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Sexual Dimorphism in Plasma Leptin Concentration¹

Department of Medicine, University of Southern California Medical School, Los Angeles, California 90033; and Linco Research, Inc. (R.L.G.), St. Louis, Missouri 63304

Address all correspondence and requests for reprints to: Mohammed F. Saad, M.D., MRCP, Division of Endocrinology and Diabetes, University of Southern California Medical School, 1200 North State Street, Unit I, P.O. Box 710, Los Angeles, California 90033.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Leptin, the obese (ob) gene product, is thought to be a lipostatic hormone that contributes to body weight regulation through modulating feeding behavior and/or energy expenditure. The determinants of plasma leptin concentration were evaluated in 267 subjects (106 with normal glucose tolerance, 102 with impaired glucose tolerance, and 59 with noninsulin-dependent diabetes). Fasting plasma leptin levels ranged from 1.8–79.6 ng/mL (geometric mean, 12.4), were higher in the obese subjects, and were not related to glucose tolerance. Women had approximately 40% higher leptin levels than men at any level of adiposity. After controlling for body fat, postmenopausal women had still higher leptin levels than men of similar age, and their levels were not different from those in younger women. Multiple regression analysis showed that adiposity, gender, and insulinemia were significant determinants of leptin concentration, explaining 42%, 28%, and 2% of its variance, respectively. Neither age nor the waist/hip ratio was significantly related to leptin concentration. Thus, our data indicate that gender is a major determinant of the plasma leptin concentration. This sex difference is not apparently explained by sex hormones or body fat distribution. Leptin’s sexual dimorphism suggests that women may be resistant to its putative lipostatic actions and that it may have a reproductive function.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
LEPTIN, the obese(ob) gene product, is a 16-kDa peptide hormone secreted by adipocytes (1, 2, 3, 4). It is highly conserved in different vertebrates, with approximately 85% structural homology in mouse, rat, and man (1, 2, 3, 4). Leptin is thought to be a homeostatic signal that contributes to body weight regulation through modulating feeding behavior and/or energy expenditure (1, 4). Mutations of the ob gene that lead to leptin deficiency or production of a truncated inactive protein are associated with hyperphagia, hypometabolism, obesity, and noninsulin-dependent diabetes mellitus (NIDDM) in obese ob/ob mice (1). Peripheral or central administration of recombinant leptin to these mice decreased food intake, increased energy expenditure, and caused weight loss (5, 6, 7, 8, 9). Similar effects were described in wild-type (5, 6, 7) and diet-induced obese (8) mice.

Leptin’s role in obesity and NIDDM in man is not known. No mutations in the ob gene (10, 11, 12) or defects in its expression (12, 13, 14) have been found in human obesity. Genetic variations at the ob locus do not appear to contribute to NIDDM susceptibility (15, 16), but may be linked to extreme obesity (17, 18). In addition, plasma leptin levels were shown to be elevated in obese subjects (19, 20). Little is known, however, about factors that regulate the plasma leptin concentration or its relation to glucose tolerance. This work was undertaken, therefore, to examine the determinants of leptin concentration in lean and obese subjects across the spectrum of glucose tolerance.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study included 267 Asian Indians (127 men and 140 women), aged 45 ± 1 yr (mean ± SEM), residing in Los Angeles, CA. Subjects were participants in a study on diabetes and cardiovascular disease among Asian Indian immigrants to the United States and were recruited by advertisement from the local community. Subjects taking any medications were excluded. The study was approved by the institutional review board of the University of Southern California, and all subjects gave informed consent.

Subjects underwent an examination that included measurement of height, weight, blood pressure, and waist and hip circumferences. Body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters. Fat mass was determined by bioelectrical impedance (RJL Systems, Mt. Clemens, MI). Total body water was estimated using sex-specific equations (21). Fat-free mass (FFM) was assumed to have a hydration constant of 0.73 and was calculated with the formula: FFM = total body water/0.73. Fat mass was also determined by dual energy x-ray absorptiometry (22) (DEXA; QDR-2000, Hologic, Waltham, MA) in a subset of 91 subjects (50 men and 41 women). Among these subjects, there was no difference in fat mass, as determined by bioelectrical impedance and DEXA (P = 0.29), and both measurements were strongly correlated (r = 0.89; P < 0.001).

All subjects underwent an oral glucose tolerance test after a 10- to 12-h overnight fast. Blood was collected at -15, 0, 30, 60, 90, and 120 min for determination of plasma glucose and insulin concentrations. According to WHO criteria (23), 106 subjects had normal glucose tolerance, 102 had impaired glucose tolerance, and 59 had NIDDM (Table 1). The plasma leptin concentration was determined at -15 and 0 min for all subjects and after the glucose load for a subset of 10 men and 10 women from each glucose tolerance category.

The plasma glucose concentration was measured by the glucose oxidase method. Plasma insulin was determined by a specific RIA with reagents from Linco Research (St. Louis, MO), with a detection limit of 6 pmol/L and interassay coefficients of variation from 6–8%. The plasma leptin concentration was measured with a recently developed RIA (Linco Research) that uses a polyclonal antibody raised in rabbits against recombinant human leptin (24). The assay had a sensitivity of 0.5 ng/mL and interassay coefficients of variation from 5–7%. To determine day to day variability, fasting plasma leptin was measured in 10 subjects on 5 different days between 0700–0800 h within a 4-week period. The individual coefficient of variation ranged between 6.9–21.1%, with an average of 11.9 ± 1.4%.

Statistical analyses

Data are expressed as the mean ± SEM or as the mean with 95% confidence interval (CI). Insulin and leptin concentrations were log transformed to normalize the distribution. Statistical analyses were performed with programs from SPSS (Chicago, IL) (25). Comparisons among groups were performed with ANOVA. Linear regression and/or Pearson product-moment correlations were used to evaluate the relation among different variables. Multiple linear regression with a backward-stepwise procedure was used to define the variables most predictive of the fasting leptin concentration.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The fasting plasma leptin concentration ranged from 1.8–79.6 ng/mL, with a geometric mean of 12.4 (95% CI, 11.3–13.6). Women had, on the average, 3-fold higher leptin levels than men [20.3 ng/mL (CI, 18.5–22.3) vs. 7.0 (CI, 6.4–7.7); P < 0.001; Fig. 1A]. After adjusting for percent body fat, women continued to have approximately 40% higher leptin levels [14.4 ng/mL (CI, 13.3–15.5) vs. 10.3 (CI, 9.5–11.2); P < 0.001; Fig. 1B]. Postmenopausal women had higher leptin concentrations than men of similar age [14.9 (CI, 11.7–19.1) vs. 10.3 (CI, 8.1–13.0), respectively; P = 0.03], but these values were not different from those in younger women (P = 0.69) after controlling for body fat. Leptin levels were similar in the three glucose tolerance categories. Women still had significantly higher levels than men in each category independent of body fat (Fig. 2). Plasma leptin did not change significantly during the oral glucose tolerance test in any glucose tolerance group.

View larger version (17K): [in this window] [in a new window]   Figure 1. Fasting plasma leptin concentration in men (solid circles) and women (open circles) before (A) and after (B) adjusting for percent body fat. Solid lines indicate the geometric means. P < 0.001 for differences between men and women in each panel.

View larger version (17K): [in this window] [in a new window]   Figure 2. Fasting plasma leptin concentration, adjusted for percent body fat, in men and women in the three glucose tolerance categories. By two-way ANOVA: P = 0.178 for glucose tolerance status, and P < 0.001 for gender.

View larger version (39K): [in this window] [in a new window]   Figure 3. The relation between leptin and BMI and fat mass in men (solid circles) and women (open circles). The upper panels show data for the whole group; fat mass was determined by bioelectrical impedance (BIA). The lower panels show data for a subset in whom fat mass was determined by DEXA. Slopes of the regression lines were significantly different in the upper left panel (P = 0.03). In all other panels, the slopes of the regression lines were similar, but the intercepts were different (P < 0.001).

View larger version (25K): [in this window] [in a new window]   Figure 4. The relation between fasting plasma insulin and leptin concentrations in men (solid circles) and women (open circles) before (A) and after (B) adjusting for percent body fat. The slopes of the regression lines were similar, but the intercepts were different (P < 0.001) in both panels.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Leptin’s role in human obesity is unclear. No mutations in the ob gene (10, 11, 12) or defects in its expression (12, 13, 14) have been found in obese subjects. Our data and others (19, 20) suggest that human obesity is not caused by leptin deficiency, because its levels increase progressively with fat mass. Nonetheless, interindividual variability in leptin production and/or sensitivity to its actions could contribute to the development of obesity. Leptin levels differed considerably in subjects with similar fat mass. For example, leptin levels ranged between 1.8–14.4 ng/mL (median, 5.9; n = 19) in men and from 7.2–28.9 ng/mL (median, 11.6; n = 11) in women with a fat mass of 14–16 kg. Likewise, Maffie et al. (19) described significant heterogeneity in leptin concentrations among subjects with similar BMI. It is possible, therefore, that subjects whose leptin levels are appropriate for their fat mass are more able to keep their weight stable, whereas those with inadequate levels are more prone to weight gain. Individuals may also differ in their sensitivity to leptin. Some animal models of obesity, such as the db/db mouse and the fa/fa rat, are leptin resistant due to mutations in its receptors (27, 28). Moreover, leptin resistance could be induced in mice by a high fat diet (29). Further studies are needed to explore whether genetic or acquired leptin resistance exists in man.

Women had higher leptin levels than men at any percent body fat or fat mass. Two studies (19, 20) described similar findings in relation to BMI, but found no difference when men and women with similar percent body fat were compared. This discrepancy could be explained by differences in sample size, subject characteristics, or methodology. The current study included a larger and more homogeneous group of subjects belonging to a single ethnic group with a balanced sex distribution. Conversely, the other studies (19, 20) included subjects of mixed ethnicity, with a preponderance of women. Although ethnicity does not appear to affect the leptin level or its relation to adiposity (19, 20, 30, 31), the precision of different methods of body composition determination varies in various ethnic groups (32, 33). Therefore, we used two different methods of body composition determination, bioelectrical impedance and DEXA, to confirm our findings. Moreover, we found a similar sex difference in the relation between leptin and body fat in African-Americans and Hispanics using yet a third method (underwater weighing) for body composition determination (unpublished observations). Leptin may circulate, however, in several biochemical or molecular forms that vary in men and women and are not equally detected by our immunoassay and those used in the other two studies (19, 20).

Our findings are supported by Lönnqvist et al. (14), who found a 75% higher ob gene expression in obese women than in obese men. Moreover, Schwartz et al. (34) have found higher cerebrospinal fluid leptin concentrations in women than in men after controlling for age, BMI, and plasma leptin level. A sex difference has also been described in mice; Frederich et al. (29) showed that female mice had higher plasma leptin levels and adipose tissue ob mRNA than males at any given body fat content. It appears, therefore, that female fat cells produce more leptin than those of males with similar body composition.

The mechanism of the sexual dimorphism in leptin production is unclear. Sex hormones do not appear to be the culprit. Postmenopausal women had leptin levels higher than men of similar age and not different from those of younger women after adjusting for body fat. Differences in fat distribution might play a role. Masuzaki et al. (2) found subcutaneous fat to express more leptin mRNA than intraabdominal fat. Thus, central (or visceral) android adipose tissue may produce less leptin than peripheral gynecoid fat, accounting for the differences between men and women. Leptin levels were not, however, related to the waist/hip ratio independent of the total fat mass. A further possibility is a sex difference in the hypothalamic regulation of leptin production. Sainsbury et al. (35) reported that intracerebroventricular administration of neuropeptide Y increased ob gene expression in white adipose tissue in normal rats. Sexual dimorphism characterizes several hypothalamic nuclei (36) as well as neuropeptide Y gene expression (37) and secretion (38). Finally, female adipose tissue may be more sensitive to hormones (e.g. insulin) or other substances that stimulate leptin production.

The sexual dimorphism in leptin levels suggests that women may be less sensitive than men to its lipostatic actions, leading to compensatory increase in its production and possibly its transport to the cerebrospinal fluid (34). Leptin may also have a reproductive function. Ahima et al. (39) recently reported that leptin administration prevented the starvation-induced delay in ovulation in female mice and the fall in testosterone concentration in males. These effects were associated with an increase in LH levels, suggesting that leptin acts at the level of the hypothalamic-pituitary axis. In addition, an isoform of leptin receptor has been described in murine and human reproductive organs (40). Leptin deficiency in the ob/ob mouse is associated with sterility. Leptin administration to homozygous female ob/ob mice corrected their sterility, resulting in ovulation, pregnancy, and parturition (41). This effect was independent of weight loss, as diet restriction failed to correct sterility. Moreover, mutations of the leptin receptor in the db/db mouse result not only in leptin resistance and adiposity but also in aberrant regulation of sex steroid sulfotransferase genes, virilization of hepatic metabolism, and sterility (42). Obesity in humans can also be associated with reproductive dysfunction. Further work is needed to explore the implications of leptin’s sexual dimorphism and its role in reproduction.

Insulinemia explained only 2% of the variance in leptin concentration. No increase was observed in leptin levels during the oral glucose tolerance test despite the increase in insulinemia. In addition, leptin concentrations do not change significantly after meals (19, 20) or after short term insulin infusion (43, 44). However, a long term effect of insulin on leptin production could be shown in vivo and in vitro (44), suggesting that insulin is involved in regulating leptin production, but not its release. Insulin may, therefore, contribute to the increased leptin levels in obesity that is commonly associated with hyperinsulinemia.

Obesity is a major risk factor for impaired glucose tolerance and NIDDM. Leptin levels were not correlated, however, with fasting or 2-h postload plasma glucose concentrations and were not different among the three glucose tolerance categories controlling for adiposity. These findings agree with those of others (45, 46), who reported no difference in leptin levels between subjects with and without NIDDM. Leptin may not, therefore, be directly related to glucose intolerance.

In conclusion, adiposity and gender are the major determinants of leptin concentration. Women had 40% higher leptin levels than men with similar fat mass. This sex difference is not related to sex hormones or fat distribution, but possibly to differences in hypothalamic regulation of leptin production or in adipose tissue biological characteristics. Leptin’s sexual dimorphism suggests that women may be resistant to its lipostatic actions and that it may have a reproductive function. Further work is needed to explore the mechanism and implications of leptin’s sexual dimorphism.

	Acknowledgments

 
We thank the nurses and the staff of the General Clinical Research Center at the University of Southern California for their excellent help in performing the study, and Mr. L. Johnson for performing the DEXA studies.

	Footnotes

 
¹ This work was supported by grants from the American Diabetes Association, Bristol-Myers Squibb, and Linco Research and by Grant M01-RR-43 from the General Clinical Research Branch, National Center for Research Resources, National Institutes of Health.

Received July 25, 1996.

Revised September 24, 1996.

Accepted October 14, 1996.

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				H. Nishizawa, I. Shimomura, K. Kishida, N. Maeda, H. Kuriyama, H. Nagaretani, M. Matsuda, H. Kondo, N. Furuyama, S. Kihara, et al. Androgens Decrease Plasma Adiponectin, an Insulin-Sensitizing Adipocyte-Derived Protein Diabetes, September 1, 2002; 51(9): 2734 - 2741. [Abstract] [Full Text] [PDF]

				H. Laivuori, H.A. Koistinen, S.-L. Karonen, B. Cacciatore, and O. Ylikorkala Comparison between 1 year oral and transdermal oestradiol and sequential norethisterone acetate on circulating concentrations of leptin in postmenopausal women Hum. Reprod., August 1, 2001; 16(8): 1632 - 1635. [Abstract] [Full Text] [PDF]

				F. Callies, M. Fassnacht, J. C. van Vlijmen, I. Koehler, D. Huebler, M. J. Seibel, W. Arlt, and B. Allolio Dehydroepiandrosterone Replacement in Women with Adrenal Insufficiency: Effects on Body Composition, Serum Leptin, Bone Turnover, and Exercise Capacity J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 1968 - 1972. [Abstract] [Full Text]

				L. Unkila-Kallio, S. Andersson, H.A. Koistinen, S.-L. Karonen, O. Ylikorkala, and A. Tiitinen Leptin during assisted reproductive cycles: the effect of ovarian stimulation and of very early pregnancy Hum. Reprod., April 1, 2001; 16(4): 657 - 662. [Abstract] [Full Text] [PDF]

				R. Lucantoni, E. Ponti, M. E. Berselli, G. Savia, A. Minocci, G. Calò, C. De Medici, A. Liuzzi, and A. M. Di Blasio The A19G Polymorphism in the 5' Untranslated Region of the Human Obese Gene Does Not Affect Leptin Levels in Severely Obese Patients J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3589 - 3591. [Abstract] [Full Text]

				M. B. HORLICK, M. ROSENBAUM, M. NICOLSON, L. S. LEVINE, B. FEDUN, J. WANG, R. N. PIERSON Jr., and R. L. LEIBEL Effect of Puberty on the Relationship between Circulating Leptin and Body Composition J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2509 - 2518. [Abstract] [Full Text]

				G. Paolisso, D. Manzella, N. Montano, A. Gambardella, and M. Varricchio Plasma Leptin Concentrations and Cardiac Autonomic Nervous System in Healthy Subjects with Different Body Weights J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 1810 - 1814. [Abstract] [Full Text]

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				B. E Wisse, L A. Campfield, E. B Marliss, J. A Morais, R. Tenenbaum, and R. Gougeon Effect of prolonged moderate and severe energy restriction and refeeding on plasma leptin concentrations in obese women Am. J. Clinical Nutrition, September 1, 1999; 70(3): 321 - 330. [Abstract] [Full Text] [PDF]

				G. Wiesner, M. Vaz, G. Collier, D. Seals, D. Kaye, G. Jennings, G. Lambert, D. Wilkinson, and M. Esler Leptin Is Released from the Human Brain: Influence of Adiposity and Gender J. Clin. Endocrinol. Metab., July 1, 1999; 84(7): 2270 - 2274. [Abstract] [Full Text]

				T. Sir-Petermann, V. Piwonka, F. Perez, M. Maliqueo, S.E. Recabarren, and L. Wildt Are circulating leptin and luteinizing hormone synchronized in patients with polycystic ovary syndrome? Hum. Reprod., June 1, 1999; 14(6): 1435 - 1439. [Abstract] [Full Text] [PDF]