881
EDITORIALS
Born to be fat? Obesity, like hypertension and hyperglycaemia with which it is associated, is a risk factor for disease1 and is increasingly encountered in developing as well as developed countries.2 The increase in overweight in the past 20 years and the association with low socioeconomic status3 suggest that environmental factors contribute to the risk of obesity, but population studies show that environmental characteristics explain only a very small proportion of the overall variation in body build.4 The similarity of body build among family members suggests that genetic factors are important. Since effects of genetic or environmental influences might be first detectable in childhood, understanding these earliest precursors of obesity could help in the formulation of preventive
strategies. Obesity can be quantified by indices of relative weight (or weight for height), which should provide measures of bodyweight that are largely independent of height. The body mass index (BMI, weight divided by height squared) should not be used as an index of childhood weight for height because of an agedependent association with height and increasing variance with age, even after log transfonnation.5 Rolland-Cachera and colleagues6 lately showed that a more complex transformation can be used to construct centiles of BMI throughout the range of ages. Familial influences on weight for height are very important. In childhood, weight for height increases with parental weight for height and varies greatly among ethnic groups.’ These associations are much stronger than the effects of environmental characteristics such as paternal social class or maternal education. Cross-sectional studies can never entirely separate genetic and environmental influences because genetically related people commonly share similar environments. Two types of investigation can be used
to overcome
this drawback:
(a) twin studies,
which are designed to investigate closely related individuals in the same environment; and (b) studies of adopted children, in which genetically related individuals are examined in different environments. Twin studies show that weight for height and skinfold thicknesses are more highly correlated among monozygotic than among dizygotic twin pairs. 8,9 It has been estimated from such studies that, at the age of ten or eleven years, more than 70% of the variation in weight for height or skinfold thickness is explained by genetic factors,.8,9 When identical twins pairs are overfed they show similar patterns of weight gain; this observation might reflect the genetically programmed response to an environmental stimulus.1O Studies of this kind may overestimate the importance of genetic influences because similarities between twins can be enhanced by various non-genetic factors.ll In view of these limitations, investigations of adopted children reared apart from their biological relatives are of great interest. Sorensen and colleagues now report that the BMI of adopted children is much more strongly associated with the BMI of their biological parents and biological siblings than with that of their adoptive parents and siblings. 12 The rearing environment had only a minor influence on weight for height during childhood, a finding that accords with the results of twin studies and of earlier cohort studies. 13 Overweight and obesity are less important in childhood than in adult life. Do influences on weight for height of children contribute to adult obesity? Stunkard and colleagues reported that the BMI of adult adoptees in their forties was strongly related to that of their biological parents14 and siblings,15 but not to that of adoptive parents. Although the BMI of adoptive parents was not a marker of early environmental influences on adult bodyweight, there was other evidence for an effect of childhood environment on adult obesity. For example, those reared in provincial areas were heavier than their urban-reared counterparts.l6 What about even earlier environmental influences on adult risk factors, including obesity? High birthweight is thought to be associated with adult obesity2’ but the intrauterine environment might have more specific effects.18 Children exposed during the first two trimesters of intrauterine life to the Dutch hunger winter of 1944-45 subsequently showed an increased prevalence of obesity.19 It was suggested that impaired nutrition at this stage of development might programme subsequent patterns of feeding and fat deposition. Regional distribution of body fat in adult life is also related to fetal growth.20 The most practical anti-obesity intervention is to modify the environment in terms of habitual physical activity and food intake, to prevent the onset of overweight in adulthood. The high prevalence of overweight and obesity and our limited understanding of variations in susceptibility do not justify a selective strategy aimed at high-risk individuals.
882
Royal College of Physicians. Obesity report. J R Coll Physicians Lond 1983; 17: 5-65. 2. World Health Organisation. Diet, nutrition and the prevention of chronic diseases. WHO Tech Rep Ser 1990; 797: 29-31. 3. Sobal J, Stunkard AJ. Socioeconomic status and obesity: a review of the literature. Psychol Bull 1989; 105: 260-75. 4. Rona RJ, Morris RW. National Study of Health and Growth: social and family factors and overweight in English and Scottish parents. Ann Human Biol 1982; 9: 147-56. 5. Chinn S, Rona RJ, Gulliford MC, Hammond J. Weight for height in children aged 4 to 12 years: a new index compared with the normalised body mass index. Eur J Clin Nutr 1992; 46: 489-500. 6. Rolland-Cachera MF, Cole TJ, Sempe M, Tichet J, Rossignol C, Charraud A. Body mass index variations: centiles from birth to 87 years. Eur J Clin Nutr 1991; 45: 13-21. 7. Rona RJ, Chinn S. National Study of Health and Growth: social and biological factors associated with weight for height and triceps skinfold of children from ethnic groups in England. Ann Human Biol 1987; 14: 1.
231-48. 8. Brook CGD, Huntley RMC, Slack J. Influence of heredity and environment in determination of skinfold thickness in children. BMJ 1975: ii: 719-21.
9. Bodurtha JN, Mosteller M, Hewitt JK, et al. Genetic analysis of anthropometric measures in 11 year old twins: The Medical College of Virginia Twin Study. Pediatr Res 1990; 28: 1-4. 10. Bouchard C, Tremblay A, Despres JP, et al. The response to long term overfeeding in identical twins. N Engl J Med 1990; 322: 1477-82. 11. Bouchard C, Perusse L. Heredity and body fat. Annu Rev Nutr 1988; 8: 259-77. 12. Sorensen TIA, Holst C, Stunkard AJ. Childhood body mass index: genetic and familial environmental influence assessed in a longitudinal adoption study. Int J Obesity 1992; 16: 705-14. 13. Poskitt EME, Cole TJ. Nature, nurture, and childhood overweight. BMJ 1978; i: 603-05. 14. Stunkard AJ, Sorensen TIA, Hanis C, et al. An adoption study of human obesity. N Engl J Med 1986; 314: 193-98. 15. Sorensen TIA, Price RA, Stunkard AJ, Schulsinger. Genetics of obesity in adult adoptees and their biological siblings. BMJ 1989; 298: 87-90. 16. Teasdale TW, Sorensen TIA, Stunkard AJ. Genetic and early environmental components of sociodemographic influences on adult body fatness. BMJ 1990; 300: 1615-18. 17. Braddon FEM, Rodgers B, Wadsworth MEJ, Davies JMC. Onset of obesity in a 36 year birth cohort study. BMJ 1986; 293: 299-303. 18. Anon. Influences of intrauterine nutritional status on the development of obesity in later life. Nutr Rev 1977; 35: 100-02. 19. Ravelli GP, Stein ZA, Susser MV. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 1976; 295: 349-53. 20. Law CM, Barker DJP, Osmond C, Fall CHD, Simmonds SJ. Early growth and abdominal fatness in adult life. J Epidemiol Community Health 1992; 46: 184-86.
Nitric oxide and erection Nitric oxide synthase exists as a constitutive enzyme present under normal physiological conditions in many cell types (cNOS), and as an inducible form which may be expressed following immunological stimulation (iNOS).l It may be either particulate or soluble, and there are multiple isofonns.2,3 Endothelial cNOS has an important role in the regulation of tone vasomotor by synthesising the potent endogenous nitrovasodilator endothelium-derived relaxing factor (EDRF). EDRF is widely believed to be the NO radical at the moment of its formation from L-arginine, and can be detected extracellularly as such near the endothelial cell membrane by use of electrochemical microsensors.4 Non-adrenergic, noncholinergic nerves synthesise and release NO and can thereby modulate the constrictor tone of cerebral and mesenteric arteries.5-7 In a third NO-mediated vasomotor control mechanism, neurotransmitters such as acetylcholine and substance P diffuse from
the endothelium in to adventitial nerves concentrations sufficient to stimulate EDRF/NO release. Thus, vagally induced coronary and pulmonary vasodilatation is blocked not only by atropine, but also by N G-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS.8,9 An analogous mechanism explains why skeletal muscle vasodilatation following nerve stimulation is blocked by the substance P antagonist spantide and by L-NAAiE.10 There is now convincing evidence that penile erection, which is generally thought to be a vascular event dependent on relaxation of the trabecular muscle of the corpora cavemosa, is mediated by NO. During erection, active filling of the sinusoids compresses the peripheral venules of the corpora against the rigid tunica albuginea, causing outflow obstruction. The process is therefore not mediated simply by passive engorgement with blood." Conversely, flaccidity is enhanced by contraction of corporal tissue after activation of adrenergic receptors by noradrenaline released from sympathetic nerve terminals. 12 Thus, intracavemosal injection of a vasodilator such as papaverine, or the ol-blocker phenoxybenzamine, can induce sustained erection for 24 hours or more." Functional studies with isolated human and animal corpus cavemosum tissue have shown that relaxation induced by electrical stimulation of autonomic nerves is abolished by blockade of NOS, and that this inhibition is reversed by excess L-arginine. 14-18 Immunohistochemical staining of both rat and canine tissue has shown that NOS is widely distributed throughout the urogenital tract, high concentrations being found in major pelvic ganglia, the membranous urethra, and the bladder neck, as well as in the penis itself. 18 In many species the smooth muscle of the corpora cavemosa and retractor penis muscle can be regarded as a single functional entity, although in some cases (notably primates) the retractor penis is absent whereas in others the cavernous bodies are virtually devoid of smooth muscle.ll Thus, neurally mediated relaxation of the retractor penis and related anococcygeus muscle is also mediated via the NO/Larginine pathway.19 As in arterial smooth muscle, NO leads to a reduction of cytosolic free Ca2’ in the retractor penis muscle as a result of activation of the soluble form of guanylyl cyclase.’9 In the penis itself, antibody to NOS stains efferent axons from the cavernous nerves that arise from the pelvic plexus and innervate both the trabecular mesh of the corpus cavemosum smooth muscle and their main arterial supply, the deep cavemosal arteries.18 Bilateral cavernous nerve transection thus abolishes staining of NOS-containing penile neurons, but not that of vascular endothelium, which could also participate in the control of erection by N0.18 Staining of NOS can also be shown in the endothelium and adventitial innervation of the dorsal penile artery and the intracorporal network of helicine arteries, which
EDITORIALS
Born to be fat? Obesity, like hypertension and hyperglycaemia with which it is associated, is a risk factor for disease1 and is increasingly encountered in developing as well as developed countries.2 The increase in overweight in the past 20 years and the association with low socioeconomic status3 suggest that environmental factors contribute to the risk of obesity, but population studies show that environmental characteristics explain only a very small proportion of the overall variation in body build.4 The similarity of body build among family members suggests that genetic factors are important. Since effects of genetic or environmental influences might be first detectable in childhood, understanding these earliest precursors of obesity could help in the formulation of preventive
strategies. Obesity can be quantified by indices of relative weight (or weight for height), which should provide measures of bodyweight that are largely independent of height. The body mass index (BMI, weight divided by height squared) should not be used as an index of childhood weight for height because of an agedependent association with height and increasing variance with age, even after log transfonnation.5 Rolland-Cachera and colleagues6 lately showed that a more complex transformation can be used to construct centiles of BMI throughout the range of ages. Familial influences on weight for height are very important. In childhood, weight for height increases with parental weight for height and varies greatly among ethnic groups.’ These associations are much stronger than the effects of environmental characteristics such as paternal social class or maternal education. Cross-sectional studies can never entirely separate genetic and environmental influences because genetically related people commonly share similar environments. Two types of investigation can be used
to overcome
this drawback:
(a) twin studies,
which are designed to investigate closely related individuals in the same environment; and (b) studies of adopted children, in which genetically related individuals are examined in different environments. Twin studies show that weight for height and skinfold thicknesses are more highly correlated among monozygotic than among dizygotic twin pairs. 8,9 It has been estimated from such studies that, at the age of ten or eleven years, more than 70% of the variation in weight for height or skinfold thickness is explained by genetic factors,.8,9 When identical twins pairs are overfed they show similar patterns of weight gain; this observation might reflect the genetically programmed response to an environmental stimulus.1O Studies of this kind may overestimate the importance of genetic influences because similarities between twins can be enhanced by various non-genetic factors.ll In view of these limitations, investigations of adopted children reared apart from their biological relatives are of great interest. Sorensen and colleagues now report that the BMI of adopted children is much more strongly associated with the BMI of their biological parents and biological siblings than with that of their adoptive parents and siblings. 12 The rearing environment had only a minor influence on weight for height during childhood, a finding that accords with the results of twin studies and of earlier cohort studies. 13 Overweight and obesity are less important in childhood than in adult life. Do influences on weight for height of children contribute to adult obesity? Stunkard and colleagues reported that the BMI of adult adoptees in their forties was strongly related to that of their biological parents14 and siblings,15 but not to that of adoptive parents. Although the BMI of adoptive parents was not a marker of early environmental influences on adult bodyweight, there was other evidence for an effect of childhood environment on adult obesity. For example, those reared in provincial areas were heavier than their urban-reared counterparts.l6 What about even earlier environmental influences on adult risk factors, including obesity? High birthweight is thought to be associated with adult obesity2’ but the intrauterine environment might have more specific effects.18 Children exposed during the first two trimesters of intrauterine life to the Dutch hunger winter of 1944-45 subsequently showed an increased prevalence of obesity.19 It was suggested that impaired nutrition at this stage of development might programme subsequent patterns of feeding and fat deposition. Regional distribution of body fat in adult life is also related to fetal growth.20 The most practical anti-obesity intervention is to modify the environment in terms of habitual physical activity and food intake, to prevent the onset of overweight in adulthood. The high prevalence of overweight and obesity and our limited understanding of variations in susceptibility do not justify a selective strategy aimed at high-risk individuals.
882
Royal College of Physicians. Obesity report. J R Coll Physicians Lond 1983; 17: 5-65. 2. World Health Organisation. Diet, nutrition and the prevention of chronic diseases. WHO Tech Rep Ser 1990; 797: 29-31. 3. Sobal J, Stunkard AJ. Socioeconomic status and obesity: a review of the literature. Psychol Bull 1989; 105: 260-75. 4. Rona RJ, Morris RW. National Study of Health and Growth: social and family factors and overweight in English and Scottish parents. Ann Human Biol 1982; 9: 147-56. 5. Chinn S, Rona RJ, Gulliford MC, Hammond J. Weight for height in children aged 4 to 12 years: a new index compared with the normalised body mass index. Eur J Clin Nutr 1992; 46: 489-500. 6. Rolland-Cachera MF, Cole TJ, Sempe M, Tichet J, Rossignol C, Charraud A. Body mass index variations: centiles from birth to 87 years. Eur J Clin Nutr 1991; 45: 13-21. 7. Rona RJ, Chinn S. National Study of Health and Growth: social and biological factors associated with weight for height and triceps skinfold of children from ethnic groups in England. Ann Human Biol 1987; 14: 1.
231-48. 8. Brook CGD, Huntley RMC, Slack J. Influence of heredity and environment in determination of skinfold thickness in children. BMJ 1975: ii: 719-21.
9. Bodurtha JN, Mosteller M, Hewitt JK, et al. Genetic analysis of anthropometric measures in 11 year old twins: The Medical College of Virginia Twin Study. Pediatr Res 1990; 28: 1-4. 10. Bouchard C, Tremblay A, Despres JP, et al. The response to long term overfeeding in identical twins. N Engl J Med 1990; 322: 1477-82. 11. Bouchard C, Perusse L. Heredity and body fat. Annu Rev Nutr 1988; 8: 259-77. 12. Sorensen TIA, Holst C, Stunkard AJ. Childhood body mass index: genetic and familial environmental influence assessed in a longitudinal adoption study. Int J Obesity 1992; 16: 705-14. 13. Poskitt EME, Cole TJ. Nature, nurture, and childhood overweight. BMJ 1978; i: 603-05. 14. Stunkard AJ, Sorensen TIA, Hanis C, et al. An adoption study of human obesity. N Engl J Med 1986; 314: 193-98. 15. Sorensen TIA, Price RA, Stunkard AJ, Schulsinger. Genetics of obesity in adult adoptees and their biological siblings. BMJ 1989; 298: 87-90. 16. Teasdale TW, Sorensen TIA, Stunkard AJ. Genetic and early environmental components of sociodemographic influences on adult body fatness. BMJ 1990; 300: 1615-18. 17. Braddon FEM, Rodgers B, Wadsworth MEJ, Davies JMC. Onset of obesity in a 36 year birth cohort study. BMJ 1986; 293: 299-303. 18. Anon. Influences of intrauterine nutritional status on the development of obesity in later life. Nutr Rev 1977; 35: 100-02. 19. Ravelli GP, Stein ZA, Susser MV. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 1976; 295: 349-53. 20. Law CM, Barker DJP, Osmond C, Fall CHD, Simmonds SJ. Early growth and abdominal fatness in adult life. J Epidemiol Community Health 1992; 46: 184-86.
Nitric oxide and erection Nitric oxide synthase exists as a constitutive enzyme present under normal physiological conditions in many cell types (cNOS), and as an inducible form which may be expressed following immunological stimulation (iNOS).l It may be either particulate or soluble, and there are multiple isofonns.2,3 Endothelial cNOS has an important role in the regulation of tone vasomotor by synthesising the potent endogenous nitrovasodilator endothelium-derived relaxing factor (EDRF). EDRF is widely believed to be the NO radical at the moment of its formation from L-arginine, and can be detected extracellularly as such near the endothelial cell membrane by use of electrochemical microsensors.4 Non-adrenergic, noncholinergic nerves synthesise and release NO and can thereby modulate the constrictor tone of cerebral and mesenteric arteries.5-7 In a third NO-mediated vasomotor control mechanism, neurotransmitters such as acetylcholine and substance P diffuse from
the endothelium in to adventitial nerves concentrations sufficient to stimulate EDRF/NO release. Thus, vagally induced coronary and pulmonary vasodilatation is blocked not only by atropine, but also by N G-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS.8,9 An analogous mechanism explains why skeletal muscle vasodilatation following nerve stimulation is blocked by the substance P antagonist spantide and by L-NAAiE.10 There is now convincing evidence that penile erection, which is generally thought to be a vascular event dependent on relaxation of the trabecular muscle of the corpora cavemosa, is mediated by NO. During erection, active filling of the sinusoids compresses the peripheral venules of the corpora against the rigid tunica albuginea, causing outflow obstruction. The process is therefore not mediated simply by passive engorgement with blood." Conversely, flaccidity is enhanced by contraction of corporal tissue after activation of adrenergic receptors by noradrenaline released from sympathetic nerve terminals. 12 Thus, intracavemosal injection of a vasodilator such as papaverine, or the ol-blocker phenoxybenzamine, can induce sustained erection for 24 hours or more." Functional studies with isolated human and animal corpus cavemosum tissue have shown that relaxation induced by electrical stimulation of autonomic nerves is abolished by blockade of NOS, and that this inhibition is reversed by excess L-arginine. 14-18 Immunohistochemical staining of both rat and canine tissue has shown that NOS is widely distributed throughout the urogenital tract, high concentrations being found in major pelvic ganglia, the membranous urethra, and the bladder neck, as well as in the penis itself. 18 In many species the smooth muscle of the corpora cavemosa and retractor penis muscle can be regarded as a single functional entity, although in some cases (notably primates) the retractor penis is absent whereas in others the cavernous bodies are virtually devoid of smooth muscle.ll Thus, neurally mediated relaxation of the retractor penis and related anococcygeus muscle is also mediated via the NO/Larginine pathway.19 As in arterial smooth muscle, NO leads to a reduction of cytosolic free Ca2’ in the retractor penis muscle as a result of activation of the soluble form of guanylyl cyclase.’9 In the penis itself, antibody to NOS stains efferent axons from the cavernous nerves that arise from the pelvic plexus and innervate both the trabecular mesh of the corpus cavemosum smooth muscle and their main arterial supply, the deep cavemosal arteries.18 Bilateral cavernous nerve transection thus abolishes staining of NOS-containing penile neurons, but not that of vascular endothelium, which could also participate in the control of erection by N0.18 Staining of NOS can also be shown in the endothelium and adventitial innervation of the dorsal penile artery and the intracorporal network of helicine arteries, which
