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Effects of testosterone on fat cell lipolysis. Species differences and possible role in polycystic ovarian syndrome
Biochimie 87 (2005) 39–43 www.elsevier.com/locate/biochi
Effects of testosterone on fat cell lipolysis. Species differences and possible role in polycystic ovarian syndrome Peter Arner * Department of Medicine at Karolinska Institutet, Stockholm, Sweden Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden Received 11 October 2004; accepted 8 November 2004 Available online 15 December 2004
Abstract Testosterone is a potent regulator of lipolysis by influencing catecholamine signal transduction in fat cells. Major species differences exist as regards the testosterone effect. In rodents testosterone increases b-adrenergic receptor mediated signals to lipolysis at multiple steps in the lipolytic cascade. The sex hormone also increases a2-adrenoceptor antilipolytic signalling in hamster which unlike rat express this receptor in their fat cells. In humans the region of adipose tissue is critical. Visceral fat cell lipolysis is not responsive to testosterone but this sex hormone decreases catecholamine-induced lipolysis in subcutaneous fat cells due to inhibition of the expression of b2-adrenoceptors and hormone sensitive lipase. In polycystic ovarian syndrome (PCOS), which is characterized as a hyperandrogenic state, the lipolytic effect of catecholamine is decreased in subcutaneous adipocytes due to low content of b2-adrenoceptors and hormone sensitive lipase. It is possible that the increased testosterone levels are responsible for these abnormalities in catecholamine signal transduction in subcutaneous fat cells of PCOS women. However, in visceral fat cells of PCOS women catecholamine-induced lipolysis is enhanced which cannot be explained by testosterone. © 2004 Elsevier SAS. All rights reserved. Keywords: Fat cell; Catecholamines; Insulin; Obesity; PCOS
1. Introduction It is well established that upper body fat distribution, in particular visceral fat accumulation is associated with insulin resistance as well as other hormonal and metabolic abnormalities which, ultimately, increase the risk of developing type 2 diabetes and atherosclerotic cardiovascular disease as discussed [1,2]. It is not known why central fat accumulation is more dangerous than peripheral adipose deposition. However, fat cells produce a number of signalling molecules that are released from the tissue into the circulation and influence insulin action, glucose metabolism lipid metabolism in liver and muscle and insulin secretion in pancreatic b-cells, as reviewed [3]. It is possible that the adipose region and the distribution of fat tissue influence the release of these signalling molecules [4]. Fatty acids derived from hydrolysis (lipolysis) of acylglycerol in fat cells are the perhaps best characterized signal* Corresponding author. Tel.: +46-8-58582342 ; fax : +46-8-58582407. E-mail address: [email protected] (P. Arner). 0300-9084/$ - see front matter © 2004 Elsevier SAS. All rights reserved. doi:10.1016/j.biochi.2004.11.012
ling molecules derived from adipose tissue. Excess fatty acids may inhibit insulin production by pancreas, induce insulin resistance and glucose intolerance in liver and skeletal muscle and alter apolipoprotein production by liver [3]. Among adipose signals fatty acids may be of particular importance in subjects with an upper body fat distribution, because their release from fat cells is subjected to marked regional variations according to reviews [4,5]. Insulin and catecholamines are the major lipolysis regulating hormones in man. The antilipolytic effect of insulin is less pronounced but the lipolytic effect of catecholamines more pronounced in visceral as compared to subcutaneous fat. This implies that in hyperinsulinized states, such as after food intake, or in hyperadrenergic states, such as emotional stress or exercise, relatively more fatty acids are released from the visceral than from sc depots, which will selectively influence the liver since visceral fat is drained by the portal system. At rest or in the pre-prandial state, when hormonal influence on lipolysis is low, the subcutaneous fatty acid release dominate over visceral release because it is the major fat depot. About 80% of fatty acids
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that are released after an overnight fast derive from subcutaneous fat [6]. Thus, at rest and pre-prandially subcutaneous release of fatty acids to the peripheral circulation will be of importance for skeletal muscle and pancreas. In upper body obesity the regional variations in lipolysis are further pronounced as discussed [7]. This is above all due to that the lipolytic effect of catecholamines is decreased in subcutaneous fat but increased in visceral fat whereas basal (resting) lipolysis is increased in subcutaneous fat. From the above discussion, it should be evident that regional variations in adipocyte lipolysis are key factors in the overall signalling effects of fatty acids in man. If so what is causing the depot variations? For a number of reasons testosterone could be a critical factor. Upper body obesity and visceral fat accumulation is more common among men than women and there are important gender variations in lipolysis as discussed [8]. Women with polycystic ovarian syndrome (PCOS), which is a hyperandrogenic state, are prone to upper body and visceral fat accumulation as well as to insulin resistance according to review [9,10]. Finally, when men are given testosterone there is a more rapid loss of lipid deposition [11,12] and selective decrease of fat mass [13] in visceral as compared to subcutaneous adipose tissue. In this review I will discuss testosterone effects on adipocyte lipolysis in rodents and humans and also argue for a pathophysiological role of this hormone in PCOS. 2. Effect of testosterone on lipolysis in rodents To the best of my knowledge only interactions between testosterone and catecholamine-induced lipolysis have been investigated so far. It is, though, interesting to note that testosterone induces resistance to insulin stimulated glucose metabolism in skeletal muscle of rats [14,15]. Catecholamines regulate adipocyte lipolysis through four different adipocyte subtypes as reviewed [16]. In all exam-
ined rodent species and in man three different b-adrenoceptors subtypes couple to Gs which stimulates adenylate cyclase so that more cyclic AMP is produced. Cyclic AMP activates the protein kinase A complex (PKA) which, in turn, stimulates hormone sensitive lipase (HSL) so that the breakdown of triglycerides is accelerated (lipolysis). However, adipocytes from some species such as humans and hamster also have a2 adrenoceptors. They couple to Gi and inhibit adenylate cyclase and cyclic AMP formation so that less PKA and HSL is activated resulting in antilipolytic effects. Therefore, in rat adipocytes (lacking a2 adrenoceptors) catecholamines are solely lipolytical whereas in humans and hamster adipocytes the catecholamine effect on lipolysis is dependent on b/a balance. The first demonstration of a testosterone effect on lipolysis was almost 25 years ago when Hansen et al. [17] showed that testosterone treatment of rats enhanced the lipolytic action on catecholamines. There seems to be multiple mechanisms responsible for testosterone stimulation of catecholamine action, which are localized at b adrenoceptors, Gs, PKI and HSL of rodent fat cells [18–20]. However, testosterone may also counteract catecholamine-induced lipolysis in certain rodent models. In hamster it augments the a2 adrenoceptor antilipolytic signal transduction [21–23]. Thus, in hamster the final outcome of the interaction between testosterone and lipolysis is dependent on the net effect of the sex hormone on b/a balance. The action of testosterone on lipolysis in rodents is summarized in Fig. 1. It enhances the lipolytic effect of catecholamines by increasing the effectiveness of the b2-adrenoceptor lipolytic signalling cascade. However, it also augments the a2 adrenoceptor mediated antilipolytic signalling of catechoalmines. Therefore, the net outcome (improved or decreased lipolytic activity) is dependent on which rodent species that is examined.
Fig. 1. Effect of testosterone on catecholamine signal transduction and lipolysis in rodent and human subcutaneous fat cells. Gs and G—G-proteins; PKA—protein kinase A complex; HSL—hormone sensitive lipase. Minus is inhibition and plus is stimulation.
P. Arner / Biochimie 87 (2005) 39–43
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3. Effect of testosterone on lipolysis in human fat cells
4. Lipolysis regulation in PCOS
As for rodents the possible interaction between testosterone and the antilipolytic effect of insulin is not investigated as far as I know. However, at least two publications have investigated the effect of testosterone on catecholamine signalling to lipolysis in human fat cells [24,25]. A depot specific effect is observed. In subcutaneous fat cells testosterone treatment causes a concentration dependent decrease of catecholamine stimulated lipolysis which can be attributed to inhibition of the expression of b2-adrenoceptors and HSL in the subcutaneous cells. The most important action is probably a decreased expression of HSL because this is the final rate limiting step for catecholamine-induced lipolysis and there is a positive relationship between the amount of HSL in subcutaneous fat cells and lipolytic effect of catecholamines in these cells [25]. The effect of testosterone is observed at concentrations that are equivalent to those in the circulation of male subjects. In visceral fat cells, on the other hand, testosterone has no effects on lipolysis although the hormone inhibits leptin secretion in these cells (as in subcutaneous fat cells). The latter suggests the testosterone receptors are active in visceral fat cells but they are not linked to lipolysis. Interestingly, there are also some regional differences in the action of testosterone on subcutaneous and epidedymal adipose tissue of hamster. The testosterone interaction with lipolysis in human fat cells is summarized in Figs. 1 and 2. The sex hormones counteracts the lipolytic effect of catecholamines in subcutaneous adipose tissue but it has no effect on lipolysis in the visceral fat depot. However, testosterone inhibits leptin production in both depots. The human data are in marked contrast to the findings in rodents and suggest that it is doubtful from a clinical point of view to extrapolate testosterone data on lipolysis from published animal models to the situation in humans as was done in a recent review [26].
It is well established that PCOS women are prone to develop obesity and many of the effects of testosterone on adipose tissue resemble the effect of obesity per se, such as lipolytic catecholamine resistance in subcutaneous adipose tissue and adipocyte insulin resistance as reviewed [7]. Therefore, it is essential to pay specific attention to PCOS studies on non-obese women because in these women an observed abnormality is independent of body fat status. As regards insulin, several studies demonstrated insulin resistance of subcutaneous adipocytes for both glucose metabolism and antilipolysis, which is independent of obesity [27–32]. It is unclear for the moment which step(s) in insulin signalling that are causing the blunted antilipolytic effect of insulin in subcutaneous fat cells in PCOS. However, visceral fat cells have a quite normal sensitivity to insulin in PCOS, at least for the antilipolytic effect of the hormone [33]. Thus, there are regional variations in the impact of PCOS on insulin action. A region specific pattern is also observed for catecholamine-induced lipolysis in non-obese PCOS women. In these women the lipolytic effect of catecholamines is blunted which can be attributed to decreased amounts of b2 adrenoceptors and HSL protein [34,35]. On the contrary, catecholamineinduced lipolysis in visceral fat cells of non-obese PCOS women is markedly increased, which seems to be due to multiple alterations of the stoichiometic proportions of various components of the PKH–HSL complex facilitating increased catecholamine signalling to lipolysis [33]. Is impaired lipolysis in PCOS secondary to the hyperandrogenic state? Resistance to catecholamines in subcutaneous fat could be due to testosterone (inhibition of b2adrenoceptor and HSL expression). Furthermore, antilipolytic insulin resistance in this adipose region could also be a test-
Fig. 2. Regional differences in testosterone effects on lipolysis and leptin production in human fat cells. See legend of Fig. 1 for details.
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Fig. 3. Catecholamine signal transduction and lipolysis in subcutaneous and visceral fat cells in polycystic ovarian syndrome. See legend of Fig. 1 for details.
osterone effect because animal data clearly show that testosterone administration cause rapid and pronounced insulin resistance as discussed above.
The latter abnormalities are often observed in PCOS as discussed [9,10].
On the other, the increased lipolytic activity of visceral fat in PCOS is clearly not due to testosterone. Catecholamine action is not influenced by testosterone in vitro and there is no change of insulin action in this region. The factors increasing catecholamine-induced lipolysis in visceral fat cells of PCOS women remain to be established. Further mechanistic studies are hampered by the fact that no good animal model of PCOS is at hand [36]. Can changes in lipolysis PCOS be attributed to unfavourable female sex hormone profile? Probably not because treatment of lean or obese PCOS women with p-pills does not normalize lipolysis in subcutaneous fat cells [34,37].
5. Conclusions
Interestingly, young non-obese PCOS women have larger subcutaneous fat cells than healthy women with the same body fat content, perhaps because of lipolytic catecholamine resistance [35]. Maybe this could be a factor for later development of diabetes and insulin resistance in PCOS because fat cell size is an independent risk factor for type 2 diabetes [38]. Catecholamine-induced lipolysis in PCOS is summarized in Fig. 2. It is increased in visceral fat cells but decreased in subcutaneous fat cells. The subcutaneous effect may promote development of upper body obesity because subcutaneous abdominal fat is the major fat depot in the upper body region. The visceral effect may elevate the portal fatty acid levels resulting in liver dysfunction which, in turn, could lead to glucose intolerance, hyperinsulinemia, and dyslipidemia.
It is evident that testosterone is an important regulator of fat cell lipolysis, in particular by interacting with the most important lipolytic hormones, the catecholamines. Major species differences are at hand making it less meaningful to extrapolate data in rodents to testosterone effects on lipolysis in humans (Fig. 3). In rats testosterone improves the lipolytic action of catecholamines due to increased effectiveness of b-adrenoceptor signalling. In hamster the effect is more complex because testosterone also enhances a2 adrenoceptor mediated antilipolytic effects of catecholamines. In man, the adipose region is critical for the interaction with testosterone. Only subcutaneous fat cells are sensitive to the sex hormone, making these cells less responsive to lipolytic stimulation by catecholamine due decreased effectiveness of catecholamine signal transduction. Testosterone may at least in part be responsible for the regional unbalance in fatty acid mobilization observed the hyperandrogenic condition PCOS favouring fatty acid mobilization from the visceral fat depots. The latter leads to elevated “portal” fatty acid levels and, as a consequence, impaired liver function. Interactions between testosterone and HSL of subcutaneous fat cells appear to be critical for the testosterone effects on lipolysis in humans. If we can elucidate the molecular mechanisms behind this interaction it might be possible to develop novel and specific treatments of insulin resistance targeting subcutaneous fat cell lipolysis.
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Effects of testosterone on fat cell lipolysis. Species differences and possible role in polycystic ovarian syndrome Peter Arner * Department of Medicine at Karolinska Institutet, Stockholm, Sweden Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden Received 11 October 2004; accepted 8 November 2004 Available online 15 December 2004
Abstract Testosterone is a potent regulator of lipolysis by influencing catecholamine signal transduction in fat cells. Major species differences exist as regards the testosterone effect. In rodents testosterone increases b-adrenergic receptor mediated signals to lipolysis at multiple steps in the lipolytic cascade. The sex hormone also increases a2-adrenoceptor antilipolytic signalling in hamster which unlike rat express this receptor in their fat cells. In humans the region of adipose tissue is critical. Visceral fat cell lipolysis is not responsive to testosterone but this sex hormone decreases catecholamine-induced lipolysis in subcutaneous fat cells due to inhibition of the expression of b2-adrenoceptors and hormone sensitive lipase. In polycystic ovarian syndrome (PCOS), which is characterized as a hyperandrogenic state, the lipolytic effect of catecholamine is decreased in subcutaneous adipocytes due to low content of b2-adrenoceptors and hormone sensitive lipase. It is possible that the increased testosterone levels are responsible for these abnormalities in catecholamine signal transduction in subcutaneous fat cells of PCOS women. However, in visceral fat cells of PCOS women catecholamine-induced lipolysis is enhanced which cannot be explained by testosterone. © 2004 Elsevier SAS. All rights reserved. Keywords: Fat cell; Catecholamines; Insulin; Obesity; PCOS
1. Introduction It is well established that upper body fat distribution, in particular visceral fat accumulation is associated with insulin resistance as well as other hormonal and metabolic abnormalities which, ultimately, increase the risk of developing type 2 diabetes and atherosclerotic cardiovascular disease as discussed [1,2]. It is not known why central fat accumulation is more dangerous than peripheral adipose deposition. However, fat cells produce a number of signalling molecules that are released from the tissue into the circulation and influence insulin action, glucose metabolism lipid metabolism in liver and muscle and insulin secretion in pancreatic b-cells, as reviewed [3]. It is possible that the adipose region and the distribution of fat tissue influence the release of these signalling molecules [4]. Fatty acids derived from hydrolysis (lipolysis) of acylglycerol in fat cells are the perhaps best characterized signal* Corresponding author. Tel.: +46-8-58582342 ; fax : +46-8-58582407. E-mail address: [email protected] (P. Arner). 0300-9084/$ - see front matter © 2004 Elsevier SAS. All rights reserved. doi:10.1016/j.biochi.2004.11.012
ling molecules derived from adipose tissue. Excess fatty acids may inhibit insulin production by pancreas, induce insulin resistance and glucose intolerance in liver and skeletal muscle and alter apolipoprotein production by liver [3]. Among adipose signals fatty acids may be of particular importance in subjects with an upper body fat distribution, because their release from fat cells is subjected to marked regional variations according to reviews [4,5]. Insulin and catecholamines are the major lipolysis regulating hormones in man. The antilipolytic effect of insulin is less pronounced but the lipolytic effect of catecholamines more pronounced in visceral as compared to subcutaneous fat. This implies that in hyperinsulinized states, such as after food intake, or in hyperadrenergic states, such as emotional stress or exercise, relatively more fatty acids are released from the visceral than from sc depots, which will selectively influence the liver since visceral fat is drained by the portal system. At rest or in the pre-prandial state, when hormonal influence on lipolysis is low, the subcutaneous fatty acid release dominate over visceral release because it is the major fat depot. About 80% of fatty acids
40
P. Arner / Biochimie 87 (2005) 39–43
that are released after an overnight fast derive from subcutaneous fat [6]. Thus, at rest and pre-prandially subcutaneous release of fatty acids to the peripheral circulation will be of importance for skeletal muscle and pancreas. In upper body obesity the regional variations in lipolysis are further pronounced as discussed [7]. This is above all due to that the lipolytic effect of catecholamines is decreased in subcutaneous fat but increased in visceral fat whereas basal (resting) lipolysis is increased in subcutaneous fat. From the above discussion, it should be evident that regional variations in adipocyte lipolysis are key factors in the overall signalling effects of fatty acids in man. If so what is causing the depot variations? For a number of reasons testosterone could be a critical factor. Upper body obesity and visceral fat accumulation is more common among men than women and there are important gender variations in lipolysis as discussed [8]. Women with polycystic ovarian syndrome (PCOS), which is a hyperandrogenic state, are prone to upper body and visceral fat accumulation as well as to insulin resistance according to review [9,10]. Finally, when men are given testosterone there is a more rapid loss of lipid deposition [11,12] and selective decrease of fat mass [13] in visceral as compared to subcutaneous adipose tissue. In this review I will discuss testosterone effects on adipocyte lipolysis in rodents and humans and also argue for a pathophysiological role of this hormone in PCOS. 2. Effect of testosterone on lipolysis in rodents To the best of my knowledge only interactions between testosterone and catecholamine-induced lipolysis have been investigated so far. It is, though, interesting to note that testosterone induces resistance to insulin stimulated glucose metabolism in skeletal muscle of rats [14,15]. Catecholamines regulate adipocyte lipolysis through four different adipocyte subtypes as reviewed [16]. In all exam-
ined rodent species and in man three different b-adrenoceptors subtypes couple to Gs which stimulates adenylate cyclase so that more cyclic AMP is produced. Cyclic AMP activates the protein kinase A complex (PKA) which, in turn, stimulates hormone sensitive lipase (HSL) so that the breakdown of triglycerides is accelerated (lipolysis). However, adipocytes from some species such as humans and hamster also have a2 adrenoceptors. They couple to Gi and inhibit adenylate cyclase and cyclic AMP formation so that less PKA and HSL is activated resulting in antilipolytic effects. Therefore, in rat adipocytes (lacking a2 adrenoceptors) catecholamines are solely lipolytical whereas in humans and hamster adipocytes the catecholamine effect on lipolysis is dependent on b/a balance. The first demonstration of a testosterone effect on lipolysis was almost 25 years ago when Hansen et al. [17] showed that testosterone treatment of rats enhanced the lipolytic action on catecholamines. There seems to be multiple mechanisms responsible for testosterone stimulation of catecholamine action, which are localized at b adrenoceptors, Gs, PKI and HSL of rodent fat cells [18–20]. However, testosterone may also counteract catecholamine-induced lipolysis in certain rodent models. In hamster it augments the a2 adrenoceptor antilipolytic signal transduction [21–23]. Thus, in hamster the final outcome of the interaction between testosterone and lipolysis is dependent on the net effect of the sex hormone on b/a balance. The action of testosterone on lipolysis in rodents is summarized in Fig. 1. It enhances the lipolytic effect of catecholamines by increasing the effectiveness of the b2-adrenoceptor lipolytic signalling cascade. However, it also augments the a2 adrenoceptor mediated antilipolytic signalling of catechoalmines. Therefore, the net outcome (improved or decreased lipolytic activity) is dependent on which rodent species that is examined.
Fig. 1. Effect of testosterone on catecholamine signal transduction and lipolysis in rodent and human subcutaneous fat cells. Gs and G—G-proteins; PKA—protein kinase A complex; HSL—hormone sensitive lipase. Minus is inhibition and plus is stimulation.
P. Arner / Biochimie 87 (2005) 39–43
41
3. Effect of testosterone on lipolysis in human fat cells
4. Lipolysis regulation in PCOS
As for rodents the possible interaction between testosterone and the antilipolytic effect of insulin is not investigated as far as I know. However, at least two publications have investigated the effect of testosterone on catecholamine signalling to lipolysis in human fat cells [24,25]. A depot specific effect is observed. In subcutaneous fat cells testosterone treatment causes a concentration dependent decrease of catecholamine stimulated lipolysis which can be attributed to inhibition of the expression of b2-adrenoceptors and HSL in the subcutaneous cells. The most important action is probably a decreased expression of HSL because this is the final rate limiting step for catecholamine-induced lipolysis and there is a positive relationship between the amount of HSL in subcutaneous fat cells and lipolytic effect of catecholamines in these cells [25]. The effect of testosterone is observed at concentrations that are equivalent to those in the circulation of male subjects. In visceral fat cells, on the other hand, testosterone has no effects on lipolysis although the hormone inhibits leptin secretion in these cells (as in subcutaneous fat cells). The latter suggests the testosterone receptors are active in visceral fat cells but they are not linked to lipolysis. Interestingly, there are also some regional differences in the action of testosterone on subcutaneous and epidedymal adipose tissue of hamster. The testosterone interaction with lipolysis in human fat cells is summarized in Figs. 1 and 2. The sex hormones counteracts the lipolytic effect of catecholamines in subcutaneous adipose tissue but it has no effect on lipolysis in the visceral fat depot. However, testosterone inhibits leptin production in both depots. The human data are in marked contrast to the findings in rodents and suggest that it is doubtful from a clinical point of view to extrapolate testosterone data on lipolysis from published animal models to the situation in humans as was done in a recent review [26].
It is well established that PCOS women are prone to develop obesity and many of the effects of testosterone on adipose tissue resemble the effect of obesity per se, such as lipolytic catecholamine resistance in subcutaneous adipose tissue and adipocyte insulin resistance as reviewed [7]. Therefore, it is essential to pay specific attention to PCOS studies on non-obese women because in these women an observed abnormality is independent of body fat status. As regards insulin, several studies demonstrated insulin resistance of subcutaneous adipocytes for both glucose metabolism and antilipolysis, which is independent of obesity [27–32]. It is unclear for the moment which step(s) in insulin signalling that are causing the blunted antilipolytic effect of insulin in subcutaneous fat cells in PCOS. However, visceral fat cells have a quite normal sensitivity to insulin in PCOS, at least for the antilipolytic effect of the hormone [33]. Thus, there are regional variations in the impact of PCOS on insulin action. A region specific pattern is also observed for catecholamine-induced lipolysis in non-obese PCOS women. In these women the lipolytic effect of catecholamines is blunted which can be attributed to decreased amounts of b2 adrenoceptors and HSL protein [34,35]. On the contrary, catecholamineinduced lipolysis in visceral fat cells of non-obese PCOS women is markedly increased, which seems to be due to multiple alterations of the stoichiometic proportions of various components of the PKH–HSL complex facilitating increased catecholamine signalling to lipolysis [33]. Is impaired lipolysis in PCOS secondary to the hyperandrogenic state? Resistance to catecholamines in subcutaneous fat could be due to testosterone (inhibition of b2adrenoceptor and HSL expression). Furthermore, antilipolytic insulin resistance in this adipose region could also be a test-
Fig. 2. Regional differences in testosterone effects on lipolysis and leptin production in human fat cells. See legend of Fig. 1 for details.
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Fig. 3. Catecholamine signal transduction and lipolysis in subcutaneous and visceral fat cells in polycystic ovarian syndrome. See legend of Fig. 1 for details.
osterone effect because animal data clearly show that testosterone administration cause rapid and pronounced insulin resistance as discussed above.
The latter abnormalities are often observed in PCOS as discussed [9,10].
On the other, the increased lipolytic activity of visceral fat in PCOS is clearly not due to testosterone. Catecholamine action is not influenced by testosterone in vitro and there is no change of insulin action in this region. The factors increasing catecholamine-induced lipolysis in visceral fat cells of PCOS women remain to be established. Further mechanistic studies are hampered by the fact that no good animal model of PCOS is at hand [36]. Can changes in lipolysis PCOS be attributed to unfavourable female sex hormone profile? Probably not because treatment of lean or obese PCOS women with p-pills does not normalize lipolysis in subcutaneous fat cells [34,37].
5. Conclusions
Interestingly, young non-obese PCOS women have larger subcutaneous fat cells than healthy women with the same body fat content, perhaps because of lipolytic catecholamine resistance [35]. Maybe this could be a factor for later development of diabetes and insulin resistance in PCOS because fat cell size is an independent risk factor for type 2 diabetes [38]. Catecholamine-induced lipolysis in PCOS is summarized in Fig. 2. It is increased in visceral fat cells but decreased in subcutaneous fat cells. The subcutaneous effect may promote development of upper body obesity because subcutaneous abdominal fat is the major fat depot in the upper body region. The visceral effect may elevate the portal fatty acid levels resulting in liver dysfunction which, in turn, could lead to glucose intolerance, hyperinsulinemia, and dyslipidemia.
It is evident that testosterone is an important regulator of fat cell lipolysis, in particular by interacting with the most important lipolytic hormones, the catecholamines. Major species differences are at hand making it less meaningful to extrapolate data in rodents to testosterone effects on lipolysis in humans (Fig. 3). In rats testosterone improves the lipolytic action of catecholamines due to increased effectiveness of b-adrenoceptor signalling. In hamster the effect is more complex because testosterone also enhances a2 adrenoceptor mediated antilipolytic effects of catecholamines. In man, the adipose region is critical for the interaction with testosterone. Only subcutaneous fat cells are sensitive to the sex hormone, making these cells less responsive to lipolytic stimulation by catecholamine due decreased effectiveness of catecholamine signal transduction. Testosterone may at least in part be responsible for the regional unbalance in fatty acid mobilization observed the hyperandrogenic condition PCOS favouring fatty acid mobilization from the visceral fat depots. The latter leads to elevated “portal” fatty acid levels and, as a consequence, impaired liver function. Interactions between testosterone and HSL of subcutaneous fat cells appear to be critical for the testosterone effects on lipolysis in humans. If we can elucidate the molecular mechanisms behind this interaction it might be possible to develop novel and specific treatments of insulin resistance targeting subcutaneous fat cell lipolysis.
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