Special Section: Molecular Genetics and Genetic Epidemiology of Cardiovascular Disease and Diabetes
Abdominal Obesity and the Metabolic Syndrome
Ann Med Downloaded from informahealthcare.com by University of Chicago Library on 06/05/12 For personal use only.
Per Bjorntorp
Abdominal obesity in man is an integrated part of the Metabolic Syndrome, and is associated with a complex neuroendocrine disturbance. Its consequences for the metabolism of the periphery seems to be insulin resistance caused by a combination of a relative hypercortisolaemia and a relative deficiency of sex steroid hormones. This hormonal aberration, in combination with a relative insufficiency of growth hormone secretion, might also direct depot triglycerides to visceral adipose tissues, a consequence at least partly due to varying densities of the specific receptors for these hormones. Visceral fat accumulation may thus be a consequence of the neuroendocrine aberrations, and may amplify the metabolic symptoms via effects on the liver of free fatty acids released in abundance from the lipolytically sensitive enlarged visceral fat depots. The origin of the neuroendocrine disturbance is not known, but epidemiological and cross-sectional information suggest that psychosocial factors are intimately involved. Animal and human studies indicate that the mediating factor(s) may be stresssensitivity, leading to the neuroendocrine consequences observed. Key words: abdominal obesity; metabolic syndrome; cortisol; testosterone; growth hormone; free fatty acids. (Annals of Medicine 24: 465468,1992)
Introduction Clinicians have been aware for some time that a group of diseases and symptoms of mainly metabolic origin are often found together. These diseases include cardiocerebrovascular disease and non-insulin-dependent diabetes mellitus. Associates or statistical predictors (‘risk factors’) for these diseases are to a large extent common, and include hypertension, dyslipidaemias and insulin resistance with hyperinsulinaemia. Internists and cardiologists know by clinical experience that a patient with myocardial infarction often also suffers from noninsulin-dependent diabetes mellitus or its precursor conditions, impaired glucose tolerance with insulin resistance, as well as lipid metabolism disorders and elevated blood pressure. Similarly, patients with diabetes are at an increased risk of developing circulatory
From the Department of Heart and Lung Diseases, Sahlgren’s Hospital, Goteborg,Sweden. Address and reprint requests: P. Bjorntorp, M.D., Department of Heart and Lung Diseases, Sahlgren’s Hospital, University of Goteborg, S-41345 Goteborg,Sweden.
catastrophes, and exhibit in many cases the metabolic derangements mentioned. Insulin resistance may be a central derangement in this syndrome. It is well known that the most common condition with insulin resistance and hyperinsulinaemia is obesity, and obesity is also an established risk factor for diabetes. The relationship is weaker, however, between obesity and cardiovascular disease and has been much debated. This question was recently made clearer when it was found that the metabolic cluster of diseases and their risk factors are more closely associated with abdominal obesity, a subgroup of human obesity, than with peripherally localized obesity. This is also true of cardiovascular disease, in which abdominally localized obesity is consistently a risk factor in both men and women. The epidemiology of this area has recently been reviewed in this journal, and the reader is referred to this overview for detailed references (1).
Abdominal Obesity and the Metabolic Syndrome discussion of the cluster of diseases and their risk factors should probably include abdominal obesity. The
Ann Med Downloaded from informahealthcare.com by University of Chicago Library on 06/05/12 For personal use only.
466
Bjorntorp
basis for this statement is found in the arguments of the preceding section, but also in a recent statistical analysis of an epidemiological study of women in Gothenburg, Sweden. The problem was analysed by dividing the cohort of women into quintiles of the waist-hip circumference ratio as well as quintiles of the body mass index. The ratio is an index of central (high ratio) or peripheral (low ratio) distribution of adipose tissue, while the body mass index (weight, kg/height2,m2) is a measurement of generalized obesity, or total fat mass, irrespective of its localization. The distribution of the metabolic risk factors triglycerides, insulin, blood glucose and plasma insulin was then analysed in the quintiles of the waist/hip ratio and body mass index or several of these risk factors (defined as above mean plus 1 or 2 SD of the values of the total population) were found with increasing prevalence in the highest quintiles of waistlhip ratio or body mass index. When both were taken into account the picture became even clearer, and all women with risk factors were found in a combination of the upper quintiles of waist/hip ratio as well as of body mass index (2). The analysis strongly suggests that abdominal obesity is an integral part of the metabolic cluster of symptoms and diseases in question. This is in agreement with the finding that the waist/hip ratio is a powerful risk factor for cardiovascular disease, stroke and diabetes (1). This syndrome has recently been labelled ‘Syndrome X’, ’The Deadly-Quartet’ or ‘The Metabolic Syndrome’. The latter name seems to be preferable because it covers the description of the condition most adequately.
Pathogenetic Considerations Neuroendocrine Dysregulations: Consequences for Insulin-Sensitivity As reviewed above there is now statistical documentation of associations between abdominal obesity and the Metabolic Syndrome. The question then remains whether there is a cause-effect relationship or whether these are only coincidental findings. We believe now that multiple neuroendocrine dysregulation is an early pathogenetic factor for this syndrome. This consists of aberrations along several hypothalamo- peripheral axes, including the adrenals and gonads as well as growth hormone secretion. There are also signs of abnormal central regulation of haemodynamics. The syndrome seems to be associated with an increased sensitivity of the corticotrophin-releasing factor-cortisol axis, found as an increased cortisol secretion after stimuli at different levels of this axis, from the central nervous system to the adrenals (3). The consequence will be a relative hypercortisolism in subjects with abdominal obesity. The analogy with Cushing’s syndrome is clearly apparent, a condition with not only hypercortisolism,but also the full Metabolic Syndrome as well as a dramatic visceral obesity. In subjects with abdominal obesity the endocrine and metabolic de‘rangements are thus identical to Cushing’s syndrome, although less pronounced. The disturbances along the gonadotrophin axis are different in men and women with this syndrome. In men a
relative hypogonadism is found, with lower than normal testosterone (T) values. An analogous finding in women may be an irregular or absent ovulation, and an associated deficiency in progesterone production. In addition, women with this syndrome are hyperandrogenic. Both the hypogonadism in men and the hyperandrogenicity in women may be contributing to their insulin resistance because T is directly regulating muscle insulin sensitivity in males. However,when the concentrations of T are too high they cause insulin resistance in both sexes. Both the cortisol and sex hormone aberrations are thus followed by a marked insulin resistance, localized mainly to muscle. The exact locus for its expression is not revealed, whether at the levels of the insulin receptor, the glucose transporters, or a post-receptor site. The glycogen synthase system seems to be one likely candidate. This problem is currently being studied.
Consequences for Depot Fat Distribution The endocrine disturbances mentioned above may also cause accumulation of depot fat in visceral adipose tissue depots, the cardinal sign of abdominal obesity. To start again with cortisol, the analogy with Cushing’s syndrome was mentioned above. Cortisol expresses lipoprotein lipase by interaction with its gene via a glucocorticoid receptor-cortisol complex. There may also be additional post-translational effects on enzyme stability (Ottosson et al, unpublished). In Cushing’s syndrome lipid mobilization seems to be less efficient in the abdominal region, but the mechanism here is not known (4).
Since the visceral fat depots might have a higher density of glucocorticoid receptors, these perturbations would be more pronounced in this particular adipose tissue region, explaining why cortisol excess is followed by visceral fat accumulation. The sex steroid hormones seem to modify the net effect of cortisol. Progesterone competes with the glucocorticoid receptor, and may therefore protect from cortisol effects on visceral fat. This might explain the scarcity of visceral fat in young women. The female sex steroid hormones probably have additional effects not yet revealed. T has a number of interesting effects of adipocyte metabolism (5). Via a specific androgen receptor, which is upregulated in density by testosterone, the lipolytic machinery becomes sensitized by expression of lipolytic P-adrenergic receptors, probably an effect of androgen receptor-testosteroneinteraction at the gene level. The coupling proteins do not seem to be affected (Xu, unpublished). In addition, testosterone inhibits the expression of lipoprotein lipase via a hitherto unknown mechanism. The net effect of this is a combination of effects which tend to empty fat depots from triglycerides, particularly those which are specifically sensitive to testosterone. The visceral depots have these characteristics, because they decrease specifically in mass after testosterone treatment of abdominal obese men after appropriate adaptation of mechanisms for lipid accumulation and mobilization (5, 6).
Ann Med Downloaded from informahealthcare.com by University of Chicago Library on 06/05/12 For personal use only.
Abdominal Obesity and Metabolism Growth hormone interacts with these steroid hormone effects at different levels. First, the cortisol-induction of lipoprotein lipase is markedly inhibited. Furthermore, the testosterone effects are amplified by the presence of growth hormone. Indeed, neither testosterone nor growth hormone seem to exert any effects on lipolysis alone; combination of the hormones seems to be necessary (Xu, unpublished observations). The growth hormone effects seen so far have thus been to inhibit the cortisol expression of the major enzyme responsible for fat accumulation, lipoprotein lipase, and to facilitate or amplify the inhibitory effects of testosterone on lipoprotein lipase, in combination with an enhancing effect on the lipolysis-promoting effect of testosterone. Growth hormone is thus apparently a hormone preventing triglyceride accumulation and facilitating mobilization. Experiments where growth hormone substitution has been given to growth hormone-deficient adults show a specific diminution of enlarged visceral depots, suggesting that the effects of growth hormone are also specifically directed towards visceral depots (7). There is thus apparently a complex interaction between corticosteroid and sex steroid hormones with growth hormone, resulting in specific localization of triglycerides in central or peripheral depots. In summary, it seems that cortisol excess and a relative deficiency of sex steroid hormones, and/or growth hormone deficiency result in visceral fat accumulation. This is compatible with the interpretation that the increased cortisol secretion in combination with a deficiency of sex steroid hormone and growth hormone secretions seen in abdominal obesity are actually causing the accumulation of visceral fat in that condition. Intervention studies with testosterone or growth hormone strongly support this interpretation. There are probably also other regulatory factors. The hormonal regulation of adipocyte metabolism modifies the density of appropriate receptors as well as the expression of key enzymes. However, the regulation of transport of substrate to the cells as well as removal of mobilized free fatty acids and glycerol are of fundamental importance in determining the triglyceride content of an adipose depot. For example, lipoprotein lipase seldom works in vivo at maximal activity, as determined under zero order kinetics in enzyme assays. Furthermore, retained free fatty acids inhibit the lipolytic machinery by feed-back mechanisms. The regulation of triglyceride and free fatty acids concentrations in the vicinity of the adipocyte therefore becomes of considerable importance for the triglyceride accumulation or mobilization. Unfortunately, this area has attracted only limited attention as yet, particularly as far as the regulation of regional distribution of body fat. Another important factor is the innervation of adipose tissue. The density of adrenergic receptors does not regulate lipolysis by itself, but the delivery of catecholamines as transmitter substances from nerve terminals is of fundamental importance for regulation of regional mobilization of triglycerides. Again, our current knowledge of such factors in the regulation of regional distribution of depot fat is incomplete. These areas of research require more attention, particularly since the
467
results of cellular studies in vitro may lead to misinterpretations for the complex integrated system present in the living body.
Consequences of Visceral Fat Accumulation The accumulation of visceral fat may lead to untoward secondary consequences. The high lipolytic sensitivity and potential of enlarged visceral adipose tissues to release free fatty acids may lead to increased concentrations of portal free fatty acids. This in turn may have several consequences for hepatic metabolism of glucose, lipoproteins and insulin. The net result, in brief, might well be a tendency towards hyperglycaemia, hyperinsulinaemia and hyperlipidaemia. all risk factors for diabetes and cardiovascular disease, together constituting the Metabolic Syndrome (8).
Synthesis of Suggested Mechanisms As briefly reviewed above there are probably multiple neuroendocrine disturbances in abdominal obesity in man. Available information is compatible with the interpretation that this is followed by both insulin resistance and visceral fat accumulation. Both these consequences may in fact develop and amplify the Metabolic Syndrome and generate risk factors for NIDDM and cardiovascular disease (9).
Origin of the Neuroendocrine Disturbances With the background provided above, the cause of the neuroendocrine aberrations (which apparently may have several metabolic consequences) becomes of primary interest. The neuroendocrine axes involved thus seem to be the hypothalamic links with the adrenals, the gonads, the sympathetic nervous system and growth hormone. These axes are known to be involved in hypothalamic arousal syndromes exhibited by physical and mental stressors. This has been well described in the results of animal research (10) and may well pertain to the human situation as well. For example, the response to stress leads to metabolic, hormonal and circulatory adaptations which are characteristic either of the so called fight-flight reaction, or of a defeat reaction, or a mixture of both (1 0). The defeat reaction seems to be of particular interest in this regard with its increased cortisol secretion and decreased sex hormone secretion, both found in abdominal obesity. Studies of psychosocial factors in relation to body fat distribution suggest that subjects with abdominal fat distribution may be subjected to stress factors of this type. Recent studies in controlled animal experiments indicate that this assumption may indeed be correct. Monkeys stressed in psychosocial situations leading to a defeat type of reaction develop a neuroendocrine response of a similar type to that found in abdominally obese humans. They also show a full picture of the Metabolic Syndrome, with insulin resistance, decreased glucose tolerance, hyperlipidaemia and
468
Bjorntorp
hypertension, followed in turn by coronary atherosclerosis. In addition, visceral fat accumulates (C. Shively, personal communication, 1992). This then seems to be an identical situation to that found in abdominal obesity in man, including symptoms in anthropometry, endocrinology and metabolism. By analogy it may be suggested that the human syndrome is caused by similar mechanisms, namely a hypothalamic arousal syndrome leading to neuroendocrine aberrations, elicited by stress factors. The information currently available is compatible with such an interpretation, as suggested and reviewed previously (1 1, 12).
Ann Med Downloaded from informahealthcare.com by University of Chicago Library on 06/05/12 For personal use only.
References Bjorntorp P. Abdominal fat distribution and disease: An overview of epidemiological data. Ann Med 1992; 24: 15-1 8. Bjorntorp P, Lapidus L. The relationship between ‘The Metabolic Syndrome’ and abdominal obesity in women. 1992 (in press). Marin P, Darin N, Amemiya T, Andersson B, Jern S, Bjorntorp P. Cortisol secretion in relation to body fat distribution in obese premenopausal women. Metabolism, 1992; 41: 882-6.
4. Rebuffe-Scrive M, Krotkiewski M, Elfverson J, Bjorntorp P. Muscle and adipose tissue morphology and metabolism in Cushing’s syndrome. J Clm Endocrinol Metab 1988; 67, 1122-5. 5. Bjorntorp P. Adipose tissue distribution and function. lnt J Obes 1991; 15: 67-81. 6. Bjorntorp P, Ottosson M, Rebuffe-Scrive M, Xu X. Regional obesity and steroid hormone interactions in human adipose tissue. In: Bray GA, Ricquier D,Spiegelman B, eds. Obesity: towards a molecular approach. UCLA Symposia on Molecular and Cellular Biology. New York: Wiley-Liss, 132; 1990: 147-57. 7. Bengtsson B-A, Eden S, Lonn L, et al. Treatment of adults with growth hormone deficiency with recombinant human growth hormone. 1992 (in press) 8. Bjorntorp P. ‘Portal’ adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 1990; 10: 493-6. 9. Bjorntorp P. Metabolic abnormalities in visceral obesity. Ann Med 1992; 24: 3-5. 10. Henry J, Grim CE. Psychosocial mechanisms in primary hypertension. J Hypertens 1990; 8: 783-9. 11. Bjorntorp P. Psychosocial factors and fat distribution. In: Ailhaud G, Guy-Grand B, Lafontan M, Ricquier D, eds. Obesity in Europe. Proc. 3rd European Congress on Obesity. London: Libbey, 1992: 377-87. 12. Bjorntorp P. Visceral fat accumulation: the missing link between psychosocial factors and cardiovascular disease? J lnt Med 1991; 230: 195-291.
Abdominal Obesity and the Metabolic Syndrome
Ann Med Downloaded from informahealthcare.com by University of Chicago Library on 06/05/12 For personal use only.
Per Bjorntorp
Abdominal obesity in man is an integrated part of the Metabolic Syndrome, and is associated with a complex neuroendocrine disturbance. Its consequences for the metabolism of the periphery seems to be insulin resistance caused by a combination of a relative hypercortisolaemia and a relative deficiency of sex steroid hormones. This hormonal aberration, in combination with a relative insufficiency of growth hormone secretion, might also direct depot triglycerides to visceral adipose tissues, a consequence at least partly due to varying densities of the specific receptors for these hormones. Visceral fat accumulation may thus be a consequence of the neuroendocrine aberrations, and may amplify the metabolic symptoms via effects on the liver of free fatty acids released in abundance from the lipolytically sensitive enlarged visceral fat depots. The origin of the neuroendocrine disturbance is not known, but epidemiological and cross-sectional information suggest that psychosocial factors are intimately involved. Animal and human studies indicate that the mediating factor(s) may be stresssensitivity, leading to the neuroendocrine consequences observed. Key words: abdominal obesity; metabolic syndrome; cortisol; testosterone; growth hormone; free fatty acids. (Annals of Medicine 24: 465468,1992)
Introduction Clinicians have been aware for some time that a group of diseases and symptoms of mainly metabolic origin are often found together. These diseases include cardiocerebrovascular disease and non-insulin-dependent diabetes mellitus. Associates or statistical predictors (‘risk factors’) for these diseases are to a large extent common, and include hypertension, dyslipidaemias and insulin resistance with hyperinsulinaemia. Internists and cardiologists know by clinical experience that a patient with myocardial infarction often also suffers from noninsulin-dependent diabetes mellitus or its precursor conditions, impaired glucose tolerance with insulin resistance, as well as lipid metabolism disorders and elevated blood pressure. Similarly, patients with diabetes are at an increased risk of developing circulatory
From the Department of Heart and Lung Diseases, Sahlgren’s Hospital, Goteborg,Sweden. Address and reprint requests: P. Bjorntorp, M.D., Department of Heart and Lung Diseases, Sahlgren’s Hospital, University of Goteborg, S-41345 Goteborg,Sweden.
catastrophes, and exhibit in many cases the metabolic derangements mentioned. Insulin resistance may be a central derangement in this syndrome. It is well known that the most common condition with insulin resistance and hyperinsulinaemia is obesity, and obesity is also an established risk factor for diabetes. The relationship is weaker, however, between obesity and cardiovascular disease and has been much debated. This question was recently made clearer when it was found that the metabolic cluster of diseases and their risk factors are more closely associated with abdominal obesity, a subgroup of human obesity, than with peripherally localized obesity. This is also true of cardiovascular disease, in which abdominally localized obesity is consistently a risk factor in both men and women. The epidemiology of this area has recently been reviewed in this journal, and the reader is referred to this overview for detailed references (1).
Abdominal Obesity and the Metabolic Syndrome discussion of the cluster of diseases and their risk factors should probably include abdominal obesity. The
Ann Med Downloaded from informahealthcare.com by University of Chicago Library on 06/05/12 For personal use only.
466
Bjorntorp
basis for this statement is found in the arguments of the preceding section, but also in a recent statistical analysis of an epidemiological study of women in Gothenburg, Sweden. The problem was analysed by dividing the cohort of women into quintiles of the waist-hip circumference ratio as well as quintiles of the body mass index. The ratio is an index of central (high ratio) or peripheral (low ratio) distribution of adipose tissue, while the body mass index (weight, kg/height2,m2) is a measurement of generalized obesity, or total fat mass, irrespective of its localization. The distribution of the metabolic risk factors triglycerides, insulin, blood glucose and plasma insulin was then analysed in the quintiles of the waist/hip ratio and body mass index or several of these risk factors (defined as above mean plus 1 or 2 SD of the values of the total population) were found with increasing prevalence in the highest quintiles of waistlhip ratio or body mass index. When both were taken into account the picture became even clearer, and all women with risk factors were found in a combination of the upper quintiles of waist/hip ratio as well as of body mass index (2). The analysis strongly suggests that abdominal obesity is an integral part of the metabolic cluster of symptoms and diseases in question. This is in agreement with the finding that the waist/hip ratio is a powerful risk factor for cardiovascular disease, stroke and diabetes (1). This syndrome has recently been labelled ‘Syndrome X’, ’The Deadly-Quartet’ or ‘The Metabolic Syndrome’. The latter name seems to be preferable because it covers the description of the condition most adequately.
Pathogenetic Considerations Neuroendocrine Dysregulations: Consequences for Insulin-Sensitivity As reviewed above there is now statistical documentation of associations between abdominal obesity and the Metabolic Syndrome. The question then remains whether there is a cause-effect relationship or whether these are only coincidental findings. We believe now that multiple neuroendocrine dysregulation is an early pathogenetic factor for this syndrome. This consists of aberrations along several hypothalamo- peripheral axes, including the adrenals and gonads as well as growth hormone secretion. There are also signs of abnormal central regulation of haemodynamics. The syndrome seems to be associated with an increased sensitivity of the corticotrophin-releasing factor-cortisol axis, found as an increased cortisol secretion after stimuli at different levels of this axis, from the central nervous system to the adrenals (3). The consequence will be a relative hypercortisolism in subjects with abdominal obesity. The analogy with Cushing’s syndrome is clearly apparent, a condition with not only hypercortisolism,but also the full Metabolic Syndrome as well as a dramatic visceral obesity. In subjects with abdominal obesity the endocrine and metabolic de‘rangements are thus identical to Cushing’s syndrome, although less pronounced. The disturbances along the gonadotrophin axis are different in men and women with this syndrome. In men a
relative hypogonadism is found, with lower than normal testosterone (T) values. An analogous finding in women may be an irregular or absent ovulation, and an associated deficiency in progesterone production. In addition, women with this syndrome are hyperandrogenic. Both the hypogonadism in men and the hyperandrogenicity in women may be contributing to their insulin resistance because T is directly regulating muscle insulin sensitivity in males. However,when the concentrations of T are too high they cause insulin resistance in both sexes. Both the cortisol and sex hormone aberrations are thus followed by a marked insulin resistance, localized mainly to muscle. The exact locus for its expression is not revealed, whether at the levels of the insulin receptor, the glucose transporters, or a post-receptor site. The glycogen synthase system seems to be one likely candidate. This problem is currently being studied.
Consequences for Depot Fat Distribution The endocrine disturbances mentioned above may also cause accumulation of depot fat in visceral adipose tissue depots, the cardinal sign of abdominal obesity. To start again with cortisol, the analogy with Cushing’s syndrome was mentioned above. Cortisol expresses lipoprotein lipase by interaction with its gene via a glucocorticoid receptor-cortisol complex. There may also be additional post-translational effects on enzyme stability (Ottosson et al, unpublished). In Cushing’s syndrome lipid mobilization seems to be less efficient in the abdominal region, but the mechanism here is not known (4).
Since the visceral fat depots might have a higher density of glucocorticoid receptors, these perturbations would be more pronounced in this particular adipose tissue region, explaining why cortisol excess is followed by visceral fat accumulation. The sex steroid hormones seem to modify the net effect of cortisol. Progesterone competes with the glucocorticoid receptor, and may therefore protect from cortisol effects on visceral fat. This might explain the scarcity of visceral fat in young women. The female sex steroid hormones probably have additional effects not yet revealed. T has a number of interesting effects of adipocyte metabolism (5). Via a specific androgen receptor, which is upregulated in density by testosterone, the lipolytic machinery becomes sensitized by expression of lipolytic P-adrenergic receptors, probably an effect of androgen receptor-testosteroneinteraction at the gene level. The coupling proteins do not seem to be affected (Xu, unpublished). In addition, testosterone inhibits the expression of lipoprotein lipase via a hitherto unknown mechanism. The net effect of this is a combination of effects which tend to empty fat depots from triglycerides, particularly those which are specifically sensitive to testosterone. The visceral depots have these characteristics, because they decrease specifically in mass after testosterone treatment of abdominal obese men after appropriate adaptation of mechanisms for lipid accumulation and mobilization (5, 6).
Ann Med Downloaded from informahealthcare.com by University of Chicago Library on 06/05/12 For personal use only.
Abdominal Obesity and Metabolism Growth hormone interacts with these steroid hormone effects at different levels. First, the cortisol-induction of lipoprotein lipase is markedly inhibited. Furthermore, the testosterone effects are amplified by the presence of growth hormone. Indeed, neither testosterone nor growth hormone seem to exert any effects on lipolysis alone; combination of the hormones seems to be necessary (Xu, unpublished observations). The growth hormone effects seen so far have thus been to inhibit the cortisol expression of the major enzyme responsible for fat accumulation, lipoprotein lipase, and to facilitate or amplify the inhibitory effects of testosterone on lipoprotein lipase, in combination with an enhancing effect on the lipolysis-promoting effect of testosterone. Growth hormone is thus apparently a hormone preventing triglyceride accumulation and facilitating mobilization. Experiments where growth hormone substitution has been given to growth hormone-deficient adults show a specific diminution of enlarged visceral depots, suggesting that the effects of growth hormone are also specifically directed towards visceral depots (7). There is thus apparently a complex interaction between corticosteroid and sex steroid hormones with growth hormone, resulting in specific localization of triglycerides in central or peripheral depots. In summary, it seems that cortisol excess and a relative deficiency of sex steroid hormones, and/or growth hormone deficiency result in visceral fat accumulation. This is compatible with the interpretation that the increased cortisol secretion in combination with a deficiency of sex steroid hormone and growth hormone secretions seen in abdominal obesity are actually causing the accumulation of visceral fat in that condition. Intervention studies with testosterone or growth hormone strongly support this interpretation. There are probably also other regulatory factors. The hormonal regulation of adipocyte metabolism modifies the density of appropriate receptors as well as the expression of key enzymes. However, the regulation of transport of substrate to the cells as well as removal of mobilized free fatty acids and glycerol are of fundamental importance in determining the triglyceride content of an adipose depot. For example, lipoprotein lipase seldom works in vivo at maximal activity, as determined under zero order kinetics in enzyme assays. Furthermore, retained free fatty acids inhibit the lipolytic machinery by feed-back mechanisms. The regulation of triglyceride and free fatty acids concentrations in the vicinity of the adipocyte therefore becomes of considerable importance for the triglyceride accumulation or mobilization. Unfortunately, this area has attracted only limited attention as yet, particularly as far as the regulation of regional distribution of body fat. Another important factor is the innervation of adipose tissue. The density of adrenergic receptors does not regulate lipolysis by itself, but the delivery of catecholamines as transmitter substances from nerve terminals is of fundamental importance for regulation of regional mobilization of triglycerides. Again, our current knowledge of such factors in the regulation of regional distribution of depot fat is incomplete. These areas of research require more attention, particularly since the
467
results of cellular studies in vitro may lead to misinterpretations for the complex integrated system present in the living body.
Consequences of Visceral Fat Accumulation The accumulation of visceral fat may lead to untoward secondary consequences. The high lipolytic sensitivity and potential of enlarged visceral adipose tissues to release free fatty acids may lead to increased concentrations of portal free fatty acids. This in turn may have several consequences for hepatic metabolism of glucose, lipoproteins and insulin. The net result, in brief, might well be a tendency towards hyperglycaemia, hyperinsulinaemia and hyperlipidaemia. all risk factors for diabetes and cardiovascular disease, together constituting the Metabolic Syndrome (8).
Synthesis of Suggested Mechanisms As briefly reviewed above there are probably multiple neuroendocrine disturbances in abdominal obesity in man. Available information is compatible with the interpretation that this is followed by both insulin resistance and visceral fat accumulation. Both these consequences may in fact develop and amplify the Metabolic Syndrome and generate risk factors for NIDDM and cardiovascular disease (9).
Origin of the Neuroendocrine Disturbances With the background provided above, the cause of the neuroendocrine aberrations (which apparently may have several metabolic consequences) becomes of primary interest. The neuroendocrine axes involved thus seem to be the hypothalamic links with the adrenals, the gonads, the sympathetic nervous system and growth hormone. These axes are known to be involved in hypothalamic arousal syndromes exhibited by physical and mental stressors. This has been well described in the results of animal research (10) and may well pertain to the human situation as well. For example, the response to stress leads to metabolic, hormonal and circulatory adaptations which are characteristic either of the so called fight-flight reaction, or of a defeat reaction, or a mixture of both (1 0). The defeat reaction seems to be of particular interest in this regard with its increased cortisol secretion and decreased sex hormone secretion, both found in abdominal obesity. Studies of psychosocial factors in relation to body fat distribution suggest that subjects with abdominal fat distribution may be subjected to stress factors of this type. Recent studies in controlled animal experiments indicate that this assumption may indeed be correct. Monkeys stressed in psychosocial situations leading to a defeat type of reaction develop a neuroendocrine response of a similar type to that found in abdominally obese humans. They also show a full picture of the Metabolic Syndrome, with insulin resistance, decreased glucose tolerance, hyperlipidaemia and
468
Bjorntorp
hypertension, followed in turn by coronary atherosclerosis. In addition, visceral fat accumulates (C. Shively, personal communication, 1992). This then seems to be an identical situation to that found in abdominal obesity in man, including symptoms in anthropometry, endocrinology and metabolism. By analogy it may be suggested that the human syndrome is caused by similar mechanisms, namely a hypothalamic arousal syndrome leading to neuroendocrine aberrations, elicited by stress factors. The information currently available is compatible with such an interpretation, as suggested and reviewed previously (1 1, 12).
Ann Med Downloaded from informahealthcare.com by University of Chicago Library on 06/05/12 For personal use only.
References Bjorntorp P. Abdominal fat distribution and disease: An overview of epidemiological data. Ann Med 1992; 24: 15-1 8. Bjorntorp P, Lapidus L. The relationship between ‘The Metabolic Syndrome’ and abdominal obesity in women. 1992 (in press). Marin P, Darin N, Amemiya T, Andersson B, Jern S, Bjorntorp P. Cortisol secretion in relation to body fat distribution in obese premenopausal women. Metabolism, 1992; 41: 882-6.
4. Rebuffe-Scrive M, Krotkiewski M, Elfverson J, Bjorntorp P. Muscle and adipose tissue morphology and metabolism in Cushing’s syndrome. J Clm Endocrinol Metab 1988; 67, 1122-5. 5. Bjorntorp P. Adipose tissue distribution and function. lnt J Obes 1991; 15: 67-81. 6. Bjorntorp P, Ottosson M, Rebuffe-Scrive M, Xu X. Regional obesity and steroid hormone interactions in human adipose tissue. In: Bray GA, Ricquier D,Spiegelman B, eds. Obesity: towards a molecular approach. UCLA Symposia on Molecular and Cellular Biology. New York: Wiley-Liss, 132; 1990: 147-57. 7. Bengtsson B-A, Eden S, Lonn L, et al. Treatment of adults with growth hormone deficiency with recombinant human growth hormone. 1992 (in press) 8. Bjorntorp P. ‘Portal’ adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 1990; 10: 493-6. 9. Bjorntorp P. Metabolic abnormalities in visceral obesity. Ann Med 1992; 24: 3-5. 10. Henry J, Grim CE. Psychosocial mechanisms in primary hypertension. J Hypertens 1990; 8: 783-9. 11. Bjorntorp P. Psychosocial factors and fat distribution. In: Ailhaud G, Guy-Grand B, Lafontan M, Ricquier D, eds. Obesity in Europe. Proc. 3rd European Congress on Obesity. London: Libbey, 1992: 377-87. 12. Bjorntorp P. Visceral fat accumulation: the missing link between psychosocial factors and cardiovascular disease? J lnt Med 1991; 230: 195-291.
