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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 566-570
Copyright © 1997 by The Endocrine Society

Clinical Studies

Effect of Regional Fat Distribution and Prader-Willi Syndrome on Plasma Leptin Levels1

David S. Weigle, Shawnda L. Ganter, Joseph L. Kuijper, Donna L. Leonetti, Edward J. Boyko and Wilfred Y. Fujimoto

Departments of Medicine (D.S.W., S.L.G., W.Y.F., E.J.B.) and Anthropology (D.L.L.), University of Washington, Seattle, Washington 98195; ZymoGenetics Corporation (J.L.K.), Seattle, Washington 98102; and Veterans Affairs Medical Center (E.J.B.), Seattle, Washington 98108

Address all correspondence and requests for reprints to: David S. Weigle, Division of Endocrinology, Box 359757, Harborview Medical Center, 325 Ninth Avenue, Seattle, Washington 98104. E-mail: weigles{at}zgi.com


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Variability in the relationship of plasma leptin level to body mass index (BMI) could be caused by imperfect estimation of adipose mass by the BMI, heterogeneity in the pathogenesis of obesity in mixed subject groups, or variation in adipose tissue distribution. To investigate these possibilities, we examined the correlation of plasma leptin and BMI in an ethnically mixed population, a group of subjects with the Prader-Willi syndrome, and a group of Japanese-American subjects who underwent computerized tomographic measurement of adipose tissue cross-sectional areas. Highly significant and indistinguishable linear relationships between plasma leptin levels and BMI were found in the three study groups. Intersubject variability was also similar in the three groups and was reduced only when more accurate techniques for assessing adipose tissue mass were substituted for the BMI. The plasma leptin level of Japanese-American subjects in the highest quartile of intraabdominal fat area (mean area = 154.5 ± 38.4 cm2) was 12.5 ± 8.7 ng/mL as compared to 12.3 ± 9.6 ng/mL (P = 0.91) for subjects in the lowest quartile of intraabdominal fat area (mean area = 51.2 ± 20.1 cm2, P < 0.001 for difference in fat areas). We conclude that the circulating leptin level reflects total adipose tissue mass rather than a combination of adipose tissue mass and distribution, and that the Prader-Willi syndrome does not alter the relationship between these two variables.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE POLYPEPTIDE hormone leptin has been proposed to be an important signal by which adipocytes communicate with the central nervous system (CNS) for the purpose of regulating long-term energy storage (1, 2, 3, 4). In support of this hypothesis, plasma leptin levels in humans demonstrate a positive relationship to indices reflecting total adipose tissue mass (5, 6, 7). This relationship is far from perfect, however, with as much as a 12-fold range in plasma leptin levels observed between individuals of the same body mass index (BMI) (5, 6, 7). Differential sensitivity to leptin has been proposed to account for this variability (5). An alternative explanation could be that individuals of comparable total body fat content have significant unmeasured differences in adipose tissue distribution, with specific adipose depots differing in their ability to produce leptin (8). To evaluate this possibility, we examined the impact of body fat distribution on circulating leptin levels in a large population of Japanese-Americans who had undergone computerized tomography (CT) scanning to assess adipose tissue cross-sectional areas. Advantages to studying this population included the ethnic homogeniety of subjects, and the precision with which CT scanning could differentiate intraabdominal from subcutaneous adipose tissue. A second alternative explanation for the variability in leptin levels among individuals with similar body composition could be heterogeniety in the mechanisms by which they attained that body composition. To investigate this possibility we examined the relationship between plasma leptin levels and BMI in a group of subjects with the Prader-Willi syndrome. All individuals in this group shared a common inherited pathogenetic factor for the accumulation of adipose tissue and ultimately for the development of obesity.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study population consisted of 46 lean and obese human subjects of mixed ethnicity recruited by newspaper advertisement, 18 individuals with a diagnosis of Prader-Willi syndrome confirmed by chromosomal analysis, and 189 Japanese-American men and women. Clinical characteristics and mean plasma leptin levels of the three study groups are summarized in Table 1Go. Obesity was defined as a BMI > 27.3 for males and 27.8 for females (9). Subjects had normal physical examinations, and with the exception of Prader-Willi individuals, whose food consumption was monitored to varying degrees in a supervised care environment, subjects were not actively limiting caloric intake, using medications, or exercising in an effort to lose weight at the time of study. The height and weight of each subject was measured, and EDTA plasma was collected between 0730 and 1100 h after an overnight fast. Plasma insulin levels were measured by RIA in all subject groups. Percentage body fat of the mixed subject group was determined by hydrodensitometry after correction for residual lung volume, as described previously (10). All study procedures were approved by the University of Washington Human Subjects Review Committee.


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  		Table 1. Subject characteristics

 
The 189 Japanese-American subjects were selected from 544 men and women currently enrolled in the Japanese-American Community Diabetes Study (11, 12, 13). All subjects in this study underwent CT assessment of adipose tissue distribution at the time of enrollment. To ensure that extremes in obesity were represented, subjects were first grouped by gender and second or third generation status. Within each of these groups, subjects were divided into quartiles based on three measures of adipose mass: BMI, total subcutaneous adipose area, and intraabdominal adipose area. Obese subjects were selected to be those who were in the highest quartiles for all three adipose measures (n = 56). Lean subjects were those in the lowest quartiles (n = 62). Of the subjects that remained, those who had measures in the highest intraabdominal adipose quartile (n = 42) and the lowest quartile (n = 29) were selected to assess the effect of a wide range of intraabdominal adipose mass on plasma leptin levels

The methodology for assessing regional adipose tissue distribution by CT scanning has been described in detail previously (14). Briefly, a GE 8800 scanner (General Electric Medical Systems Americas, Milwaukee, WI) was used to obtain single 10-mm slices of the thorax on inspiration at the level of the nipples, of the abdomen at the level of the umbilicus, and of the midthigh at a level halfway between the greater trochanter and the superior margin of the patella. Each CT slice was analyzed for cross-sectional area in cm2 of adipose tissue defined to range between -250 and -50 Hounsfield Units using standard GE 8800 computer software. Total subcutaneous adipose area was taken as the sum of thorax, abdominal, and midthigh subcutaneous adipose area measurements, and intraabdominal adipose area was measured within the confines of the transversalis fascia.

Leptin measurements were made with a commercially available RIA kit based on a polyclonal antiserum raised against full-length recombinant human leptin (Linco, St. Charles, MO). The interassay coefficient of variation was 11.9%, and the intraassay coefficient of variation was 4.8%. Recovery of recombinant leptin added to human serum was 91.7 ± 5.1% at 2 ng/mL, 97.6 ± 4.2% at 4 ng/mL, and 105.5 ± 4.9% at 10 ng/mL.

Statistical analyses

Student’s t tests were used to compare mean leptin levels and other continuous measures by groups. The significance of categorical data by groups was assessed with chi-square tests. Relationships between leptin and other continuous measures were assessed with Pearson correlation coefficients. Analysis of covariance and multiple linear regression were used to adjust means and correlations for potential confounders. All data are expressed as mean ± SD.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
As summarized in Table 1Go, a wide range of BMI values was represented in the three study groups. The Prader-Willi subjects were significantly younger (P < 0.0001), tended to be more obese, and had a significantly greater mean plasma leptin level (P = 0.012) than the other groups. Continuous analysis of BMI and plasma leptin levels demonstrated highly significant and remarkably similar linear relationships in the three separate study groups (Fig. 1Go). When all three groups were combined using a linear regression model of leptin on BMI, group, and the interaction between BMI and group, the coefficients for the group and interaction terms were insignificant, whereas the BMI coefficient was significant at the P < 0.0001 level. These results confirmed the equivalence of the BMI-leptin relationships among the three groups. The variance of the regressions shown in Fig. 1Go was considerably reduced when a nonlinear model was used, and either percent body fat or the sum of total subcutaneous and intraabdominal adipose area was substituted for BMI as an index of body composition (Fig. 2Go). Of a variety of models tested, the exponential functions shown in Fig. 2Go provided an optimal fit to the data.



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  		Figure 1. Relationship of plasma leptin levels to BMI in mixed (A), Prader-Willi syndrome (B), and Japanese-American (C) subject groups. Lines and equations represent best least squares linear fit to each data set. All regressions were significant at P < 0.001 level.

 


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  		Figure 2. Relationship of plasma leptin levels to percent body fat determined by hydrodensitometry in mixed subject group (A) and to sum of intraabdominal and total subcutaneous adipose areas in Japanese-American subject group (B). Lines and equations represent best least squares exponential fit to each data set. Both regressions were significant at P < 0.0001 level.

 
The relationship between fasting plasma insulin and leptin levels in the combined subject groups is shown in Fig. 3Go. The correlation coefficient for this relationship was 0.51 (P < 0.0001). After adjustment for group membership, age, gender, and BMI, the correlation coefficient dropped to 0.14, but the relationship remained significant with a P-value of 0.0096.



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  		Figure 3. Relationship between fasting plasma leptin and insulin levels in combined mixed, Prader-Willi syndrome, and Japanese-American subject groups. Line represents best least squares linear fit to data set (y = 0.821x + 4.189, r = 0.505, P < 0.0001).

 
To evaluate the effect of regional fat distribution on plasma leptin levels, Japanese-American subjects in the highest and lowest quartiles for intraabdominal adipose area, but not in the highest and lowest quartiles for BMI or total subcutaneous adipose area, were compared (Analysis A, Table 2Go). Mean plasma leptin levels of the two quartiles were identical despite a significant 3-fold difference in intraabdominal adipose area. The subjects were then divided into highest and lowest quartiles for all of BMI, intraabdominal fat area, and total subcutaneous fat area (Analysis B, Table 3Go). In this analysis the plasma leptin level of the highest quartile was five times that of the lowest quartile (P < 0.001), as expected from the data shown in Figs. 1Go and 2Go. To exclude the possibility that impaired glucose tolerance (IGT) or noninsulin-dependent diabetes mellitus (NIDDM) confounded the interpretation of data from the Japanese-American subject group, the relationship between plasma leptin levels and diagnosis was examined in both Analyses A and B. There was no correlation between plasma leptin and the presence of IGT or NIDDM in subjects with widely differing intraabdominal adipose areas but comparable total adipose mass (Analysis A, P = 0.80). Similarly, after adjusting for obesity quartile, there was no correlation between plasma leptin and the presence of IGT or NIDDM in subjects selected for extremes of all measures of adipose mass (Analysis B, P = 0.79).


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  		Table 2. Analysis A: Japanese-American subjects divided into highest and lowest quartiles for intraabdominal fat only

 

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  		Table 3. Analysis B: Japanese-American subjects divided into highest and lowest quartiles for all of BMI, total subcutaneous fat, and intraabdominal fat

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our data clearly confirm a direct relationship between plasma leptin levels and the BMI of an ethnically mixed study group, as reported by others (5, 6, 7). The slope, intercept, and precision of this relationship do not differ significantly in comparison with a diagnostically homogeneous group of subjects with the Prader-Willi syndrome or an ethnically homogeneous group of Japanese Americans. The precision of the relationship is considerably improved, however, when a more accurate technique for measuring body fat such as hydrodensitometry or CT scanning is substituted for the BMI. These techniques also demonstrate that leptin rises exponentially with body adiposity, confirming the log/linear relationship between leptin and percent body fat reported by two other groups (5, 6). This nonlinear relationship suggests that positive regulators of leptin secretion independently related to the accumulation of body fat may augment the production of leptin by an increased number of adipocytes in severely obese individuals.

Insulin has been suggested on the basis of in vitro and animal studies to be an important positive regulator of leptin secretion (15, 16, 17). Our data confirmed a direct relationship between fasting plasma insulin and leptin levels in the combined subject groups. The significance of this relationship was attenuated, but not eliminated, by adjustment for BMI. Thus, there appeared to be a weak association between insulin and leptin levels that was not explained by the strong association between insulin level and adiposity. These findings are in agreement with a recent report that sustained hyperinsulinemia leads to increased circulating leptin levels in lean human subjects (18).

The possibility that adipocytes from different anatomic regions differ in their ability to secrete leptin has been examined to date only through analysis of adipose tissue leptin messenger RNA (mRNA) levels using hybridization and PCR techniques. One study (19) found similar leptin mRNA levels in mesenteric and subcutaneous adipose tissues from both lean rats and rats that had been made obese by electrolytic ventromedial hypothalamic lesions. Another study (20) found leptin mRNA levels to be lower in the inguinal and parametrial fat pads of lean mice than in abdominal or perirenal fat pads. Limited human data are available from adipose tissue samples obtained during surgical procedures. These data are also confusing with one study of five subjects reporting no regional differences in leptin mRNA expression (21) and another study of seven subjects finding higher leptin mRNA levels in subcutaneous adipose tissue than in omental, retroperitoneal, or mesenteric adipose tissue (8). Even if conclusive data were available from animal and human studies of this nature, it would be necessary to examine the relationship between regional fat distribution and circulating leptin, the pool which presumably gains access to the CNS.

Analysis of the Japanese-American subject group clearly demonstrates that subjects with comparable total adipose mass but widely different adipose distributions have comparable circulating leptin levels. The division of subjects in Analysis A was designed to create maximal interindividual differences in intraabdominal fat, motivated by the abundant literature suggesting that this depot is more metabolically active than subcutaneous adipose tissue. Because the BMI and total adipose areas of the two quartiles were similar, this division also resulted in a significantly greater subcutaneous adipose area in the lowest quartile of intraabdominal fat as compared to the highest quartile. It is, therefore, unlikely that we would have overlooked an effect of intraabdominal adipose tissue, subcutaneous adipose tissue, or the ratio of these two depots on circulating leptin levels.

These results indicate that leptin behaves as if it is monitoring total body fat content independent of regional fat distribution, insulin level, presence of diabetes, or presence of the chromosomal disorder that results in the Prader-Willi syndrome. Leptin is, therefore, an ideal candidate for the lipostatic factor postulated by Kennedy (22) to play a dominant role in regulating body composition. The positive exponential relationship of plasma leptin level to body fat content should result in the delivery of an increasingly strong satiety and thermogenic signal to the CNS as obesity becomes more severe (1, 2, 3, 4). The fact that obesity can coexist with a high leptin level has been interpreted to indicate the presence of leptin resistance with increasing body fat content (5). An alternative explanation could be that a totally unrelated defect leads to a progressive gain in adipose tissue that is limited only when the plasma leptin level becomes high enough to deliver a supernormal counterregulatory signal to a normally leptin-sensitive CNS. Future research should clarify these issues.


   Acknowledgments
 
We thank Dr. Stephen Sulzbacher, Stephen Lund, and Russ Myler for their assistance in recruiting subjects with the Prader-Willi syndrome, Jane Shofer for her assistance with statistical analysis, and Rob Hastings for his excellent technical assistance.


   Footnotes
 
1 This work was supported in part by NIH Grants DK 31170, HL 49293, RR 00037, DK 35816, and DK 17047. Back

Received June 17, 1996.

Accepted October 31, 1996.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Weigle DS, Bukowski TR, Foster DC, et al. 1995 Recombinant ob protein reduces feeding and body weight in the ob/ob mouse. J Clin Invest. 96:2065–2070.
  2. Pelleymounter MA, Cullen MJ, Baker MB, et al. 1995 Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 269:540–543.[Abstract/Free Full Text]
  3. Halaas JL, Gajiwala KS, Maffei M, et al. 1995 Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 269:543–546.[Abstract/Free Full Text]
  4. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. 1995 Recombinant mouse ob protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 269:546–549.[Abstract/Free Full Text]
  5. Maffei M, Halaas J, Ravussin E, et al. 1995 Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Med. 1:1155–1161.[CrossRef][Medline]
  6. Considine RV, Sinha MK, Heiman ML, et al. 1996 Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 334:292–295.[Abstract/Free Full Text]
  7. McGregor GP, Desaga JF, Ehlenz K, et al. 1996 Radioimmunological measurement of leptin in plasma of obese and diabetic human subjects. Endocrinology. 137:1501–1504.[Abstract]
  8. Masuzaki H, Ogawa Y, Isse N, et al. 1995 Human obese gene expression. Adipocyte-specific expression and regional differences in the adipose tissue. Diabetes. 44:855–858.[Abstract]
  9. National Institutes of Health Consensus Development Panel on the Health Implications of Obesity. 1995 Consensus conference statement. Ann Intern Med. 103:1073–1077.
  10. Weigle DS. 1988 Contribution of decreased body mass to diminished thermic effect of exercise in reduced-obese men. Int J Obesity. 12:567–578.[Medline]
  11. Fujimoto WY, Leonetti DL, Kinyoun JL, et al. 1987 Prevalence of diabetes mellitus and impaired glucose tolerance among second generation Japanese-American men. Diabetes. 36:721–729.[Abstract]
  12. Fujimoto WY, Leonetti DL, Bergstrom RW, Kinyoun JL, Stolov WC, Wahl PW. 1991 Glucose intolerance and diabetic complications among Japanese-American women. Diab Res Clin Pract. 13:119–130.[CrossRef][Medline]
  13. Fujimoto WY, Bergstrom RW, Leonetti DL, Newell-Morris LL, Shuman WP, Wahl PW. 1994 Metabolic and adipose risk factors for NIDDM and coronary disease in third generation Japanese-American men and women with impaired glucose tolerance. Diabetologia. 37:524–532.[CrossRef][Medline]
  14. Shuman WP, Newell-Morris LL, Leonetti DL, et al. 1986 Abnormal body fat distribution detected by computed tomography in diabetic men. Invest Radiol. 21:483–487.[Medline]
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  16. Cusin I, Sainsbury A, Doyle P, Rohner-Jeanrenaud F, Jeanrenaud B. 1995 The ob gene and insulin: a relationship leading to clues to understanding of obesity. Diabetes. 44:1467–1470.[Abstract]
  17. Saladin R, De Vos P, Guerre-Millo M, et al. 1995 Transient increase in obese gene expression after food intake or insulin administration. Nature. 377:527–529.[CrossRef][Medline]
  18. Kolaczynski JW, Nyce MR, Considine RV, et al. 1996 Acute and chronic effect of insulin on leptin production in humans. Studies in vivo and in vitro. Diabetes. 45:699–701.[Abstract]
  19. Funahashi T, Shimomura I, Hiraoka H, et al. 1995 Enhanced expression of rat obese (ob) gene in adipose tissues of ventromedial hypothalamus (VMH)-lesioned rats. Biochem Biophys Res Commun. 211:469–475.[CrossRef][Medline]
  20. Maffei M, Fei H, Lee G-H, et al. 1995 Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations at the db locus. Proc Natl Acad Sci USA. 92:6957–6960.[Abstract/Free Full Text]
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