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Glycerol transport: an additional target for obesity therapy?
Update
TRENDS in Endocrinology and Metabolism
Vol.17 No.3 April 2006
Research Focus
Glycerol transport: an additional target for obesity therapy? E. Marelyn Wintour and Belinda A. Henry Department of Physiology, Monash University, Clayton, 3800, Australia
There is increasing evidence that the glycerol channel, aquaporin 7(AQP7), has an important role in adipose tissue formation and function – deletion of the gene in a mouse strain leads to obesity and diabetes type 2 if the mice are aged or fed earlier with a high-fat or sucrose diet. Can increased levels of AQP7 in adipose tissue protect against obesity? New studies on AQP7 highlight the important role of glycerol transport in the development of obesity and metabolic disease. Functional glycerol channel For generations, physiologists have taught that all cells in the body, with the exception of principal cells of the renal collecting duct, are intrinsically permeable to water. In 2003, Peter Agre shared the Nobel Prize for his discoveries over the previous 15 years of specific water channels or aquaporins [1]. Aquaporins exist in bacteria, plants and the whole animal kingdom. To date, thirteen have been identified in mammalian tissues (AQPs 0–12) and some have been shown to function as more than simple water channels [2]. At least four (AQPs 3,7,9,10) also function as channels for the passage of glycerol and/or urea. Adipose tissue shows quantitatively the highest levels of expression of mRNA of AQP7, with omental adipose tissue expressing this gene at the highest levels in human [3]. The importance of AQP7 as a glycerol channel has been highlighted by a recent paper in which mice lacking a functional AQP7 gene were shown to develop obesity and insulin resistance, in part by an increase in adipose tissue glycerol kinase activity, and increased triglyceride synthesis [4]. Adipose tissue: an energy store and lots, lots more White adipose tissue was seen, conventionally, as tissue that can take up free fatty acids (FFA) and store them as triglyceride in times of plenty, and release the energy from FFA and glycerol in times of need. It is now known that the tissue is capable of synthesizing and releasing a variety of hormones and cytokines (Table 1), which can act in an autocrine, paracrine and/or endocrine manner to regulate many areas of behavioral, metabolic, cardiovascular, reproductive and immunological activities [5,6]. Adipose tissue is capable of hypertrophy (increasing cell volume O 1000-fold) and hyperplasia, and it has been suggested that there are two functionally different pre-adipocytes [7]. These two ‘pools’ (omental and subcutaneous) of adipose Corresponding author: Wintour, E.M. ([email protected]). Available online 17 February 2006 www.sciencedirect.com
tissue enlarge at different rates, receive differential sympathetic innervation and differentially release ‘beneficial’ humoral factors, such as adiponectin, or more ‘harmful’ products, such as tumor necrosis factor. Factors affecting outcome in knockout mice Age Earlier studies [8] had shown that at 7–10 weeks there was normal weight gain in the AQP7-knockout (KO) male mice. Although plasma glucose and glycerol levels were lower in the AQP7-KO animals, there was no change in plasma insulin or FFA levels, and glucose tolerance test (GTT) was normal. However, by 20–24 weeks, obesity began to develop as weight gain increased because of an increase in the size of subcutaneous and visceral fat depots. Increased adiposity was not associated with altered food intake or energy expenditure but correlated with increased glyceride synthesis. Fasting blood glucose increased, and GTT was abnormal. High-fat feeding increased weight gain and the activity of glycerol kinase after 10 weeks, while decreasing secretion of the ‘good’ hormone adiponectin. This demonstrates that under ‘normal’ chow-fed conditions the AQP7-KO mice exhibit an age-dependent obese phenotype. Strain If the knockouts were done in CD1 mice, without a backcross to C57BK/6, the phenotype was somewhat different in that no increase in overall body weight was seen by 16 weeks in either sex, but there was significant reduction in body length in females [9]. Importantly, although total body weight was maintained in the AQP7-KO mice, there was still significantly greater whole body fat accumulation. Individual adipocytes were approximately three times larger and adipose tissue glycerides were increased, but plasma glycerol was unchanged. The permeability of adipocytes to glycerol was decreased about fourfold, demonstrating that glycerol transport was reduced but not abolished. Implications for human A mouse is not a human, and it has been suggested that not all functions of aquaporins in humans can be revealed by KO studies in mice [10]. There is at least one striking example that illustrates this fact. When the AQP4 gene was disrupted in mouse astrocytes, there were only very mild morphological changes, whereas its disruption (knock-down with small interfering RNA) in human
Update
78
TRENDS in Endocrinology and Metabolism
Table 1. Summary of major adipokines secreted from adipose tissuea Adipokine
Impact of Obesity Increased
TNF-a IL-6 IL-8 TGF-b Adiponectin
Increased Decreased
Leptin
Increased
Resistin
Increased
Visfatin Angiotensinogen
Increased Increased
Function † Pro-inflammatory cytokines † Atherosclerotic † Insulin resistance † Growth factor † Anti-inflammatory † Anti-atherosclerotic † Insulin sensitivity † Satiety factor † Cardiovascular disease † Some types of cancer † Regulates pituitary hormone secretion † Insulin resistance (in mice) † Atherosclerotic † Glucose homeostasis (in mice) † Blood pressure and cardiovascular disease
a
Abbreviations: TNF-a, tumor necrosis factor a; IL-6, interleukin 6; IL-8, interleukin 8; TGF-b, transforming growth factor b.
astrocytes substantially altered cell morphology [11]. The reported individual with a homozygous mutation in the coding region of the AQP7 gene, which resulted in decreased AQP7 expression [12], was neither obese nor diabetic. This subject was unable to increase plasma glycerol in response to exercise, although he showed the normal exercise-induced increase in plasma noradrenaline. However, in lean and obese but healthy young men, with similar high-fat diets and similar daily activity profiles, there were differences in the AQP7 mRNA levels in adipose tissue of subcutaneous fat biopsies [13]. The AQP7 gene was downregulated in the adipose tissue of the obese men and they had higher plasma glucose and insulin levels, whereas glucose tolerance was still in the normal range. Plasma adiponectin concentrations were lower than normal in the obese, in agreement with studies in the AQP7-KO mouse. Did the lower AQP7 levels in the adipose tissue increase susceptibility to develop obesity, or were the higher levels of the lean individuals protective? It could be postulated that decreased levels of AQP7 would perpetuate the obese phenotype and hamper weight loss because of the lack of ability of the adipocyte to release glycerol. It would be interesting to follow these subjects as they age. Additional studies might determine whether
Vol.17 No.3 April 2006
AQP7 gene expression follows a circadian rhythm, as do many of the major adipokines [14]. Is AQP7 gene expression disrupted in diabetes? As pre-perinatal factors might increase adult susceptibility to obesity [15], it would be important to establish whether the prenatal environment can alter the expression of this gene by epigenetic mechanisms. This might be another target for drug control of obesity and/or diabetes type 2 [6]. References 1 Agre, P. (2004) Nobel Lecture. Aquaporin water channels. Biosci. Rep. 24, 127–163 2 Verkman, A.S. (2005) More than just water channels: unexpected cellular roles of aquaporins. J. Cell Sci. 118, 3225–3232 3 Sjoholm, K. et al. (2005) A microarray search for genes predominantly expressed in human omental adipocytes:adipose tissue as a major production site of serum amyloid A. J. Clin. Endocrinol. Metab. 90, 2233–2239 4 Hibuse, T. et al. (2005) Aquaporin 7 deficiency is associated with development of obesity through activation of adipose glycerol kinase. Proc. Natl. Acad. Sci. U. S. A. 102, 10993–10998 5 Mitchell, M. et al. (2005) Adipokines: implications for female fertility and obesity. Reproduction 130, 583–597 6 Klein, J. et al. Adipose tissue as a source and target for novel therapies. Trends Endocrinol. Metab. 17, 26–32 7 Smith, J. et al. (2006) The adipocyte life cycle hypothesis. Clin. Sci. 110, 1–9 8 Maeda, N. et al. (2004) Adaptation to fasting by glycerol transport through aquaporin 7 in adipose tissue. Proc. Natl. Acad. Sci. U. S. A. 101, 17801–17806 9 Hara-Chikuma, M. et al. (2005) Progressive adipocyte hypertrophy in aquaporin-7-deficient mice. J. Biol. Chem. 280, 15493–15496 10 Liu H and Wintour EM (2005) Aquaporins in development – a review. Reprod. Biol. Endocrinol. DOI: 10.1186/1477-7827 3-18 11 Nicchia G.P. et al. (2005) New possible roles for aquaporin-4 in astrocytes: cell cytoskeleton and functional relationship with connexin43 FASEB J. DOI: 10.1096/fj.04-3281fje 12 Kondo, H. et al. (2002) Human aquaporin adipose (AQPap) gene. Eur. J. Biochem. 269, 1814–1826 13 Marrades, M.P. et al. (2006) Differential expression of aquaporin 7 in adipose tissue of lean and obese high fat consumers. Biochem. Biophys. Res. Commun. 339, 785–789 14 Ando, H. et al. (2005) Rhythmic messenger ribonucleic acid expression of clock genes and adipocytokines in mouse visceral adipose tissue. Endocrinology 146, 5631–5636 15 Budge, H. et al. (2005) Maternal nutritional programming of fetal adipose tissue development: long term consequences for later obesity. Birth Defects Res. C. Embryol. Today 75, 193–199 1043-2760/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2006.01.009
Free journals for developing countries The WHO and six medical journal publishers have launched the Access to Research Initiative, which enables nearly 70 of the world’s poorest countries to gain free access to biomedical literature through the Internet. Gro Harlem Brundtland, director-general for the WHO, said that this initiative was ‘perhaps the biggest step ever taken towards reducing the health information gap between rich and poor countries’. See http://www.healthinternetwork.net for more information.
www.sciencedirect.com
TRENDS in Endocrinology and Metabolism
Vol.17 No.3 April 2006
Research Focus
Glycerol transport: an additional target for obesity therapy? E. Marelyn Wintour and Belinda A. Henry Department of Physiology, Monash University, Clayton, 3800, Australia
There is increasing evidence that the glycerol channel, aquaporin 7(AQP7), has an important role in adipose tissue formation and function – deletion of the gene in a mouse strain leads to obesity and diabetes type 2 if the mice are aged or fed earlier with a high-fat or sucrose diet. Can increased levels of AQP7 in adipose tissue protect against obesity? New studies on AQP7 highlight the important role of glycerol transport in the development of obesity and metabolic disease. Functional glycerol channel For generations, physiologists have taught that all cells in the body, with the exception of principal cells of the renal collecting duct, are intrinsically permeable to water. In 2003, Peter Agre shared the Nobel Prize for his discoveries over the previous 15 years of specific water channels or aquaporins [1]. Aquaporins exist in bacteria, plants and the whole animal kingdom. To date, thirteen have been identified in mammalian tissues (AQPs 0–12) and some have been shown to function as more than simple water channels [2]. At least four (AQPs 3,7,9,10) also function as channels for the passage of glycerol and/or urea. Adipose tissue shows quantitatively the highest levels of expression of mRNA of AQP7, with omental adipose tissue expressing this gene at the highest levels in human [3]. The importance of AQP7 as a glycerol channel has been highlighted by a recent paper in which mice lacking a functional AQP7 gene were shown to develop obesity and insulin resistance, in part by an increase in adipose tissue glycerol kinase activity, and increased triglyceride synthesis [4]. Adipose tissue: an energy store and lots, lots more White adipose tissue was seen, conventionally, as tissue that can take up free fatty acids (FFA) and store them as triglyceride in times of plenty, and release the energy from FFA and glycerol in times of need. It is now known that the tissue is capable of synthesizing and releasing a variety of hormones and cytokines (Table 1), which can act in an autocrine, paracrine and/or endocrine manner to regulate many areas of behavioral, metabolic, cardiovascular, reproductive and immunological activities [5,6]. Adipose tissue is capable of hypertrophy (increasing cell volume O 1000-fold) and hyperplasia, and it has been suggested that there are two functionally different pre-adipocytes [7]. These two ‘pools’ (omental and subcutaneous) of adipose Corresponding author: Wintour, E.M. ([email protected]). Available online 17 February 2006 www.sciencedirect.com
tissue enlarge at different rates, receive differential sympathetic innervation and differentially release ‘beneficial’ humoral factors, such as adiponectin, or more ‘harmful’ products, such as tumor necrosis factor. Factors affecting outcome in knockout mice Age Earlier studies [8] had shown that at 7–10 weeks there was normal weight gain in the AQP7-knockout (KO) male mice. Although plasma glucose and glycerol levels were lower in the AQP7-KO animals, there was no change in plasma insulin or FFA levels, and glucose tolerance test (GTT) was normal. However, by 20–24 weeks, obesity began to develop as weight gain increased because of an increase in the size of subcutaneous and visceral fat depots. Increased adiposity was not associated with altered food intake or energy expenditure but correlated with increased glyceride synthesis. Fasting blood glucose increased, and GTT was abnormal. High-fat feeding increased weight gain and the activity of glycerol kinase after 10 weeks, while decreasing secretion of the ‘good’ hormone adiponectin. This demonstrates that under ‘normal’ chow-fed conditions the AQP7-KO mice exhibit an age-dependent obese phenotype. Strain If the knockouts were done in CD1 mice, without a backcross to C57BK/6, the phenotype was somewhat different in that no increase in overall body weight was seen by 16 weeks in either sex, but there was significant reduction in body length in females [9]. Importantly, although total body weight was maintained in the AQP7-KO mice, there was still significantly greater whole body fat accumulation. Individual adipocytes were approximately three times larger and adipose tissue glycerides were increased, but plasma glycerol was unchanged. The permeability of adipocytes to glycerol was decreased about fourfold, demonstrating that glycerol transport was reduced but not abolished. Implications for human A mouse is not a human, and it has been suggested that not all functions of aquaporins in humans can be revealed by KO studies in mice [10]. There is at least one striking example that illustrates this fact. When the AQP4 gene was disrupted in mouse astrocytes, there were only very mild morphological changes, whereas its disruption (knock-down with small interfering RNA) in human
Update
78
TRENDS in Endocrinology and Metabolism
Table 1. Summary of major adipokines secreted from adipose tissuea Adipokine
Impact of Obesity Increased
TNF-a IL-6 IL-8 TGF-b Adiponectin
Increased Decreased
Leptin
Increased
Resistin
Increased
Visfatin Angiotensinogen
Increased Increased
Function † Pro-inflammatory cytokines † Atherosclerotic † Insulin resistance † Growth factor † Anti-inflammatory † Anti-atherosclerotic † Insulin sensitivity † Satiety factor † Cardiovascular disease † Some types of cancer † Regulates pituitary hormone secretion † Insulin resistance (in mice) † Atherosclerotic † Glucose homeostasis (in mice) † Blood pressure and cardiovascular disease
a
Abbreviations: TNF-a, tumor necrosis factor a; IL-6, interleukin 6; IL-8, interleukin 8; TGF-b, transforming growth factor b.
astrocytes substantially altered cell morphology [11]. The reported individual with a homozygous mutation in the coding region of the AQP7 gene, which resulted in decreased AQP7 expression [12], was neither obese nor diabetic. This subject was unable to increase plasma glycerol in response to exercise, although he showed the normal exercise-induced increase in plasma noradrenaline. However, in lean and obese but healthy young men, with similar high-fat diets and similar daily activity profiles, there were differences in the AQP7 mRNA levels in adipose tissue of subcutaneous fat biopsies [13]. The AQP7 gene was downregulated in the adipose tissue of the obese men and they had higher plasma glucose and insulin levels, whereas glucose tolerance was still in the normal range. Plasma adiponectin concentrations were lower than normal in the obese, in agreement with studies in the AQP7-KO mouse. Did the lower AQP7 levels in the adipose tissue increase susceptibility to develop obesity, or were the higher levels of the lean individuals protective? It could be postulated that decreased levels of AQP7 would perpetuate the obese phenotype and hamper weight loss because of the lack of ability of the adipocyte to release glycerol. It would be interesting to follow these subjects as they age. Additional studies might determine whether
Vol.17 No.3 April 2006
AQP7 gene expression follows a circadian rhythm, as do many of the major adipokines [14]. Is AQP7 gene expression disrupted in diabetes? As pre-perinatal factors might increase adult susceptibility to obesity [15], it would be important to establish whether the prenatal environment can alter the expression of this gene by epigenetic mechanisms. This might be another target for drug control of obesity and/or diabetes type 2 [6]. References 1 Agre, P. (2004) Nobel Lecture. Aquaporin water channels. Biosci. Rep. 24, 127–163 2 Verkman, A.S. (2005) More than just water channels: unexpected cellular roles of aquaporins. J. Cell Sci. 118, 3225–3232 3 Sjoholm, K. et al. (2005) A microarray search for genes predominantly expressed in human omental adipocytes:adipose tissue as a major production site of serum amyloid A. J. Clin. Endocrinol. Metab. 90, 2233–2239 4 Hibuse, T. et al. (2005) Aquaporin 7 deficiency is associated with development of obesity through activation of adipose glycerol kinase. Proc. Natl. Acad. Sci. U. S. A. 102, 10993–10998 5 Mitchell, M. et al. (2005) Adipokines: implications for female fertility and obesity. Reproduction 130, 583–597 6 Klein, J. et al. Adipose tissue as a source and target for novel therapies. Trends Endocrinol. Metab. 17, 26–32 7 Smith, J. et al. (2006) The adipocyte life cycle hypothesis. Clin. Sci. 110, 1–9 8 Maeda, N. et al. (2004) Adaptation to fasting by glycerol transport through aquaporin 7 in adipose tissue. Proc. Natl. Acad. Sci. U. S. A. 101, 17801–17806 9 Hara-Chikuma, M. et al. (2005) Progressive adipocyte hypertrophy in aquaporin-7-deficient mice. J. Biol. Chem. 280, 15493–15496 10 Liu H and Wintour EM (2005) Aquaporins in development – a review. Reprod. Biol. Endocrinol. DOI: 10.1186/1477-7827 3-18 11 Nicchia G.P. et al. (2005) New possible roles for aquaporin-4 in astrocytes: cell cytoskeleton and functional relationship with connexin43 FASEB J. DOI: 10.1096/fj.04-3281fje 12 Kondo, H. et al. (2002) Human aquaporin adipose (AQPap) gene. Eur. J. Biochem. 269, 1814–1826 13 Marrades, M.P. et al. (2006) Differential expression of aquaporin 7 in adipose tissue of lean and obese high fat consumers. Biochem. Biophys. Res. Commun. 339, 785–789 14 Ando, H. et al. (2005) Rhythmic messenger ribonucleic acid expression of clock genes and adipocytokines in mouse visceral adipose tissue. Endocrinology 146, 5631–5636 15 Budge, H. et al. (2005) Maternal nutritional programming of fetal adipose tissue development: long term consequences for later obesity. Birth Defects Res. C. Embryol. Today 75, 193–199 1043-2760/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2006.01.009
Free journals for developing countries The WHO and six medical journal publishers have launched the Access to Research Initiative, which enables nearly 70 of the world’s poorest countries to gain free access to biomedical literature through the Internet. Gro Harlem Brundtland, director-general for the WHO, said that this initiative was ‘perhaps the biggest step ever taken towards reducing the health information gap between rich and poor countries’. See http://www.healthinternetwork.net for more information.
www.sciencedirect.com