical Societies. Pub-lished by Elsevier B.V. All rights reserved.

Keywords: Aquaporin-7; Adipocyte; Glycerol; Obesity;Diabetes

1. Aquaporin-7

Aquaporins (AQP) are channel-forming integral membrane

proteins that allow the movement of water through cell mem-

branes [1]. These selective channels belong to the broad super-

family of the major intrinsic protein (MIP) transmembrane

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-

paired function of aquaporins has been associated with several

human diseases, such as congenital cataracts or nephrogenic

diabetes insipidus [1]. Aquaporins assemble as tetramers in

the plasma membrane, with each monomer containing a chan-

nel [1]. The aquaporin family can be divided into two sub-

Abbreviations: AQP, aquaporin; BAT, brown adipose tissue; FABP,fatty acid binding protein; FATP, fatty acid transporter protein; FFA,free fatty acids; GK, glycerol kinase; HSL, hormone-sensitive lipase;IRE, insulin response element; IRS, insulin receptor substrate; PEP-CK, phosphoenolpyruvate carboxykinase; PPARc, peroxisome prolif-erator-activated receptor c; TG, triglycerides; TZD, thiazolidinediones;WAT, white adipose tissue

*Corresponding author. Address: Department of Endocrinology,Clınica Universitaria de Navarra, University of Navarra, Avda. PıoXII, 36. 31008 Pamplona, Spain. Fax: +34 948 29 65 00.E-mail address: gfruhbeck@unav.es (G. Fruhbeck).

0014-5793/$32.00 � 2006 Federation of European Biochemical Societies. Pu

doi:10.1016/j.febslet.2006.07.080

groups on the basis of their permeability characteristics:

aquaporins (pure water channels) and aquaglyceroporins

(channels permeated by water and small solutes, such as gly-

cerol). Aquaporin-7 (AQP7), together with AQP3, AQP9

and AQP10, belongs to the aquaglyceroporin subfamily [2].

The human AQP7 gene, mapped to chromosome 9p13, was

cloned from adipose tissue in 1997 (originally named AQPap)

[3,4]. Despite its initial description as an adipose-specific gly-

cerol channel, this pore has been shown to be also expressed

in kidney, testis, ovary, heart, gastrointestinal tract, and skeletal

muscle [5–10]. AQP7 facilitates the secretion of glycerol from

adipocytes. Glycerol constitutes a key metabolite in the control

of fat accumulation (as the carbon backbone of triglycerides

(TG)) and glucose metabolism (as the major substrate for hepa-

tic gluconeogenesis during fasting) [11,12]. Since mice lacking

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-

vated receptor c (PPARc) agonists [14–17], whereas refeeding,

insulin, dexamethasone and tumour necrosis factor-a (TNF-a)

suppress the expression of this glycerol channel [14,18]. Thus,

the regulation of AQP7 expression in adipose tissue might be

one of the determining factors for the control of fat accumula-

tion and whole body glucose homeostasis [19,20].

2. Control of adipogenesis and adipocyte function

Adipocyte differentiation is a highly controlled process,

where the expression of adipose-specific genes is crucial for

determining phenotypic characteristics of adipocytes. The

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

gene promoter presents binding sites for these transcription

factors, suggesting that this glycerol channel is involved in adi-

pocyte differentiation. In this sense, it has been shown that the

expression of AQP7 in undifferentiated 3T3-L1 preadipocytes

is almost negligible, while AQP7 becomes markedly expressed

during the late adipogenesis in a process mediated by PPARc,

the master adipogenic transcription factor [12,15].

In differentiated adipocytes, TG synthesis and hydrolysis are

stimulated according to the energetic status [20]. During peri-

ods of caloric excess, adipocytes take up free fatty acids (FFA),

blished by Elsevier B.V. All rights reserved.

Fig. 1. Role of AQP7 in adipocyte formation and function. During fasting or exercise, triglycerides are hydrolysed to glycerol and FFA and releasedto the bloodstream. Glycerol is secreted from the adipose tissue through AQP7, a glycerol channel mainly expressed in adipocytes during lateadipogenesis.

4772 A. Rodrıguez et al. / FEBS Letters 580 (2006) 4771–4776

which are stored as TG. The other metabolite required for TG

biosynthesis, glycerol-3-phosphate, proceeds from three meta-

bolic sources: (i) glucose; (ii) glycerol derived from lipolysis,

which is phosphorylated by glycerol kinase (GK); or (iii)

pyruvate, which is converted to glycerol by the activity of

phosphoenolpyruvate carboxykinase (PEPCK) (Fig. 1). In

circumstances of negative energy balance, such as fasting

or exercise, TG are hydrolysed to glycerol and FFA by the

hormone-sensitive lipase (HSL) and released into the blood-

stream. Several membrane proteins, including fatty acid bind-

ing protein (FABP), fatty acid translocase (FAT, CD36) or

fatty acid transporter protein (FATP), facilitate the FFA

transport across the membrane [14]. About 30–40% of FFA

are recycled back to TG in white adipose tissue (WAT) [11].

However, the recycling of FFA also occurs in other peripheral

tissues, such as liver, skeletal muscle, heart, pancreas or brown

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

that contributes to the regulation of fat accumulation. In this

sense, it has been shown that adipocytes of AQP7-deficient

mice exhibit a higher intracellular glycerol content than those

of wild type (WT) mice [13]. A recent study has reported that

glycerol induces conformational changes and enzymatic activ-

ity of GK, which is a key enzyme in the conversion of glycerol

to glycerol-3-phosphate [21]. Thus, a defective glycerol exit re-

sults in intracellular glycerol accumulation, which induces the

enzymatic activity of GK. The consequent increase in glycerol-

3-phosphate concentrations promotes the biosynthesis of TG,

resulting in a progressive adipocyte hypertrophy [22].

The expression of AQP7 and the molecules that contribute to

the efflux of FFA from adipocytes are tightly regulated by the

nutritional state. Fasting increases the levels of AQP7 and

FATP1 (a FFA transport protein) in adipose tissue, whereas

refeeding suppresses the expression of these proteins [14,15].

In addition, insulin decreases AQP7 and FATP1 expression

in WAT, since their gene promoters present a negative insulin

response element (IRE) [14,15]. Therefore, a coordinated regu-

lation of the expression levels of AQP7 and FATP1 by insulin is

programmed to work as an efficient mechanism for supplying

energy in accordance with nutritional needs.

3. Glucose homeostasis

Glycerol is one of the major factors that determine plasma

glucose [11]. During fasting and post-absorptive states, hepatic

glucose output is the main source of plasma glucose in rodents,

and plasma glycerol becomes the major substrate for hepatic

gluconeogenesis [11,12]. Adipose tissue constitutes the most

A. Rodrıguez et al. / FEBS Letters 580 (2006) 4771–4776 4773

important source of plasma glycerol. AQP7, the adipose-spe-

cific glycerol channel, represents a gateway for the delivery

of fat-derived glycerol into plasma. This plasma glycerol is

introduced into hepatocytes by the liver-specific aquaglycero-

porin AQP9, where it is converted into glycerol-3-phosphate

by the enzymatic activity of GK for de novo synthesis of glu-

cose (Fig. 2) [23]. After feeding, plasma concentrations of insu-

lin increase and this hormone inhibits the expression of AQP7

in WAT and of AQP9 in liver through the negative IRE in the

promoter regions of these genes. Interestingly, the insulin-

resistant obese db/db mice exhibit increased expression levels

of the fat-specific AQP7 and the liver-specific AQP9, despite

their hyperinsulinemia [23]. The increase of these aquaglycero-

porins in the setting of insulin resistance may be caused by

impaired IRS-1-mediated insulin signalling in adipocytes

and reduced IRS-2-induced insulin signalling in hepatocytes

[14,23]. Taken together, under physiological conditions, insu-

lin-mediated regulation of AQP7 and AQP9 may account for

the increase or decrease of glycerol release from fat and gluco-

neogenesis in liver, in order to regulate the glucose production

depending on the nutritional state. However, in the context

of insulin resistance, the overexpression of AQP7 and AQP9

leads to an increase of plasma glycerol and hepatic glucose

production associated with elevated circulating glycerol con-

Fig. 2. AQP7 and AQP9 function in glucose homeostasis. Insulin constituthepatocytes, through the negative IRE in their gene promoters. Plasma insutherefore, AQP7 and AQP9 expression in fat cells and liver, respectively, incsetting of insulin resistance, AQP7 and AQP9 are overexpressed, despite thglycerol use for hepatic gluconeogenesis increase, enhancing the hyperglycem

centrations, a circumstance that further aggravates the hyper-

glycemia.

Thiazolidinediones (TZD), e.g. pioglitazone and rosig-

litazone, are oral antidiabetic agents that increase insulin-

sensitivity via the stimulation of PPARc. Pioglitazone and

rosiglitazone administration to rodents has been shown to

increase the expression of AQP7 in adipose tissue [15,17].

Despite the upregulation of AQP7 by TZDs, glycerol release

from adipocytes is not increased. This apparent paradox could

be understood when Lee et al. [17] reported that TZD also

increase GK activity, favouring the recycling of glycerol for

TG synthesis instead of stimulating the release of glycerol to

bloodstream. The authors further observed that hepatic

AQP9 expression was not affected by TZD treatment, proba-

bly due to a lower expression of PPARc in the liver. Therefore,

the undesirable increase of adipose AQP7 expression in insu-

lin-resistant states, which might lead to elevated plasma gly-

cerol levels and, consequently, hepatic gluconeogenesis, can

be overcome through an increased glycerol recycling in adipo-

cytes using TZDs.

Cathecolamines induce lipolysis, increasing the release of

FFA and glycerol from fat into the bloodstream [18]. This pro-

cess has been suggested as one of the mechanisms by which

cathecolamines may impair insulin sensitivity. Interestingly,

es a repressor of the expression of AQP7 in adipocytes and AQP9 inlin concentrations change in accordance to the nutritional state and,rease or decrease in relation to the nutritional needs. However, in thee hyperinsulinemia. Consequently, glycerol output from fat cells andia.

4774 A. Rodrıguez et al. / FEBS Letters 580 (2006) 4771–4776

isoproterenol, a b-adrenergic agonist, apparently represses

AQP7 expression through activation of Gs-proteins and aden-

ylyl cyclase in accordance with the classical induction of b-

adrenergic receptors [18]. Although the effect of isoproterenol

on AQP7 expression has been observed in cultured 3T3-L1

adipocytes, the finding suggests that, under physiological cir-

cumstances, increased cAMP levels induced by cathecolamines

may not only enhance lipolysis but also repress AQP7 expres-

sion in adipocytes, thereby restricting to some extent glycerol

release from adipocytes. In an insulin-resistant state, the bal-

ance between stimulation of lipolysis and downregulation of

the AQP7 gene induced by cathecolamines might be impaired.

However, observations made in isolated adipocytes or cell cul-

tures do not necessarily reflect the processes taking place in

whole-body regulation. In this sense, additional work is needed

to better clarify the true impact of adrenergic stimulation.

4. Aquaporin-7 deficiency leads to obesity and insulin resistance

The suppression of the AQP7 gene in mice is associated with

adult-onset obesity [13,22,24]. The latest insights into AQP7

function regarding fat accumulation regulation stem from

two different strains of mice, C57BL/6N and CD1, lacking

the protein [13,22,24]. AQP7 knockout (KO) mice backcrossed

Fig. 3. AQP7 deletion effect on lipid and glucose homeostasis. The loss of glyin intracellular glycerol, favouring the new biosynthesis of triglycerides. In adimpaired IRS-1-mediated insulin signalling, and its inhibition of hepaticConsequently, AQP7-deficient mice exhibit a progressive fat accumulationinsulin resistance. Striped arrows indicate inhibition; solid arrows indicate s

into the C57BL/6N genetic background exhibit similar body

weights to WT animals until 12 weeks of age, when AQP7-null

mice start to accumulate fat and become heavier, despite having

the same food intake as WT mice [13,24]. The other line of

AQP7 KO, generated in CD1 mice by Hara-Chikuma et al.,

did not put on excess weight but exhibited a significantly in-

creased whole body fat accumulation [22]. The differences in

body weight of the two lines of mice may be ascribed to the di-

verse genetic backgrounds [13]. Why do AQP7-deficient mice

become obese? A plausible mechanism is related to the fact of

a reduced energy expenditure in AQP7-KO mice since their

body temperature is lower than that of WT mice after 20 weeks

of age [13]. A reduction in triglyceride/FFA cycling (Fig. 3) and

the associated heat production may underlie the lower body

temperature observed in AQP7 knockout mice [11,12]. Alterna-

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

studies are needed to disentangle the exact mechanisms under-

lying the effect of AQP7 deficiency on body temperature. To

date, the main cause for the increased weight gain in adult

AQP7-null mice constitutes the excessive accumulation of tri-

glycerides in subcutaneous and visceral fat pads [13,22,24]. This

excess of fat mass is not the result of either a decreased lipolysis

or an increased adipogenesis, since the activity of HSL, a key

cerol release from adipocytes of AQP7-deficient mice causes an increasedition, insulin fails to exert its antilipolytic action in adipocytes, due togluconeogenesis, as a result of low IRS-2-associated PI3K activity.and metabolic alterations, such as elevated FFA, hyperglycemia andtimulation.

A. Rodrıguez et al. / FEBS Letters 580 (2006) 4771–4776 4775

regulator of the lipolytic process, and the expression of PPARcand C/EBPa, two important transcription factors involved in

adipogenesis, are not affected by AQP7 deletion. The major

reason for the enlargement of adipose tissue in AQP7-deficient

mice is the progressive hypertrophy of adipocytes, character-

ised by larger sized lipid droplets [13,22]. AQP7 disruption

results in a reduced glycerol permeability of the plasma mem-

brane of adipocytes and, hence, in an intracellular glycerol

accumulation. The increased enzymatic activity of GK in

adipocytes from AQP7-null mice accelerates TG synthesis,

leading to a progressive fat accumulation (Fig. 3).

AQP7 deletion in mice is accompanied by an age-related

development of severe insulin resistance [13]. Young AQP7-

KO mice (10-week-old) present decreased fasting plasma gly-

cerol and glucose concentrations. Glycerol secretion from

adipocytes is not completely abolished in AQP7-KO mice, sug-

gesting that other mechanisms, such as simple diffusion and/or

other glycerol channels, are also probably involved in glycerol

secretion [24,25]. The fasting hypoglycemia of these young

mice may be related to a low glycerol transport to the liver to-

gether with an inefficient gluconeogenesis, despite an increased

PEPCK activity, a key liver enzyme that converts glucose from

pyruvate and/or glycerol, as well as due to the effect of coun-

terregulatory hormones, like glucagon and corticosterone.

On the other hand, fasting plasma insulin concentrations and

glucose tolerance tests of young AQP7-KO mice are similar

to age-matched WT mice. Insulin signalling also appears to

be functional in young AQP7-null mice, since insulin-stimu-

lated phosphorylation of Akt in WAT, liver and muscle is sim-

ilar to that of WT mice [24]. However, adult AQP7-KO mice

(20-week-old) show increased fasting plasma glucose and insu-

lin concentrations, disturbed insulin-mediated suppression of

plasma glucose and impaired glucose tolerance [13]. Why do

AQP7 deficient mice become insulin-resistant? Insulin signal-

ling is impaired in insulin-sensitive tissues of adult AQP7 defi-

cient mice [13]. Insulin stimulation of IRS-1-associated PI3K

activity in WAT and muscle, and IRS-2 associated PI3K activ-

ity in liver and muscle, are markedly decreased in AQP7 KO

mice (Fig. 3). Moreover, insulin-stimulated phosphorylation

of Akt in WAT, liver and muscle is significantly lower in

AQP7 null mice. In addition, young AQP7 KO mice (8-

week-old) fed a high fat diet or sucrose during 4 weeks showed

higher plasma insulin and glucose concentrations, as well as

impaired insulin-mediated suppression of plasma glucose and

impaired glucose tolerance. Thus, AQP7-deficient mice are

also vulnerable to diet-induced obesity and insulin resistance

[13]. Together, these results suggest that deletion of AQP7

leads to whole-body insulin resistance associated with adult-

onset obesity.

5. Concluding remarks

The functional importance of AQP7 in mammalian patho-

physiology has been extensively studied by analysing the

phenotype of transgenic knockout mice lacking this aquaglyc-

eroporin. Although the expression and regulation of AQP7 in

liver and adipose tissue have been extensively addressed, its

expression in skeletal muscle, a key metabolic organ in glucose

and lipid metabolism, merits further research. AQP7 has been

shown to be expressed on the surface of human type 1 and type

2 fibres as well as of murine type 2 muscle fibres [10]. In this

context, efforts aimed at elucidating the contribution of skele-

tal muscle AQP7 expression both under physiological circum-

stances as well as in relation to potential changes related to

different insulin resistance states deserve preferential consider-

ation. In addition, the tissue-specific invalidation of AQP7 in

adipose tissue, liver and skeletal muscle may prove useful to

decipher the relative impact of this glycerol channel to glucose

and energy homeostasis in well-known insulin-sensitive or-

gans.

Until now, results of AQP7 expression in humans are scarce.

Therefore, abusive extrapolation of rodent data to humans

should be avoided, until the contribution of AQP7 to the path-

ophysiology of obesity and insulin resistance is specifically

addressed in these patients as well as in normal-weight, normo-

glycaemic individuals. For instance, only a single human case

of homozygous mutation in the coding region of the AQP7

gene has been reported up to date [16]. Contrary to what

was observed in AQP7 deficient mice, this subject was neither

obese nor diabetic. The only apparent consequence of this

mutation was an impaired glycerol increase in response to

exercise. Moreover, a number of results in humans are limited

to mRNA determinations without functional studies on intact

adipocytes. In lean and obese individuals eating similar high-

fat diets, a decreased expression of AQP7 was observed in sub-

cutaneous adipose tissue [26]. From a clinical point of view, it

would be interesting to discern whether the presence of insulin

resistance modifies AQP7 gene expression in WAT of lean and

obese subjects. Apparently, the coordinated regulation of

fat-specific AQP7 and liver-specific AQP9 expression might

be disrupted in human obesity and type 2 diabetes mellitus.

However, additional studies related to gene expression and

protein stability are needed to better establish a firm mechanis-

tic basis for the involvement of AQP7 in the etiopathogenesis

of these metabolic disorders in humans. A deeper understand-

ing of the regulation of AQP7 together with that of AQP9 in

key metabolic organs might be useful to design drugs specifi-

cally targeting plasma membrane channels aimed at obesity

and/or type 2 diabetes mellitus control.

Acknowledgements: This work was supported by the Instituto de SaludCarlos III, FIS RGTO (G03/028) and the Department of Health of theGobierno de Navarra (20/2005), Spain. The PIUNA Foundation isalso gratefully acknowledged.

References

[1] King, L.S., Kozono, D. and Agre, P. (2004) From structure todisease: the evolving tale of aquaporin biology. Nat. Rev. Mol.Cell Biol. 5, 687–698.

[2] Agre, P. and Kozono, D. (2003) Aquaporin water channels:molecular mechanisms for human diseases. FEBS Lett. 555, 72–78.

[3] Ishibashi, K., Kuwahara, M., Gu, Y., Kageyama, Y., Tohsaka,A., Suzuki, F., Marumo, F. and Sasaki, S. (1997) Cloning andfunctional expression of a new water channel abundantlyexpressed in the testis permeable to water, glycerol, and urea. J.Biol. Chem. 272, 20782–20786.

[4] Ishibashi, K., Yamauchi, K., Kageyama, Y., Saito-Ohara, F.,Ikeuchi, T., Marumo, F. and Sasaki, S. (1998) Molecularcharacterization of human Aquaporin-7 gene and its chromo-somal mapping. Biochim. Biophys. Acta 1399, 62–66.

[5] Nejsum, L.N., Elkjaer, M., Hager, H., Frokiaer, J., Kwon, T.H.and Nielsen, S. (2000) Localization of aquaporin-7 in rat and

4776 A. Rodrıguez et al. / FEBS Letters 580 (2006) 4771–4776

mouse kidney using RT-PCR, immunoblotting, and immuno-cytochemistry. Biochem. Biophys. Res. Commun. 277, 164–170.

[6] Saito, K., Kageyama, Y., Okada, Y., Kawakami, S., Kihara, K.,Ishibashi, K. and Sasaki, S. (2004) Localization of aquaporin-7 inhuman testis and ejaculated sperm: possible involvement inmaintenance of sperm quality. J. Urol. 172, 2073–2076.

[7] McConnell, N.A., Yunus, R.S., Gross, S.A., Bost, K.L., Clemens,M.G. and Hughes Jr., F.M. (2002) Water permeability of anovarian antral follicle is predominantly transcellular and mediatedby aquaporins. Endocrinology 143, 2905–2912.

[8] Sjoholm, K., Palming, J., Olofsson, L.E., Gummesson, A.,Svensson, P.A., Lystig, T.C., Jennische, E., Brandberg, J.,Torgerson, J.S., Carlsson, B. and Carlsson, L.M. (2005) Amicroarray search for genes predominantly expressed in humanomental adipocytes: adipose tissue as a major production site ofserum amyloid A. J. Clin. Endocrinol. Metab. 90, 2233–2239.

[9] Laforenza, U., Gastaldi, G., Grazioli, M., Cova, E., Tritto, S.,Faelli, A., Calamita, G. and Ventura, U. (2005) Expression andimmunolocalization of aquaporin-7 in rat gastrointestinal tract.Biol. Cell 97, 605–613.

[10] Wakayama, Y., Inoue, M., Kojima, H., Jimi, T., Shibuya, S.,Hara, H. and Oniki, H. (2004) Expression and localization ofaquaporin 7 in normal skeletal myofiber. Cell Tissue Res. 316,123–129.

[11] Reshef, L., Olswang, Y., Cassuto, H., Blum, B., Croniger, C.M.,Kalhan, S.C., Tilghman, S.M. and Hanson, R.W. (2003) Glyc-eroneogenesis and the triglyceride/fatty acid cycle. J. Biol. Chem.278, 30413–30416.

[12] MacDougald, O.A. and Burant, C.F. (2005) Obesity and meta-bolic perturbations after loss of aquaporin 7, the adipose glyceroltransporter. Proc. Natl. Acad. Sci. USA 102, 10759–10760.

[13] Hibuse, T., Maeda, N., Funahashi, T., Yamamoto, K., Nagas-awa, A., Mizunoya, W., Kishida, K., Inoue, K., Kuriyama, H.,Nakamura, T., Fushiki, T., Kihara, S. and Shimomura, I. (2005)Aquaporin 7 deficiency is associated with development of obesitythrough activation of adipose glycerol kinase. Proc. Natl. Acad.Sci. USA 102, 10993–10998.

[14] Kishida, K., Shimomura, I., Kondo, H., Kuriyama, H., Makino,Y., Nishizawa, H., Maeda, N., Matsuda, M., Ouchi, N., Kihara,S., Kurachi, Y., Funahashi, T. and Matsuzawa, Y. (2001)Genomic structure and insulin-mediated repression of the aqu-aporin adipose (AQPap), adipose-specific glycerol channel. J.Biol. Chem. 276, 36251–36260.

[15] Kishida, K., Shimomura, I., Nishizawa, H., Maeda, N., Kuriy-ama, H., Kondo, H., Matsuda, M., Nagaretani, H., Ouchi, N.,Hotta, K., Kihara, S., Kadowaki, T., Funahashi, T. andMatsuzawa, Y. (2001) Enhancement of the aquaporin adiposegene expression by a peroxisome proliferator-activated receptorgamma. J. Biol. Chem. 276, 48572–48579.

[16] Kondo, H., Shimomura, I., Kishida, K., Kuriyama, H., Makino,Y., Nishizawa, H., Matsuda, M., Maeda, N., Nagaretani, H.,Kihara, S., Kurachi, Y., Nakamura, T., Funahashi, T. andMatsuzawa, Y. (2002) Human aquaporin adipose (AQPap) gene.Genomic structure, promoter analysis and functional mutation.Eur. J. Biochem. 269, 1814–1826.

[17] Lee, D.H., Park, D.B., Lee, Y.K., An, C.S., Oh, Y.S., Kang, J.S.,Kang, S.H. and Chung, M.Y. (2005) The effects of thiazolidin-edione treatment on the regulations of aquaglyceroporins andglycerol kinase in OLETF rats. Metabolism 54, 1282–1289.

[18] Fasshauer, M., Klein, J., Lossner, U., Klier, M., Kralisch, S. andPaschke, R. (2003) Suppression of aquaporin adipose geneexpression by isoproterenol, TNFa, and dexamethasone. Horm.Metab. Res. 35, 222–227.

[19] Fruhbeck, G. (2005) Obesity: aquaporin enters the picture.Nature 438, 436–437.

[20] Fruhbeck, G., Catalan, V., Gomez-Ambrosi, J. and Rodrıguez,A. (2006) Aquaporin-7 and glycerol permeability as novel obesitydrug-target pathways. Trends Pharmacol. Sci. 27, 345–347.

[21] Yeh, J.I., Charrier, V., Paulo, J., Hou, L., Darbon, E., Claiborne,A., Hol, W.G. and Deutscher, J. (2004) Structures of enterococcalglycerol kinase in the absence and presence of glycerol: correlationof conformation to substrate binding and a mechanism ofactivation by phosphorylation. Biochemistry 43, 362–373.

[22] Hara-Chikuma, M., Sohara, E., Rai, T., Ikawa, M., Okabe, M.,Sasaki, S., Uchida, S. and Verkman, A.S. (2005) Progressiveadipocyte hypertrophy in aquaporin-7-deficient mice: adipocyteglycerol permeability as a novel regulator of fat accumulation. J.Biol. Chem. 280, 15493–15496.

[23] Kuriyama, H., Shimomura, I., Kishida, K., Kondo, H., Furuy-ama, N., Nishizawa, H., Maeda, N., Matsuda, M., Nagaretani,H., Kihara, S., Nakamura, T., Tochino, Y., Funahashi, T. andMatsuzawa, Y. (2002) Coordinated regulation of fat-specific andliver-specific glycerol channels, aquaporin adipose and aquaporin9. Diabetes 51, 2915–2921.

[24] Maeda, N., Funahashi, T., Hibuse, T., Nagasawa, A., Kishida,K., Kuriyama, H., Nakamura, T., Kihara, S., Shimomura, I. andMatsuzawa, Y. (2004) Adaptation to fasting by glycerol transportthrough aquaporin 7 in adipose tissue. Proc. Natl. Acad. Sci.USA 101, 17801–17806.

[25] Kuriyama, H., Kawamoto, S., Ishida, N., Ohno, I., Mita, S.,Matsuzawa, Y., Matsubara, K. and Okubo, K. (1997) Molecularcloning and expression of a novel human aquaporin from adiposetissue with glycerol permeability. Biochem. Biophys. Res. Com-mun. 241, 53–58.

[26] Marrades, M.P., Milagro, F.I., Martınez, J.A. and Moreno-Aliaga, M.J. (2006) Differential expression of aquaporin 7 inadipose tissue of lean and obese high fat consumers. Biochem.Biophys. Res. Commun. 339, 785–789.