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Hypertension and the Metabolic Syndrome: closely related central origin?
International Congress Series 1241 (2002) 81 – 86
Hypertension and the Metabolic Syndrome: closely related central origin? Per Bjo¨rntorp* Department of Heart and Lung Diseases, Sahlgren’s Hospital, University of Go¨teborg, 41345 Go¨teborg, Sweden
Abstract Hypertension is often associated with the metabolic aberrations of the Metabolic Syndrome. Both of these conditions have a background in a hypothalamic arousal, which produces neuroendocrine and autonomic changes in the periphery, which generate the Metabolic Syndrome and primary hypertension. Such arousal is due to various environmental factors, including stressors of various origin. The parallel increase of insulin and blood pressure is probably mostly due to this parallel activation of both the stress axes, but it seems likely that insulin may amplify the arousal of the sympathetic nervous system. A new factor in this interplay seems to be leptin, which when elevated, such as in the obesity of the Metabolic Syndrome, activates the sympathetic nervous system through the leptin receptor. This seems to require a normal leptin receptor gene locus, because when polymorphisms are present, blood pressure does not increase even in the presence of obesity with elevated leptin levels. This might be the explanation as to why all obese subjects are not hypertensive (see schematic summary in Fig. 1). D 2002 Elsevier Science B.V. All rights reserved. Keywords: Hypertension; Metabolic Syndrome; Stress; Insulin; Leptin; Leptin receptor
It is now well established that primary hypertension is originating from central mechanisms, where the sympathetic nervous system is involved. The original observations were made by Brod et al. [1] already in the fifties, showing the hyperkinetic characteristics of these early phases of established hypertension. Lund-Johansen [2] then followed up such subjects and found a development into a stage where circulatory resistance was more prominent, due to adaptations of peripheral resistance vessels. This is what we usually see clinically in patients with essential hypertension. The dependence on environment for this
*
Tel.: +46-31-3421661; fax: +46-31-826540. E-mail address: [email protected] (P. Bjo¨rntorp).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 2 ) 0 0 6 3 8 - 6
82
P. Bjo¨rntorp / International Congress Series 1241 (2002) 81–86
development has recently been elegantly demonstrated in studies utilising continuous measurements of blood pressure in a prospective design [3]. The other prevailing hypothesis for the development of hypertension is the salt theory, suggesting that increased salt consumption will be followed by elevated blood pressure due to volume expansion. This possibility cannot be discarded, but seems to be applicable only in salt sensitive populations [4]. Essential hypertension is frequently associated with metabolic abnormalities. These include obesity of the central, visceral subtype, insulin resistance with or without impaired glucose tolerance and dyslipidemia, consisting of elevated very low density lipoproteins and low levels of high density lipoproteins. This cluster of symptoms is now called the Metabolic Syndrome. Recent studies have now revealed that the Metabolic Syndrome probably has a central neuroendocrine background [5]. The central feature here seems to be a frequent or chronic activation of the hypothalamic – pituitary – adrenal (HPA) axis with elevated cortisol secretion. Secondarily, the gonadal and growth hormone axes are inhibited, resulting in a relative peripheral deficiency of corresponding hormones. These endocrine perturbations alone and particularly in combinations are able to create the Metabolic Syndrome through essentially known mechanisms. It seems highly likely that the susceptibility to develop this abnormality often rests on a genetic basis and some associated polymorphisms in candidate genes have been disclosed.
1. The association between hypertension and the Metabolic Syndrome There are numerous statistical correlations between hyperinsulinemia, secondary to insulin resistance, and hypertension, although this is not always the case [6]. This has led researchers to examine potential pathogenetic pathways linking these two phenomena. Two major hypotheses have been put forward. One is that insulin facilitates sodium uptake in the kidney and would therefore cause a volume-dependent hypertension. The problem here is, however, that only the first step, sodium uptake elevation, has been demonstrated and the development of hypertension is a supposition. It seems rather unlikely that hypertension will develop with normally regulatory mechanisms for volume control. The other mechanistic possibility seems to be more plausible. Insulin has been shown to activate the sympathetic nervous system [7]. Hyperinsulinemia is a prominent abnormality of the Metabolic Syndrome, and insulin might therefore be considered as the link to hypertension. There are, however, observations that do not fit into this explanatory possibility. Patients with insulinoma are exposed more or less constantly to elevated insulin levels, but do not develop hypertension [8]. Furthermore, rats exposed to only insulin excess, with control of adrenal and sympathetic overactivity, do not develop elevated blood pressure until very late [9]. Such observations suggest that insulin by itself might not be responsible for the development of hypertension. It is, however, still possible that insulin might amplify the hemodynamic effects of elevated sympathetic nervous system activity. Recent information from studies in men provide additional information. When the activities of the HPA axis and the sympathetic nervous system are measured in parallel in
P. Bjo¨rntorp / International Congress Series 1241 (2002) 81–86
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men with the Metabolic Syndrome, they seem to be activated together, particularly during laboratory stress conditions [10], suggesting parallel activation of both axes. This is a wellknown phenomenon, actually it is difficult to activate one axis without activating the other due to several interconnections at different levels [11]. These studies then suggest strongly that both the HPA axis and the central sympathetic nervous system are tightly interconnected at central levels, and when activated then are responsible for the pathogenesis of primary hypertension and the Metabolic Syndrome. Other information supports this contention because the development of both primary hypertension and the Metabolic Syndrome are both preceded and followed by similar environmental problems. These include psychosocial and socioeconomic handicaps which would be expected to be followed by frequent stress reactions, alcohol and smoking as well as robust associations to depressive and anxiety traits, which are all known to activate both the HPA and sympathetic axes [12]. This, however, does not provide information on the potential role of insulin, as mentioned above. Statistical examinations on a population basis are of interest for this question. In a population-based study of men, all 52 years of age, blood pressure correlated strongly in bivariate analyses with various components of the Metabolic Syndrome, including insulin and the insulin/glucose ratio and with cortisol measurements, mirroring the activity of the HPA axis. When multiple correlations were performed, the only remaining factor of those mentioned, which remained associated with blood pressure, was the cortisol measurements. Taken together these observations indicate that the both stress axes, the HPA axis and the sympathetic nervous system, are activated simultaneously, and that the Metabolic
Fig. 1. The synergism between the hypothalamic – pituitary – adrenal (HPA) axis and the central sympathetic nervous system (n.s.) in the generation of primary hypertension and the metabolic syndrome. Stress activates the HPA axis and the sympathetic nervous system. Central obesity, insulin resistance (metabolic syndrome) will be the consequence of HPA axis activation, and hypertension the consequence of sympathetic nervous system activation. The latter is amplified by leptin and insulin.
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Syndrome emanates from the HPA axis and the hypertension from the sympathetic nervous system. This would explain the close statistical associations. It seems possible that insulin may be involved in the blood pressure elevation by amplifying the activation of the sympathetic nervous system (see Fig. 1).
2. The involvement of leptin Obesity is an important part of the Metabolic Syndrome, particularly when the obesity is localised to central regions. Leptin is a newly discovered peptide, secreted mainly for adipose tissue [13]. Leptin signals satiety to centers in the hypothalamic area via a specific receptor. Leptin secretion is elevated in obesity, which is a somewhat surprising finding, because with elevated leptin, food intake would be expected to be diminished. The term leptin-resistant obesity has therefore been coined. It seems possible that leptin is more of a ‘‘starvation hormone’’ than a ‘‘satiety hormone’’ and is active as regulator of energy intake only under conditions of poor availability of nutrients to assure optimally regulated supply. With obesity, the threshold for the physiological activity of leptin on energy intake has been passed, and now other activities of leptin play a more important role than regulating food intake. Leptin has been shown to regulate many other systems than food intake, including, for example, reproduction, bone mass and the hematological systems. A major role is to regulate the activity of the sympathetic nervous system, particularly at elevated levels of leptin. It was found rather soon after the discovery of leptin that the thermogenetic branches were activated by the peptide. Recently, it has been observed that other branches of the sympathetic nervous system are also activated, including those to the hemodynamic system. Most experimental obese models with elevated leptin display hypertension. Blood pressure increases after leptin infusion systemically or intrathecally. Furthermore, genetic manipulation to overproduce leptin is followed by hypertension. There are, however, exceptions. Rats or mice with a defect leptin receptor (lepr) do not become hypertensive in spite of massive elevations of leptin(for review, see Ref. [14]). These data might be interpreted to mean that leptin at high levels induces hypertension via the lepr, but does not regulate the food intake, which is occurring at lower levels of body fat mass and leptin production. One might speculate that the lepr is sensitive to lower levels of leptin in the regulation of food intake, while at higher levels of leptin, the sympathetic nervous system is activated, which is a protective mechanism to prevent further obesity through activation of thermogenesis, whereby the sympathetic branches to blood pressure regulation are also activated, resulting in hypertension. This requires an intact lepr. We have examined this interesting possibility in a population-based study of middleaged men [15] focussing on the associations between blood pressure and the molecular genetic status of the lepr. Several polymorphisms of the lepr gene locus have been reported. We examined the Lys109Arg substitution in exon 4, the Gln223Arg substitution in exon 6 and the Lys656Asn substitution in exon 14 in relation to blood pressure and other variables. The number of men with the latter polymorphism was too few to allow meaningful analyses. Arg 109 homozygotes (9%) had about 10/8 mm Hg lower blood pressure than those with the Lys109Lys allele, the presumably ‘‘wild type’’ normal variant.
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This was more pronounced in homozygotes than heterozygotes and in obese with elevated leptin than in normal weight men. Similarly, lower blood pressures were found with the polymorphism in exon 6 where the Arg 223 homozygotes constituted 26.8%. Men with both of these polymorphisms had 13/10 mm Hg lower blood pressure, which is not only statistically but also clinically significant. These results suggest that polymorphisms in the lepr might protect from the development of hypertension even in obese men with elevated leptin. If there is a functional connection between leptin and blood pressure regulation via the lepr, and if the lepr polymorphisms described above are of functional importance, then one would expect a direct relationship between blood pressure and leptin levels in men with the wild type, normal lepr gene. This is indeed the case because there is a strong correlation between leptin and blood pressure in these men (r: 0.47/0.42, systolic/diastolic, p < 0.0001), remaining after adjustment for the BMI. In contrast, in the men with a polymorphic lepr gene, there is no significant correlation. Taken together these observations indicate the possibility that leptin is of importance for blood pressure regulation only when the lepr gene is normal, and in this case, when leptin levels are elevated in obesity, blood pressure levels increase. If this is a correct interpretation, one would expect a higher frequency of the normal lepr gene in men with hypertension. We therefore selected out the 64 men who had elevated blood pressure according to WHO criteria ( > 140>90 mm Hg). All of these men except one had the normal gene variant of the lepr (Ref. [15] and unpublished). These studies strongly suggest that leptin is involved in blood pressure regulation via the lepr, and seems to depend on the status of the lepr gene. This is probably of particular interest in the common combination of obesity and hypertension and might explain why all obese subjects are not hypertensive. This view of the association between the concomitant activation by stress of the HPA axis and the central sympathetic nervous system, followed by the Metabolic Syndrome and primary hypertension is summarized in Fig. 1.
References [1] J. Brod, V. Fencl, Z. Hejl, J. Jirka, M. Ulrych, General and regional hemodynamic pattern underlying essential hypertension, Clin. Sci. 23 (1962) 339 – 349. [2] P. Lund-Johansen, Hemodynamic alterations in essential hypertension-spontaneous changes and effects of drug therapy: a review, Acta Med. Scand. 603 (1977) (Suppl. 1). [3] P.L. Schnall, J.E. Schwartz, P.A. Landsbergis, K. Warrer, T.G. Pickering, A longitudinal study of job strain and ambulatory blood pressure: results from a three-year follow-up, Psychosom. Med. 60 (1988) 697 – 706. [4] B. Folkow, Psychosocial and central nervous influences in primary hypertension, Circulation 76 (Suppl. 1) (1987) 110 – 119. [5] P. Bjo¨rntorp, Visceral obesity: a civilization syndrome, Obes. Res. 1 (1993) 206 – 222. [6] P. Bjo¨rntorp, G. Holm, R. Rosmond, B. Folkow, Hypertension and the Metabolic Syndrome: closely related central origin? Blood Press. 9 (2000) 71 – 82. [7] L. Landsberg, D.R. Krieger, Obesity, metabolism and the sympathetic nervous system, Am. J. Hypertens. 2 (1989) 125s – 132s. [8] N. Tsutsu, K. Nunoi, T. Koama, R. Nomiyama, M. Iwase, M. Fujishima, Lack of association between blood pressure and insulin in patients with insulinoma, J. Hypertens. 8 (1990) 479 – 482.
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[9] A. Holma¨ng, E. Jennische, P. Bjo¨rntorp, The effects of long-term hyperinsulinemia on insulin sensitivity in rats, Acta Physiol. Scand. 153 (1995) 67 – 73. ˚ . Bengtsson, J. Svensson, M. Dallman, B. McEwen, [10] T. Ljung, G. Holm, P. Friberg, B. Andersson, B.A P. Bjo¨rntorp, The activity of the hypothalamic – pituitary – adrenal axis and the sympathetic nervous system in relation to waist/hip circumference ratio in men, Obes. Res. 8 (2000) 487 – 495. [11] G.P. Chrousos, P.W. Gold, The concept of stress and stress system disorders. Overview of physical and behavioral homeostasis, JAMA 267 (1992) 1244 – 1252. [12] P. Bjo¨rntorp, R. Rosmond, The metabolic syndrome—a neuroendocrine disorder? Br. J. Nutr. 83 (2000) S49 – S57. [13] J.M. Friedman, Leptin, leptin receptors, and the control of body weight, Nutr. Rev. 56 (1998) 38 – 46. [14] W.G. Haynes, D.A. Morgan, S.A. Walsh, A.L. Mark, W.I. Sivitz, Receptor-mediated regional sympathetic nerve activation by leptin, J. Clin. Invest. 100 (1997) 270 – 278. [15] R. Rosmond, Y.C. Chagnon, G. Holm, M. Chagnon, L. Pe´russe, K. Lindell, B. Carlsson, C. Bouchard, P. Bjo¨rntorp, Hypertension in obesity and the leptin receptor gene locus, J. Clin. Endocrinol. Metab. 85 (2000) 3126 – 3131.
Hypertension and the Metabolic Syndrome: closely related central origin? Per Bjo¨rntorp* Department of Heart and Lung Diseases, Sahlgren’s Hospital, University of Go¨teborg, 41345 Go¨teborg, Sweden
Abstract Hypertension is often associated with the metabolic aberrations of the Metabolic Syndrome. Both of these conditions have a background in a hypothalamic arousal, which produces neuroendocrine and autonomic changes in the periphery, which generate the Metabolic Syndrome and primary hypertension. Such arousal is due to various environmental factors, including stressors of various origin. The parallel increase of insulin and blood pressure is probably mostly due to this parallel activation of both the stress axes, but it seems likely that insulin may amplify the arousal of the sympathetic nervous system. A new factor in this interplay seems to be leptin, which when elevated, such as in the obesity of the Metabolic Syndrome, activates the sympathetic nervous system through the leptin receptor. This seems to require a normal leptin receptor gene locus, because when polymorphisms are present, blood pressure does not increase even in the presence of obesity with elevated leptin levels. This might be the explanation as to why all obese subjects are not hypertensive (see schematic summary in Fig. 1). D 2002 Elsevier Science B.V. All rights reserved. Keywords: Hypertension; Metabolic Syndrome; Stress; Insulin; Leptin; Leptin receptor
It is now well established that primary hypertension is originating from central mechanisms, where the sympathetic nervous system is involved. The original observations were made by Brod et al. [1] already in the fifties, showing the hyperkinetic characteristics of these early phases of established hypertension. Lund-Johansen [2] then followed up such subjects and found a development into a stage where circulatory resistance was more prominent, due to adaptations of peripheral resistance vessels. This is what we usually see clinically in patients with essential hypertension. The dependence on environment for this
*
Tel.: +46-31-3421661; fax: +46-31-826540. E-mail address: [email protected] (P. Bjo¨rntorp).
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 2 ) 0 0 6 3 8 - 6
82
P. Bjo¨rntorp / International Congress Series 1241 (2002) 81–86
development has recently been elegantly demonstrated in studies utilising continuous measurements of blood pressure in a prospective design [3]. The other prevailing hypothesis for the development of hypertension is the salt theory, suggesting that increased salt consumption will be followed by elevated blood pressure due to volume expansion. This possibility cannot be discarded, but seems to be applicable only in salt sensitive populations [4]. Essential hypertension is frequently associated with metabolic abnormalities. These include obesity of the central, visceral subtype, insulin resistance with or without impaired glucose tolerance and dyslipidemia, consisting of elevated very low density lipoproteins and low levels of high density lipoproteins. This cluster of symptoms is now called the Metabolic Syndrome. Recent studies have now revealed that the Metabolic Syndrome probably has a central neuroendocrine background [5]. The central feature here seems to be a frequent or chronic activation of the hypothalamic – pituitary – adrenal (HPA) axis with elevated cortisol secretion. Secondarily, the gonadal and growth hormone axes are inhibited, resulting in a relative peripheral deficiency of corresponding hormones. These endocrine perturbations alone and particularly in combinations are able to create the Metabolic Syndrome through essentially known mechanisms. It seems highly likely that the susceptibility to develop this abnormality often rests on a genetic basis and some associated polymorphisms in candidate genes have been disclosed.
1. The association between hypertension and the Metabolic Syndrome There are numerous statistical correlations between hyperinsulinemia, secondary to insulin resistance, and hypertension, although this is not always the case [6]. This has led researchers to examine potential pathogenetic pathways linking these two phenomena. Two major hypotheses have been put forward. One is that insulin facilitates sodium uptake in the kidney and would therefore cause a volume-dependent hypertension. The problem here is, however, that only the first step, sodium uptake elevation, has been demonstrated and the development of hypertension is a supposition. It seems rather unlikely that hypertension will develop with normally regulatory mechanisms for volume control. The other mechanistic possibility seems to be more plausible. Insulin has been shown to activate the sympathetic nervous system [7]. Hyperinsulinemia is a prominent abnormality of the Metabolic Syndrome, and insulin might therefore be considered as the link to hypertension. There are, however, observations that do not fit into this explanatory possibility. Patients with insulinoma are exposed more or less constantly to elevated insulin levels, but do not develop hypertension [8]. Furthermore, rats exposed to only insulin excess, with control of adrenal and sympathetic overactivity, do not develop elevated blood pressure until very late [9]. Such observations suggest that insulin by itself might not be responsible for the development of hypertension. It is, however, still possible that insulin might amplify the hemodynamic effects of elevated sympathetic nervous system activity. Recent information from studies in men provide additional information. When the activities of the HPA axis and the sympathetic nervous system are measured in parallel in
P. Bjo¨rntorp / International Congress Series 1241 (2002) 81–86
83
men with the Metabolic Syndrome, they seem to be activated together, particularly during laboratory stress conditions [10], suggesting parallel activation of both axes. This is a wellknown phenomenon, actually it is difficult to activate one axis without activating the other due to several interconnections at different levels [11]. These studies then suggest strongly that both the HPA axis and the central sympathetic nervous system are tightly interconnected at central levels, and when activated then are responsible for the pathogenesis of primary hypertension and the Metabolic Syndrome. Other information supports this contention because the development of both primary hypertension and the Metabolic Syndrome are both preceded and followed by similar environmental problems. These include psychosocial and socioeconomic handicaps which would be expected to be followed by frequent stress reactions, alcohol and smoking as well as robust associations to depressive and anxiety traits, which are all known to activate both the HPA and sympathetic axes [12]. This, however, does not provide information on the potential role of insulin, as mentioned above. Statistical examinations on a population basis are of interest for this question. In a population-based study of men, all 52 years of age, blood pressure correlated strongly in bivariate analyses with various components of the Metabolic Syndrome, including insulin and the insulin/glucose ratio and with cortisol measurements, mirroring the activity of the HPA axis. When multiple correlations were performed, the only remaining factor of those mentioned, which remained associated with blood pressure, was the cortisol measurements. Taken together these observations indicate that the both stress axes, the HPA axis and the sympathetic nervous system, are activated simultaneously, and that the Metabolic
Fig. 1. The synergism between the hypothalamic – pituitary – adrenal (HPA) axis and the central sympathetic nervous system (n.s.) in the generation of primary hypertension and the metabolic syndrome. Stress activates the HPA axis and the sympathetic nervous system. Central obesity, insulin resistance (metabolic syndrome) will be the consequence of HPA axis activation, and hypertension the consequence of sympathetic nervous system activation. The latter is amplified by leptin and insulin.
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P. Bjo¨rntorp / International Congress Series 1241 (2002) 81–86
Syndrome emanates from the HPA axis and the hypertension from the sympathetic nervous system. This would explain the close statistical associations. It seems possible that insulin may be involved in the blood pressure elevation by amplifying the activation of the sympathetic nervous system (see Fig. 1).
2. The involvement of leptin Obesity is an important part of the Metabolic Syndrome, particularly when the obesity is localised to central regions. Leptin is a newly discovered peptide, secreted mainly for adipose tissue [13]. Leptin signals satiety to centers in the hypothalamic area via a specific receptor. Leptin secretion is elevated in obesity, which is a somewhat surprising finding, because with elevated leptin, food intake would be expected to be diminished. The term leptin-resistant obesity has therefore been coined. It seems possible that leptin is more of a ‘‘starvation hormone’’ than a ‘‘satiety hormone’’ and is active as regulator of energy intake only under conditions of poor availability of nutrients to assure optimally regulated supply. With obesity, the threshold for the physiological activity of leptin on energy intake has been passed, and now other activities of leptin play a more important role than regulating food intake. Leptin has been shown to regulate many other systems than food intake, including, for example, reproduction, bone mass and the hematological systems. A major role is to regulate the activity of the sympathetic nervous system, particularly at elevated levels of leptin. It was found rather soon after the discovery of leptin that the thermogenetic branches were activated by the peptide. Recently, it has been observed that other branches of the sympathetic nervous system are also activated, including those to the hemodynamic system. Most experimental obese models with elevated leptin display hypertension. Blood pressure increases after leptin infusion systemically or intrathecally. Furthermore, genetic manipulation to overproduce leptin is followed by hypertension. There are, however, exceptions. Rats or mice with a defect leptin receptor (lepr) do not become hypertensive in spite of massive elevations of leptin(for review, see Ref. [14]). These data might be interpreted to mean that leptin at high levels induces hypertension via the lepr, but does not regulate the food intake, which is occurring at lower levels of body fat mass and leptin production. One might speculate that the lepr is sensitive to lower levels of leptin in the regulation of food intake, while at higher levels of leptin, the sympathetic nervous system is activated, which is a protective mechanism to prevent further obesity through activation of thermogenesis, whereby the sympathetic branches to blood pressure regulation are also activated, resulting in hypertension. This requires an intact lepr. We have examined this interesting possibility in a population-based study of middleaged men [15] focussing on the associations between blood pressure and the molecular genetic status of the lepr. Several polymorphisms of the lepr gene locus have been reported. We examined the Lys109Arg substitution in exon 4, the Gln223Arg substitution in exon 6 and the Lys656Asn substitution in exon 14 in relation to blood pressure and other variables. The number of men with the latter polymorphism was too few to allow meaningful analyses. Arg 109 homozygotes (9%) had about 10/8 mm Hg lower blood pressure than those with the Lys109Lys allele, the presumably ‘‘wild type’’ normal variant.
P. Bjo¨rntorp / International Congress Series 1241 (2002) 81–86
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This was more pronounced in homozygotes than heterozygotes and in obese with elevated leptin than in normal weight men. Similarly, lower blood pressures were found with the polymorphism in exon 6 where the Arg 223 homozygotes constituted 26.8%. Men with both of these polymorphisms had 13/10 mm Hg lower blood pressure, which is not only statistically but also clinically significant. These results suggest that polymorphisms in the lepr might protect from the development of hypertension even in obese men with elevated leptin. If there is a functional connection between leptin and blood pressure regulation via the lepr, and if the lepr polymorphisms described above are of functional importance, then one would expect a direct relationship between blood pressure and leptin levels in men with the wild type, normal lepr gene. This is indeed the case because there is a strong correlation between leptin and blood pressure in these men (r: 0.47/0.42, systolic/diastolic, p < 0.0001), remaining after adjustment for the BMI. In contrast, in the men with a polymorphic lepr gene, there is no significant correlation. Taken together these observations indicate the possibility that leptin is of importance for blood pressure regulation only when the lepr gene is normal, and in this case, when leptin levels are elevated in obesity, blood pressure levels increase. If this is a correct interpretation, one would expect a higher frequency of the normal lepr gene in men with hypertension. We therefore selected out the 64 men who had elevated blood pressure according to WHO criteria ( > 140>90 mm Hg). All of these men except one had the normal gene variant of the lepr (Ref. [15] and unpublished). These studies strongly suggest that leptin is involved in blood pressure regulation via the lepr, and seems to depend on the status of the lepr gene. This is probably of particular interest in the common combination of obesity and hypertension and might explain why all obese subjects are not hypertensive. This view of the association between the concomitant activation by stress of the HPA axis and the central sympathetic nervous system, followed by the Metabolic Syndrome and primary hypertension is summarized in Fig. 1.
References [1] J. Brod, V. Fencl, Z. Hejl, J. Jirka, M. Ulrych, General and regional hemodynamic pattern underlying essential hypertension, Clin. Sci. 23 (1962) 339 – 349. [2] P. Lund-Johansen, Hemodynamic alterations in essential hypertension-spontaneous changes and effects of drug therapy: a review, Acta Med. Scand. 603 (1977) (Suppl. 1). [3] P.L. Schnall, J.E. Schwartz, P.A. Landsbergis, K. Warrer, T.G. Pickering, A longitudinal study of job strain and ambulatory blood pressure: results from a three-year follow-up, Psychosom. Med. 60 (1988) 697 – 706. [4] B. Folkow, Psychosocial and central nervous influences in primary hypertension, Circulation 76 (Suppl. 1) (1987) 110 – 119. [5] P. Bjo¨rntorp, Visceral obesity: a civilization syndrome, Obes. Res. 1 (1993) 206 – 222. [6] P. Bjo¨rntorp, G. Holm, R. Rosmond, B. Folkow, Hypertension and the Metabolic Syndrome: closely related central origin? Blood Press. 9 (2000) 71 – 82. [7] L. Landsberg, D.R. Krieger, Obesity, metabolism and the sympathetic nervous system, Am. J. Hypertens. 2 (1989) 125s – 132s. [8] N. Tsutsu, K. Nunoi, T. Koama, R. Nomiyama, M. Iwase, M. Fujishima, Lack of association between blood pressure and insulin in patients with insulinoma, J. Hypertens. 8 (1990) 479 – 482.
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P. Bjo¨rntorp / International Congress Series 1241 (2002) 81–86
[9] A. Holma¨ng, E. Jennische, P. Bjo¨rntorp, The effects of long-term hyperinsulinemia on insulin sensitivity in rats, Acta Physiol. Scand. 153 (1995) 67 – 73. ˚ . Bengtsson, J. Svensson, M. Dallman, B. McEwen, [10] T. Ljung, G. Holm, P. Friberg, B. Andersson, B.A P. Bjo¨rntorp, The activity of the hypothalamic – pituitary – adrenal axis and the sympathetic nervous system in relation to waist/hip circumference ratio in men, Obes. Res. 8 (2000) 487 – 495. [11] G.P. Chrousos, P.W. Gold, The concept of stress and stress system disorders. Overview of physical and behavioral homeostasis, JAMA 267 (1992) 1244 – 1252. [12] P. Bjo¨rntorp, R. Rosmond, The metabolic syndrome—a neuroendocrine disorder? Br. J. Nutr. 83 (2000) S49 – S57. [13] J.M. Friedman, Leptin, leptin receptors, and the control of body weight, Nutr. Rev. 56 (1998) 38 – 46. [14] W.G. Haynes, D.A. Morgan, S.A. Walsh, A.L. Mark, W.I. Sivitz, Receptor-mediated regional sympathetic nerve activation by leptin, J. Clin. Invest. 100 (1997) 270 – 278. [15] R. Rosmond, Y.C. Chagnon, G. Holm, M. Chagnon, L. Pe´russe, K. Lindell, B. Carlsson, C. Bouchard, P. Bjo¨rntorp, Hypertension in obesity and the leptin receptor gene locus, J. Clin. Endocrinol. Metab. 85 (2000) 3126 – 3131.