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Endocrine Unit (A.P.G., J.K.H., S.R.B.); MRI Unit (E.L.T., J.D.B., N.S., J.V.H.), MRC Clinical Sciences Centre; Department of Dietetics (A.E.B., G.F.), Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom; and Section of Developmental Psychiatry (A.H.), University of Cambridge CB2 2AH, United Kingdom
Address all correspondence and requests for reprints to: Prof. S. R. Bloom, Department of Metabolic Medicine, 6th Floor Commonwealth Building, Imperial College School of Medicine, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom.
Abstract
Visceral obesity is detrimental to health, but the mechanisms controlling body fat distribution are not fully understood. In premenopausal adult females (30 nonobese, 14 obese [body mass index >30kg/m2]), variance in fasting insulin, glucose, insulin/glucose ratio, C-peptide/insulin ratio, triglycerides, and high-density lipoprotein/low-density lipoprotein-cholesterol ratio, were independently influenced by visceral but not total sc or abdominal sc adipose tissue, as measured by whole-body magnetic resonance imaging. Adult females with Prader-Willi syndrome (n = 13) had significantly reduced visceral adiposity, compared with obese controls (visceral/total sc adipose tissue ratio: 0.067 ± 0.017 vs. 0.108 ± 0.021), independent of their total adiposity (P < 0.001), or use of exogenous sex steroids. This is in contrast to that expected by their physical inactivity, hypogonadism, adult GH deficiency, and psychiatric problems. Females with Prader-Willi syndrome not receiving sex steroids (n = 8) had significantly reduced fasting insulin, insulin/glucose ratio, and triglycerides and increased C-peptide/insulin ratio, compared with obese controls, adjusting for total (P < 0.05) but not visceral adiposity (P = 0.3–0.6), supporting their association. The cause of the reduced visceral adiposity in Prader-Willi syndrome may reflect novel hormonal, hypothalamic, and/or genetic influences on body fat distribution.
INCREASED BODY FAT, and particularly visceral obesity, has adverse effects on health (1, 2, 3). The mechanisms controlling body fat distribution are not fully understood but are thought to include environmental, genetic, and hormonal influences, such as sex steroids, GH, and glucocorticoids (2, 3). A general finding has been that conditions associated with increased fat deposition, such as GH deficiency, hypercortisolism, hypogonadism, and hyperandrogenism in females, are associated with preferential deposition of central or visceral fat (2, 3, 4). This may primarily be owing to differences in the metabolic activity, receptor expression, and molecular characteristics of adipocytes in these sites (2, 3, 4). Central or visceral obesity is associated with increased insulin resistance, glucose intolerance, hyperlipidemia, cardiovascular disease, and mortality (1, 5).
Prader-Willi syndrome (PWS) is a genetic disorder characterized by hyperphagia and life-threatening obesity from childhood, mental retardation, behavioral problems, and short stature from GH deficiency and hypogonadism (6). Many of the features are thought to arise from developmental abnormalities in the hypothalamus (7). The relationship with the underlying chromosome 15q11–13 imprinted gene defect(s) is currently unclear (8).
A peculiar body composition has been identified in PWS, with a marked increase in fat relative to lean tissue (9, 10). In addition to the increased calorific intake, there may be a contribution from GH deficiency, hypogonadism, and reduced physical activity (11). Previous studies have suggested that some obesity-related metabolic complications, such as insulin resistance and reduced hepatic insulin extraction, may be less than expected for the degree of obesity in PWS (12, 13, 14). Body fat distribution in PWS has not previously been examined in detail. We therefore examined adipose tissue (AT) distribution, using whole-body magnetic resonance imaging (MRI) (15), in nonobese and obese healthy control and PWS female adults (16). We assessed the relationships between different regional AT depots and markers of glucose and lipid metabolism and examined differences in these obesity-related metabolic parameters in PWS, adjusting for such relationships. We demonstrate for the first time a selective reduction in visceral adiposity in PWS, which appears to protect against metabolic complications of obesity, despite their overall increased adiposity. Possible explanations for these findings are discussed in view of the other phenotypes, neuroendocrine and genetic abnormalities seen in PWS.
Materials and Methods
Subject characteristics
Ethical approval for the study was obtained from the Research Ethics Committee, Hammersmith Hospital (No. 92/3995 and 96/4807). Control female subjects (n = 44) were recruited from hospital staff, dietetic clinics, and public advertisement. PWS female adults (n = 13) were recruited through the Section of Developmental Psychiatry, University of Cambridge (A.H.), and the United Kingdom Prader-Willi Syndrome Association. Consent was obtained from both the PWS subject and caregiver or next of kin. All subjects were Caucasian, aged over 18 yr, and nondiabetic and had normal renal and hepatic function. All controls were premenopausal and had no known endocrine pathology. One PWS female, but none of the control subjects, was a smoker. There was no history of diabetes mellitus in any first-degree relative. All subjects reported stable body weight in the previous 2 months. All PWS subjects met diagnostic criteria for PWS (6) and suffered from childhood-onset obesity, requiring vigorous behavioral modification, such as locking food and dietary supervision, for extreme hyperphagia and obsession with food. All PWS subjects had experienced primary amenorrhea or severe oligomenorrhea. Four PWS subjects were receiving the oral contraceptive pill (OCP) (two subjects: ethinyloestradiol 20 µg/norethisterone 1 mg; one subject each: cyclical ethinyloestradiol 30 µg/levonorgesterol 0.15 mg, norethisterone 0.35 mg); and one PWS female was on hormone replacement therapy (HRT) (as cyclical estradiol valerate 2 mg/levonorgestrel 75 µg). No PWS subject was currently receiving GH therapy, but one PWS subject on the OCP, aged 22 yr, had received GH during childhood only. No control or PWS subjects were receiving any other pituitary hormone replacement, except for one PWS subject who was biochemically euthyroid on thyroxine replacement. Four PWS females were receiving selective serotonin reuptake inhibitors, and two of these were also on phenothiazines for management of behavioral and psychiatric problems.
Anthropometry and body composition
Height; weight; waist; hip; mean arm circumference; and, to assess SCAT distribution, four-site skinfold thickness (limb = triceps and biceps, trunk = subscapular and suprailiac) were measured in all subjects by one trained observer (A.E.B.). Controls were divided into nonobese (body mass index [BMI] < 30 kg/m2) and obese (BMI > 30kg/m2) groups.
Whole-body MRI
Whole-body MRI was acquired in all subjects on a 1.0T HPQ system (Marconi Medical, Cleveland, OH) using a rapid T1-weighted SE sequence, as previously described (10, 16, 17, 18). Subjects were scanned from fingertips to toes with 10-mm-thick transverse images every 10–30 mm. Interactive computer analysis was used to quantify total body and regional AT volumes: total sc (SCAT), abdominal sc (ASCAT), visceral (VAT), and nonvisceral internal (INAT) adipose tissue, as previously described (17, 18). INAT consisted primarily of AT around muscle fibers. Central AT was defined as VAT + ASCAT. Peripheral AT was defined as total AT –central AT. MRI total fat mass and total and regional fat as percent of body mass were calculated as previously described (17, 18), using body weight to calculate fat-free mass (FFM).
Blood sampling and assays
Blood sampling was performed after a 12-h overnight fast. Plasma glucose was measured using an automated analyzer (RA-1000, Technicon Instrument Co. Ltd., Basingstoke, UK) and serum assayed for total cholesterol and triglycerides using an enzymatic method (Technicon Dax system, Tarrytown, NY); high-density lipoprotein (HDL) cholesterol using direct measurement with an RIAXT machine (Biostat Diagnostics, Cheshire, United Kingdom) and low-density lipoprotein (LDL) cholesterol was calculated using the Friedwald formula. Serum or plasma was assayed using established assays for insulin (IRMA, guinea pig anti-insulin antibody; SAPU, Glasgow, Scotland), C-peptide (enzyme immunometric assay, Immulite, DPC, Los Angeles, CA), total T, dehydroepiandrosterone sulfate (DHEAS) (St. Thomas’s extraction assay, Chelsea Kits, United Kingdom), and SHBG (enzyme tracer and chemiluminescent automated assay, Immulite, DPC). Serum E2 (enzyme tracer and chemiluminescent automated assay; IUX Abbott, Chicago, IL) was also measured in PWS subjects. Coefficient of variation values for all assays were < 10%. Free T index was calculated (100 x total T/SHBG). Fasting insulin resistance index (FIRI) was calculated (fasting insulin x fasting glucose/25) (19). The basal C-peptide/insulin molar ratio was used as a measurement of hepatic insulin extraction (13).
Statistical analysis
Between-group comparisons were made using one-way ANOVA with posthoc Tukey’s test. Pearson product moment correlation coefficients (r) were used to assess the relationship among variables. Log10 transformation was used to normalize data that were not normally distributed. In control females, forward stepwise regression analysis was used to assess the relative contributions of age and each AT depot to the variance in metabolic and hormonal parameters. Examination of the effect of PWS on fat distribution and metabolic or hormonal parameters, correcting for differences in age and total or visceral adiposity, was performed using multiple linear regression analysis to calculate PWS regression coefficient (ß). Significance was taken as P < 0.05. Statistical analysis was performed using SigmaStat 2.0 (Jandel Corp., San Rafael, CA) and Systat 8.0 (SPSS, Inc., Chicago, IL).
Results
Subject characteristics and body composition
Subject characteristics are given in Table 1
. There were no significant differences
between those PWS females not receiving or receiving the OCP/HRT, and
PWS data were therefore combined. PWS subjects were significantly
shorter than both nonobese and obese controls. PWS subjects had a
similar BMI, total AT volume, and MRI percent body fat to obese
controls but had a significant lower mean arm circumference and FFM. In
view of the reduced height and FFM of PWS subjects, correction was made
for both AT volume and fat as percent of body mass, when comparing
metabolic parameters between PWS subjects and controls.
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In controls, obesity was associated with a relative increase in
visceral adiposity, as evident by significant increases in the VAT
volume as percent of total AT volume, visceral fat as percent of total
body mass, VAT/SCAT and VAT/ASCAT ratios (Table 1
). The VAT/SCAT ratio
was positively correlated with total AT volume (r =
+0.58, P < 0.001) or percent body fat
(r = +0.61, P < 0.001) in controls,
but there was no significant additional effect of age in multiple
linear regression (both P = 0.7). Correction for total
adiposity, but not age, was therefore made when comparing ratios
between PWS and controls. Obese controls also had significantly
increased surrogate measurements of abdominal obesity, compared with
nonobese controls, namely waist, waist/hip ratio (WHR), and
waist/height ratio, but the trunk/limb skinfold ratio was not increased
(Table 1).
There was a lower level of visceral adiposity in PWS, compared with
obese controls, as evident by significantly lower absolute VAT volume,
VAT as percent of total AT or visceral fat as percent total body mass
(Table 1, Fig. 1). The proportion of VAT
in PWS females was in fact similar to nonobese controls. In contrast,
there was no significant decrease in the amount or proportion of SCAT,
ASCAT, or INAT in PWS subjects, compared with obese controls (Table 1).
The VAT/SCAT and VAT/ASCAT ratios were lower in PWS subjects,
compared with obese controls, but there was no significant decrease in
the central/peripheral AT ratio, waist diameter, WHR, waist/height
ratio, or trunk/limb skinfold ratio (Table 1). This reduction in
visceral adiposity was significant in both PWS females not receiving or
receiving the OCP/HRT (VAT/SCAT ratio: 0.063 ± 0.017,
P < 0.001 vs. obese controls, or 0.073
± 0.016, P < 0.01; VAT/ASCAT ratio: 0.221 ±
0.056 or 0.226 ± 0.032, both P < 0.001).
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),
and this remained significant when correcting for age in multiple
linear regression analysis (P < 0.001), although this
was not a significant covariate (P = 0.6). At the
highest levels of obesity, this resulted in around a 50% lower level
of VAT in PWS (Fig. 1). By contrast there was no significant difference
in the relationship between ASCAT and total AT volume between all PWS
subjects and controls (slope P = 0.1, intercept
P = 0.3) (Fig. 2B). Both the VAT/SCAT and VAT/ASCAT
ratios were significantly lower in PWS subjects than obese controls,
correcting for either total AT volume (PWS ß [95% confidence
interval]: -0.042 [-0.034, -0.049], -0.136 [-0.114, -0.158],
both P < 0.001) or percent body fat (PWS ß: -0.041
[-0.032, -0.049], -0.127 [-0.103, -0.151], both
P < 0.001), and these findings were independent of
OCP/HRT usage, selective serotonin reuptake inhibitor/phenothiazine
usage, and height (data not shown).
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In control females, fasting insulin, fasting glucose,
insulin/glucose ratio, and triglycerides were positively correlated,
and C-peptide/insulin, and HDL/LDL-cholesterol ratios were negatively
correlated to the total body AT, independent of age (Tables 2 and 3).
In forward stepwise multiple linear regression analysis, similar
correlations were found with VAT, but there was no independent
additional relationship between any of these metabolic parameters and
either SCAT or ASCAT (Table 3). Similar results were found using FIRI
instead of insulin/glucose ratio (data not shown). Similar results were
obtained when using fat depots as percent of body mass rather than AT
volume in stepwise multiple linear regression (data not shown). There
was no significant influence of height on any metabolic parameters in
forward stepwise multiple regression analysis, independent of age and
total or visceral AT volume (PE 0.45 -
0.99).
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In view of the complex effects of exogenous sex hormones on
metabolism (20), analysis of metabolic parameters in PWS
was restricted to those subjects not receiving OCP/HRT (n = 8)
(Table 2). In these PWS subjects, as with controls, VAT was positively
related to fasting insulin (r2 = 0.31,
P = 0.15), insulin/glucose ratio
(r2 = 0.31, P = 0.15), and
triglycerides (r2 = 0.62, P
= 0.02), and negatively related to C-peptide/insulin ratio
(r2 = 0.27, P = 0.19) and
HDL/LDL-cholesterol ratio (r2 =
0.58, P = 0.03), although owing to the smaller
sample size, this did not always reach statistical significance
(all dependent variables log10-transformed).
In view of the strong dependency of metabolic parameters on obesity
seen above, comparisons between PWS subjects and obese controls used
multiple regression analysis, adjusting for differences in total and
regional adiposity (Table 4). Adjusting
for total adiposity (total AT volume or percent body fat), PWS subjects
had significantly lower fasting insulin, insulin/glucose ratio, FIRI,
and triglycerides and significantly higher C-peptide/insulin ratio than
obese controls (Table 4). However, there was no significant difference
in fasting insulin, insulin/glucose ratio, FIRI, triglycerides, or
C-peptide/insulin ratio between PWS subjects and obese controls,
adjusting for visceral (in contrast to total) adiposity (as AT
volume or percent body mass, P = 0.3 - 0.6)
(Table 4).
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), or multiple regression
analysis, adjusting for total or visceral adiposity (data not shown).
In the eight PWS subjects not on OCP/HRT, serum E2 levels (mean ±
SD, range) were 201 ± 107 (57–350) pmol/liter. Two
subjects had levels in the postmenopausal range (<100 pmol/liter), and
these were the subjects with the lowest percent body fat. Serum total T (mean ± SD: 1.3 ± 0.4 nmol/liter), SHBG (59 ± 37 nmol/liter), free T index (3.8 ± 3.9), and DHEAS (6.8 ± 3.9 µmol/liter) in the five PWS subjects receiving exogenous sex steroids were not significantly different from obese controls by ANOVA (all P > 0.05) or multiple regression analysis, adjusting for total or visceral adiposity (data not shown).
Discussion
An understanding of the factors controlling body fat distribution is important given the adverse consequences of obesity, particularly visceral fat accumulation, to health. PWS adults are an example of human obesity related to hypothalamic dysfunction, with several interacting endocrine and metabolic abnormalities that have previously been thought to influence fat distribution (2, 3). We have found a selective reduction in visceral adiposity in PWS adult females, which appears to explain a reduction in insulin resistance and triglyceride levels, and an increase in hepatic insulin extraction, correcting for their overall obesity.
Body fat distribution in PWS
PWS adult females had a relative reduction in VAT, but not SCAT or ASCAT, leading to lower VAT/SCAT and VAT/ASCAT ratios, compared with obese controls. This change in visceral adiposity was not reflected by the waist diameter, WHR, waist/height ratio or trunk/limb skinfold measurements. Furthermore, it was not apparent by measurement of the central/peripheral AT ratio, which may explain why no change in truncal/limb fat ratio was seen in a previous dual-energy x-ray photon absorptiometry study in PWS (9), and questions the predominantly central fat distribution mentioned in the PWS diagnostic criteria (6). Normal amounts of ASCAT, as found in the present study, would have masked any reductions in VAT when using dual-energy x-ray photon absorptiometry. This also implies that the reduced VAT in PWS is not caused by any disproportionate reduction in the length or size of the abdomen, compared with the rest of the body.
Body fat distribution, insulin resistance, and hyperlipidemia
We found that, in control premenopausal women, measurements of insulin resistance (fasting glucose, insulin, insulin/glucose ratio, and FIRI) (21, 22) and hypertriglyceridemia were positively correlated and a measurement of hepatic insulin extraction (fasting C-peptide/insulin ratio) (13) and HDL/LDL cholesterol ratio were negatively correlated with total and, in particular, visceral adiposity, as measured by whole-body MRI, in agreement with previous studies (23, 24, 25). These associations are thought to result, at least in part, from the direct hepatic effects of visceral AT-derived free-fatty acids via the portal vein (26). Increased free fatty acid efflux reduces hepatic insulin extraction, leading to hyperinsulinemia; enhances hepatic glucose production through increased gluconeogenesis; and increases hepatic very low-density lipoprotein, and hence triglyceride, secretion. There was no significant influence of SCAT or ASCAT, independent of VAT, on measurements of insulin resistance, in agreement with other studies in women (24, 25, 27) but in contrast to studies in men that have found an independent relationship with truncal sc fat (28).
Reduced metabolic complications of obesity in PWS
PWS females had reduced insulin resistance (assessed by fasting insulin, insulin/glucose ratio, and FIRI), greater hepatic insulin extraction (assessed by fasting C-peptide/insulin ratio), and lower hypertriglyceridemia, compared with obese controls, when adjusting for age and total adiposity. When correcting for the lower levels of VAT, these metabolic differences were no longer apparent in PWS subjects. This is consistent with an association between these reduced metabolic complications of obesity and the lower amounts of VAT in PWS females. Such differences have been found in other studies of children and adults with PWS, even though appropriate adjustment for adiposity, as in our study, has not been made (12, 13, 14, 29). Fasting insulin levels are lower in PWS children than BMI-matched children (13, 14, 29), despite the fact that BMI underestimates the degree of adiposity in PWS (9, 30). Mean fasting insulin was normal and C- peptide/insulin ratio was raised in a study of PWS adults, compared with obese controls, despite a tendency for increased percent body fat, measured by bioelectrical impedance (13), which is still likely to have underestimated their obesity owing to GH deficiency in PWS (31).
Although our study used surrogate measurements of insulin resistance, studies have found good correlations between the ratio or product of fasting glucose and insulin with insulin resistance measured by the iv glucose tolerance test (21, 22). Previous studies have shown greater falls in glucose in PWS children following iv insulin administration, compared with obese controls (12). Schuster et al. (13) meanwhile found lower insulin, but normal glucose responses, following oral glucose in PWS children, and iv glucose in PWS adults (with a tendency to greater rate of glucose disposal), compared with obese controls (13). This dissociation between obesity and insulin resistance in PWS again occurred despite the limitations of BMI and impedance measurements to match adiposity discussed above. Our results are therefore consistent with improved insulin sensitivity in PWS, independent of overall adiposity, but appropriate body composition analysis, in combination with an iv insulin tolerance test or hyperinsulinemic euglycemic clamp, will be needed to confirm this. Furthermore, our conclusions have some limitations in view of the small number of PWS subjects studied.
Reduced visceral adiposity in PWS
The finding of reduced visceral adiposity in PWS females is of particular interest. This is an unusual, perhaps unique, situation in which increased obesity is associated with reduced visceral adiposity. This reduction occurs despite the presence of several phenotypes in PWS, such as reduced physical activity, hypogonadism, adult GH deficiency, and psychiatric problems, which by contrast would be expected to increase the proportion of VAT.
Reduced physical activity and visceral adiposity
Physical exercise leads to greater reductions in VAT than SCAT in
women (2, 3, 18). Although we did not formally assess
physical activity levels in our study, anecdotally our PWS subjects
described reduced mobility and exercise, previous reports have found
reduced physical activity in PWS (11), and the reduction
in VAT was greatest in the more obese PWS subjects (Fig. 2A), the
opposite of that expected if increased physical activity was the
explanation.
Hypogonadism and visceral adiposity
Visceral adiposity increases during menopause, independent of age and total adiposity (32), and VAT is stable during puberty in obese females (33). Furthermore the majority of PWS females not receiving the OCP/HRT still had E2 levels above postmenopausal levels, despite their oligo- or amenorrhea, probably from increased aromatization of androgens by peripheral fat because the lowest levels were seen in less obese subjects. Although a lack of cyclical changes in estrogens and progesterone might cause changes in fat distribution (34), the reduction in visceral adiposity was also seen in PWS females receiving cyclical exogenous sex hormones. Hypogonadism and incomplete or delayed puberty are therefore unlikely to explain the reduced visceral adiposity seen in PWS adult females.
GH deficiency and visceral adiposity
GH deficiency is a recognized feature of PWS children and adults, independent of obesity (14, 35), and suggested by the short stature of our subjects. GH has important effects on body fat content and distribution (31, 36, 37), with GH deficiency in adults producing an increase in both total and truncal adiposity, and the VAT/SCAT ratio, in contrast to the reduction in visceral adiposity in PWS adults seen in our study. Care must be taken to distinguish childhood-onset from adult-onset GH deficient adults, who may differ in their body composition and hormonal and metabolic perturbations (38), and to adjust for total adiposity (39), but studies using computed tomography (CT) or MRI have shown greater reductions in VAT than SCAT during GH therapy in adult-onset (40), childhood-onset (41), or mixed-onset (39) GH-deficient adults and greater increases in VAT on discontinuation of childhood-onset GH therapy in adults (42). Interestingly, a recent preliminary report found no change in VAT after 6 months of GH treatment to PWS adults, as assessed by single-slice CT (43), that might reflect already reduced visceral adiposity at baseline, as seen in our study.
Although GH deficiency in children leads to increased abdominal sc adiposity (44) and GH therapy decreases abdominal sc and total body fat in GH-deficient (45) and PWS children (46, 47), the effects on visceral adiposity are unknown from published literature. Although one study found normal visceral adiposity in childhood-onset GH deficient adults using single-slice CT (41), these subjects had received GH treatment for short stature in childhood, a therapy that was received by only one PWS subject as a child in our study.
Treatment of neonatal rats with GH antibodies over 8 wk reduces visceral fat much more than sc fat (48). Furthermore, both GH-deficient and PWS children have increased adipocyte volume but no increase, and even a decrease, in adipocyte cell number (49, 50), suggesting contrasting effects of GH to increase lipolysis but also to increase adipocyte differentiation and proliferation (2, 49, 50). The speculation that GH deficiency during early childhood might have opposite effects on visceral adiposity to that seen in adults, could account for our observed reduction in visceral adiposity in adult PWS subjects. Both non-PWS (51) and PWS (12, 13, 14, 29, 52) GH-deficient children have increased insulin sensitivity, suggesting that similar processes are at play, that may be not only a consequence of the loss of anti-insulin action of GH but also a reduction in visceral adiposity.
Adrenal steroids, androgens, and visceral adiposity
Stressful social circumstances, anxiety, and depression (the hypothalamic arousal mechanism), associated with chronic activation of the hypothalamic-pituitary (HP)-adrenal axis, may also predispose to the development of obesity, and particularly visceral adiposity (53). It is interesting to note, therefore, that we found a reduction in visceral adiposity in PWS in our study, despite high levels of stress being reported in PWS (54), depression being observed in 27% of PWS adults (55), and 31% of our PWS subjects using antidepressant or antipsychotic medication (56), with this reduction being independent of their usage. Alternatively reduced cortisol secretion in PWS could contribute to the reduced visceral adiposity (57). We did not find any reduction in DHEAS levels in our PWS subjects, and all PWS subjects not receiving OCP/HRT had basal cortisol levels greater than 215 nmol/liter (unpublished observations), suggesting that there is no gross impairment in HP-adrenal axis activity. Although clinical cortisol deficiency is not a recognized problem in PWS, more detailed dynamic testing of glucocorticoid secretion than has previously been reported (12, 52) will be needed to investigate whether there could be a subtle impairment of cortisol secretion during obesity in PWS, perhaps related to hypothalamic abnormalities.
Androgens increase the VAT/SCAT ratio in females (34, 58). However, there was no evidence for androgen deficiency (free T index or DHEAS) in our study to explain the reduced visceral adiposity in PWS females.
Hypothalamic or genetic defects and visceral adiposity
Other factors particular to PWS could account for their reduced visceral adiposity. Developmental abnormalities in the hypothalamus might alter control of peripheral fat distribution, perhaps through the autonomic system (59), distinct from its effects on the HP-axis. However, this remains speculative because fat distribution has not yet been reported in other causes of human hypothalamic obesity (60, 61), and there is no evidence of such changes from animal studies of hypothalamic damage (5, 62). Secondly, genes in the PWS chromosomal region (chromosome 15q11–13) could regulate body fat distribution through direct adipocyte effects. Lack of expression of imprinted PWS candidate genes or haploinsufficiency for other genes in the PWS chromosomal region, in adipocytes, and perhaps regional variation in their expression or degree of imprinting among various fat depots might also lead to changes in regional fat physiology. However, genetic linkage studies have shown no association of this region with visceral adiposity (63).
Conclusion
Using whole-body MRI, a selective reduction in VAT was found in PWS female adults, despite their increased overall obesity, that was independent of the use of exogenous sex steroids. This appeared unrelated to and occurred despite the hypogonadism, physical inactivity, adult GH deficiency, and psychiatric problems seen in adults with PWS. PWS females had lower fasting insulin, insulin/glucose ratio, FIRI, or triglycerides and increased C-peptide/insulin ratio that appeared to be associated with the reduction in visceral adiposity. This protection against the insulin resistance and other metabolic complications of obesity would reduce the risk of development of diabetes mellitus and cardiovascular complications in PWS, relative to their degree of obesity. However, there will still be an absolute increased prevalence of type 2 diabetes mellitus and cardiovascular disease, such as hypertension, despite the relatively less severe visceral adiposity (19% and 17%, respectively, in a study of 232 PWS adults) (64). The cause of the reduction in visceral adiposity in PWS is unclear but could be related to childhood-onset GH deficiency, subtle defects in HP-adrenal axis activity, or novel hypothalamic or genetic influences on the control of body fat distribution.
Acknowledgments
We thank PWS and other patients, their caregivers, and families and the United Kingdom PWS Association for their support and keen participation; Department of Biochemical Endocrinology, Hammersmith Hospital for performing hormone assays; Caroline Doré, Department of Medical Statistics and Evaluation, ICSM, Hammersmith Hospital; and Joan Morris, Department of Medical Statistics, Queen Mary and Westfield College, University of London, for statistical advice.
Footnotes
This work was supported by United Kingdom Medical Research Council and Marconi Medical Systems. A.P.G. and J.H. are United Kingdom Medical Research Council Training Fellows.
E.L.T. and A.E.B. contributed equally to this work.
Anthony P. Goldstone is now with the Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, United Kingdom.
Abbreviations: ASCAT, Abdominal sc adipose tissue; AT, adipose tissue; BMI, body mass index; CT, computed tomography; DHEAS, dehydroepiandrosterone sulfate; FFM, fat-free mass; FIRI, fasting insulin resistance index; HDL, high-density lipoprotein; HP, hypothalamic-pituitary; HRT, hormone replacement therapy; INAT, nonvisceral internal adipose tissue; LDL, low-density lipoprotein; MRI, magnetic resonance imaging; OCP, oral contraceptive pill; PWS, Prader-Willi syndrome; SCAT, total sc adipose tissue; VAT, visceral adipose tissue; WHR, waist/hip ratio.
Received October 30, 2000.
Accepted May 2, 2001.
References
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) females, PWS
females not on OCP/HRT (
) and PWS females receiving OCP/HRT (+);
r indicates Pearson correlation coefficient. Linear
regression line is solid for control and
dashed for PWS females (combined for both PWS groups).
Note that PWS subjects have a reduction in visceral AT but not
abdominal sc AT, relative to their total AT.