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Catteda di Andrologia, Università La Sapienza (A.M.I., M.C., A.A., A.F.), Italian National Research Centers on Aging (F.S., M.M., G.R.), Cattedra di Endocrinologia, Università di Tor Vergata (C.M., G.F.), 00100 Rome, Italy; and St. Bartholomew’s Hospital (A.F.), London, United Kingdom EC1A 7BE
Address all correspondence and requests for reprints to: Andrea Fabbri, M.D., Ph.D., Cattedra di Andrologia, Dipartimento di Fisiopatologia Medica, Università di Roma La Sapienza, 00100 Rome, Italy. E-mail: a.fabbri{at}caspur.it
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Leptin, the ob gene product secreted by adipose tissue, has been shown to be an integral component of energy homeostasis and regulation of body weight. Leptin circulates in plasma at levels that parallel the amount of body fat. In the adipose tissue of obese subjects, the leptin gene is overexpressed (2), and obese subjects have been found to be resistant to the putative regulatory function of circulating leptin (3). In addition, women have increased ob gene expression (4) and higher plasma leptin concentrations than men, even after correcting serum leptin levels for percent or total body fat (5), indicating that an endocrine involvement may be at the basis of the distinction between males and females.
Leptin secretion is influenced by many hormonal and metabolic factors. In humans, insulin (6, 7, 8, 9, 10), glucocorticoids (11, 12, 13, 14), thyroid hormones (15, 16), estradiol (17, 18, 19), and testosterone (20, 21, 22, 23) have been claimed to stimulate (insulin, glucocorticoids, thyroid hormones, estradiol) or inhibit (testosterone) leptin secretion; at present, however, the respective roles of these hormonal factors in the overall regulation of leptin production have not been fully ascertained. Furthermore, little is known about whether the age-related changes in the hormones known to regulate leptin production might modify circulating leptin levels during aging. Several researchers investigated the effect of age on serum leptin and body composition, but results are discordant and sometimes in conflict (24, 25, 26, 27, 28, 29, 30, 31). It has been suggested that the age-related increase in fat mass can be a major confounding factor in studies that examine the relationship between leptin and age, because adiposity is usually the dominant determinant of leptin (24, 32). Indeed, the effect of age independent of adiposity may be more easily observed in populations in which adiposity is not substantially changing with age.
These studies prompted us to investigate the age-related change in plasma leptin and its correlation with known hormonal modifiers of circulating leptin in a large sample size of nonobese and obese adult male and females with comparable body mass indexes (BMIs). The effects of menopause and aging on the correlation between leptin and BMI were also studied.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A cross-sectional study was made in 470 adult healthy subjects, 150 men and 320 women. Subjects were separated into nonobese [BMI, <30; n = 38 men (age range, 23–68 yr) and 66 women (18–62 yr)] and obese [BMI, >30; n = 112 men (18–77 yr) and 254 women (18–77 yr)]. Physical examination and routine biochemistry were performed to exclude significant diseases. Some of the obese subjects had an impaired glucose tolerance test (according to WHO criteria), but none was overtly diabetic. Some had moderate hypertension. All subjects were weight stable and were consuming the usual Mediterranean-style diet. None of the subjects was taking any medication or reported excessive alcohol consumption. Smokers were not considered as a separate group. All subjects provided informed consent before taking part in the study, and the research protocol was approved by the local ethical committee.
Study protocol
BMI was calculated dividing weight (kilograms) by the square of length (meters). Blood samples were obtained in the morning (0700–0800 h) after an overnight fast. Sera were frozen at -80 C until analysis. In obese subjects an oral glucose (75 g) tolerance test was performed, and samples were taken at 0, 30, 60, 90, 120, and 180 min for glucose and insulin determinations. The hormonal evaluation included leptin, estradiol, testosterone, DHEAS, SHBG, GH, insulin-like growth factor I (IGF-I), TSH, free T3 (fT3), free T4 (fT4), and PRL.
Assays
Testosterone, estradiol, fT3, and fT4 were measured with solid phase commercial RIAs (provided by Diagnostic Products, Los Angeles, CA; and Diagnostics Systems Laboratories, Inc., Webster, TX). TSH, PRL, GH, IGF-I, and SHBG levels were measured by immunoradiometric assay (provided by Diagnostic Products; Diagnostics Systems Laboratories, Inc., and Radim, Pomezia, Italy). Leptin concentrations were measured with a commercial RIA kit (Linco Research, Inc., St. Louis, MO). The intra- and interassay coefficients of variations for all hormonal assays ranged between 3.4–6.2% and 3.6–8.4%, respectively. All determinations were performed in duplicate.
Data analysis
Data are presented as the mean ± SEM of absolute values. The fasting insulin resistance index (FIRI) was calculated as described by Duncan et al. (33); this index was derived as the product of fasting glucose (millimoles per L) and fasting insulin (milliunits per L), normalized by dividing by 25 (5 mmol/L glucose x 5 mU/L insulin). The Kolmogorov-Smirnov one-sample test was used to assess distribution normality for each variable. The Wilcoxon signed rank test was used to evaluate differences in serum leptin and other variables between sexes. Differences in leptin levels of nonobese and obese subjects, and gender differences in other investigated variables were evaluated by means of unpaired t test. Comparisons between age groups were performed using the general factorial analysis of covariance model, controlling for the effect of BMI (ANCOVA). Because of extreme values in the distribution of serum leptin concentrations and BMI, the relations between continuous variables were evaluated by Spearman correlations. Three regression models were fitted to determine the relation among the serum leptin concentration, BMI, and age. The models included a simple linear regression of BMI with either serum leptin on the absolute value or the natural logarithm of the serum leptin concentration. A tridimensional plane surface model was developed from a multivariate regression model that evaluated the simultaneous contributions of BMI and age to serum leptin concentration. Finally, multiple regression analysis with use of the quadratic model was performed in standard, backward, and forward stepwise selection to evaluate the relation of other variables to the serum leptin concentration after controlling for BMI and age. The goal of the regression analysis was to obtain a predictor model that contained relatively few significant determinant variables with the highest coefficient of determination. All analyses were two tailed and conducted with SPSS software (version 7.5 for Windows 5, SPSS, Inc., Chicago, IL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. The large population (n = 470)
covered a wide range of age and body weight; women (n = 320) and
men (n = 150) were considered separately. BMI and age were
normally distributed and similar between sexes (by Wilcoxon test). In
nonobese subjects mean serum leptin was 2 times higher in women than in
men (23.5 ± 1.5 vs. 9.0 ± 0.8 ng/mL;
P < 0.01) and 33% higher in obese women than in obese
men (43.5 ± 1.5 vs. 29.0 ± 1.5 ng/mL;
P < 0.01). Leptin distribution could be considered
normal by Kolmogorov-Smirnov analysis. In both sexes insulin, C peptide
and FIRI were significantly higher in obese than in nonobese subjects,
whereas SHBG, GH, and IGF-I were lower in the groups of obese subjects.
Serum testosterone was significantly lower in obese than in nonobese
men, whereas in women it was statistically higher in obese than in
nonobese subjects.
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. The
boxes indicate the lower and upper quartiles, and the
central line is the median of leptin distribution. The
bars at the ends of the whisker are the 2.5% and 97.5%
values; values outside this range are plotted individually.
Interestingly, the values of plasma leptin showed a tendency toward a
reduction in older obese subjects of both sexes, but not in nonobese
subjects. Therefore, a multifactor ANOVA was performed with leptin as
the dependent variable, the three age groups as the main factor effect,
and BMI as a covariate to identify significant differences in leptin
levels between age groups. Table 2
summarizes the effect of grouping the population by age on mean
BMI-adjusted leptin levels according to BMI and sex. The BMI-adjusted
leptin levels were progressively lower with increasing age in obese and
nonobese women (P < 0.001 and P <
0.05, by ANCOVA) and tended to an age-related reduction in obese
(P = 0.087) and nonobese (P = 0.163)
men that did not reach statistical significance. In women, the percent
difference in BMI-adjusted mean leptin concentrations was 5–6 times
greater between the older and middle-age groups than between the
middle-age and younger groups (Table 2). Furthermore, in pre- and
postmenopausal women a significant difference in mean leptin levels was
observed between subjects [premenopause, 41.7 ± 1.7 ng/mL;
postmenopause, 33.1 ± 1.7 ng/mL; change, -21%;
P < 0.001, by ANCOVA]. In contrast, in men there was
no age cut-off capable of splitting subjects into two groups with
different leptin levels.
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shows that
leptin levels were positively correlated with BMI in fertile (r =
0.65; P < 0.001) and postmenopausal women (r =
0.32; P < 0.05). Importantly, however, we found
distinct differences in the slopes of the regression lines. Leptin
levels rose more rapidly (2 times) as a function of BMI in fertile
(leptin = 1.97 x BMI - 27.6; r2
= 0.4) than in postmenopausal women (leptin = 1.04 x
BMI - 6.1; r2 = 0.19). Also, in
postmenopausal women the magnitude of the correlation was weak, and the
coefficient, r2, was low, indicating a possible
dysregulation of leptin secretion. In males the BMI-dependent rise in
leptin levels (leptin = 1.38 x BMI - 27.1;
r2 = 0.58; Fig. 2B) was 40% lower and 30%
higher than those in pre- and postmenopausal women, respectively.
However, because the y-intercept of the regression line in
men (-27.2) was much lower than that in postmenopausal women (-6.1),
in absolute values men still had mean serum leptin levels lower
(30–50%) than postmenopausal women.
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, A and B, shows the
three-dimensional plane surface models (z =
zo + ax + by)
obtained by multiple regression of the relationship among leptin
(z), BMI (x), and age (y), considering
the whole population of both genders. In women (Fig. 3A), the
association among the three variables was expressed by the linear
equation: leptin = +1.71 x BMI - 0.29 x
years - 6.82 (r = 0.63; P < 0.001). In men
(Fig. 3B), the relation was expressed by the linear equation:
leptin = +1.38 x BMI - 0.18 x years -
19.43 (r = 0.71; P < 0.01). BMI-adjusted leptin
levels declined during aging in both genders, and the slope of the
decline tended to be higher in women than in men (-0.29 ± 0.06
vs. -0.18 ± 0.05; P = 0.15).
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, A and B, shows the relationship
between estradiol (A) or testosterone (B) and BMI-adjusted serum leptin
in the whole population divided by means of sex and BMI (<30 and
>30). To identify independent contributors of sex hormones to serum
leptin levels, leptin was regressed on BMI, and the residuals from
regression were added to serum leptin values separately for each group.
The obtained distribution was transformed into a natural logarithm.
Because of extreme values in the distribution of sex hormones, the
natural logarithms were preferred for linear regression analysis. A
positive significant association was observed between the natural
logarithms of BMI-adjusted leptin and serum estradiol obtained by
linear regression in the group of nonobese (r = 0.30;
P = 0.014) and obese (r = 0.27; P
< 0.001) women (Fig. 4A). Figure 4B shows that ln of serum
testosterone contributed as a negative determinant to the natural
logarithms of serum leptin in obese (r = -0.20; P
= 0.031), but not in nonobese (r = -0.16; P =
0.333), men. Interestingly, in nonobese men the relationship between ln
leptin and ln testosterone was statistically significant when
controlled for the effect of age (see also Table 4).
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. In nonobese women, serum leptin did
not correlate with any of the hormonal parameters evaluated; whereas in
obese women, leptin was positively correlated with estradiol, FIRI,
insulin area under the curve, fasting insulin, and C peptide and
negatively correlated with SHBG and GH. In nonobese men, leptin was
positively correlated with TSH and C peptide, whereas in obese men,
leptin was positively correlated with FIRI, fasting insulin, and C
peptide and negatively correlated with testosterone. In both genders
age was negatively correlated with sex hormones, GH, and IGF-I and
positively correlated with indexes of glucose metabolism (glucose area
under the curve, fasting glucose, FIRI, or C peptide). In women, the
correlation between leptin and estradiol increased after adjustment for
BMI, especially in the group of nonobese subjects. To the contrary, in
both sexes the associations among leptin, GH, IGF-I, and indexes of
glucose metabolism lost significance when controlled for BMI.
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).
Fasting plasma leptin concentration, age, BMI, and all the hormonal
parameters that significantly correlated with leptin or age were
included in the regression model. In nonobese and obese women, the
multiple linear regression in backward selection produced a model that
explained 34.2% (adjusted r2) and 36.4% of
leptin variability, respectively; BMI, age, and estradiol were
significantly and independently associated with circulating leptin.
Furthermore, in obese women, DHEAS contributed to serum leptin levels.
In nonobese and obese men, BMI, age, and testosterone were significant
contributors to serum leptin levels. SHBG was also an independent
contributor in the group of obese subjects.
To evaluate the independent contributions of the hormonal parameters to
the serum leptin concentration, we examined the model by forward
multiple regression analysis (Table 5).
The variables included at the level of P < 0.05 were
the same of those shown in Table 4. Notably, only age brought an
independent significant contribution to residuals of the regression of
leptin on BMI, whereas all other hormones had a significance of
P > 0.05 Also, the unstandardized coefficients
reported in Table 5 indicate that the age-related decline in leptin
levels tended to be higher in obese than in nonobese subjects and more
pronounced in women than in men, although these differences did not
achieve statistical significance. Thus, the backward and forward
regression analyses provided evidence that the age-related decline in
serum leptin levels was independent from BMI and other hormonal
contributors. In addition, age emerged as the strongest negative
influence exerted on the serum leptin concentration when BMI and all
other hormones were included in the regression model. Finally, a
general linear model was developed to analyze the effect of the
investigated variables on the gender difference in serum leptin levels.
As expected, the effect of grouping by sex was still very strong
(P < 0.001), and when adjusted for the covariates that
were significant determinants in the multiple regression analysis
(Table 4) and considering all subjects, serum leptin levels were still
significantly higher in women than in men (38.2 ± 1.3
vs. 28.1 ± 1.4 ng/mL; P < 0.001).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is well established that aging affects body composition, such as reduced muscle strength and increased fat depots (1). It has been suggested that these phenomena might be related at least in part to changes in serum leptin levels and/or its pattern of secretion. Based on previous studies, which equally reported that leptin is reduced (25, 26, 34), unchanged (24, 35, 36), or even increased (27) during aging, the relationship between age and leptin is not yet clear. Ostlund et al. (26) presented data on leptin concentrations in a mixed gender population of a wide age range and showed that circulating leptin is inversely related to age and is reduced by as much as 53% in subjects older than 60 yr. In this study leptin and age were inversely related in men and women; also, both young and old subjects had similar percent body fat. Shortly after this study Ryan and Elahy (34) found that in women athletes, women aged 58 ± 9 yr exhibited a 35% decrease in plasma leptin levels compared to women aged 20 ± 0.8 yr, and Rosembaum et al. (25) found that in postmenopausal women, leptin levels were 30% lower than in fertile women. In subsequent studies, however, these findings have been questioned, and it has been shown that leptin levels rose with age in old to very old men (37) and remained unchanged between young and postmenopausal women (28). The reason for these conflicting results is not understood. Possibly, it might stem from the variability in the experimental design, different ages and/or BMIs of the study subjects, statistical analysis, or the fact that often the age-leptin relationship was not the main focus of most of the studies.
In the present study we have attempted to circumvent the potentially confounding influence of differences in gender and BMI by using BMI as a covariate in the ANOVA and including BMI in the multivariate regression analysis. Also, because ob gene expression is enhanced in obese subjects (2, 3, 38), and leptin levels undergo high interindividual fluctuations in the presence of the relatively minor increases in body weight that are common during aging (39), subjects of both genders were divided into nonobese and obese, and comparisons were made between subjects with similar BMIs. We have shown that obese and nonobese women older than 50 yr had 30–50% lower BMI-adjusted leptin levels than younger subjects. In addition, obese and (less evident) nonobese subjects showed a tendency toward lower BMI-adjusted leptin levels in older than younger subjects. Multiple regression analysis showed that age was negatively correlated with leptin in both genders, even if the slope of decline was twice as high in women as in men. Together, these results indicate that in both genders, most prominently in females, aging is associated with impaired leptin production that is independent from the amount of fat.
The gender difference in serum leptin levels is well established (5). Although there is considerable variability in serum leptin concentrations among individuals, circulating leptin is systematically higher in women than in men. It has been proposed that the higher leptin levels in women involve the different pattern of fat deposition (40, 41) and/or the role of sex hormones (42). Murakami (43) demonstrated that 17ß-estradiol, but not testosterone, increased leptin messenger ribonucleic acid accumulation in isolated rat adipocytes in culture. Shimizu et al. (44) observed that the leptin concentration was decreased by ovariectomy and was then reversed by treatment with estradiol. In humans, even if contradictory, it has been demonstrated that after menopause women have lower serum leptin concentrations than during the fertile period (25, 34). Also, it has been found that adipocytes isolated from adipose tissue from female donors secreted significantly higher amounts of leptin in culture than those from men (4, 17). In vitro studies showed that both estradiol and dexamethasone increased leptin release in incubations of adipose tissue samples obtained from female, but not male, donors (17). In the present study we observed a positive contribution of estradiol to leptin in women, but not in men, while testosterone, even if adjusted for SHBG, was not correlated with leptin. Together, these observations would favor a major role for estradiol in modulating leptin levels in women and that estradiol is responsible for the gender difference in plasma leptin. However, even if estradiol and leptin were positively correlated, and there was a fast decline in circulating leptin after menopause, multiple regression analysis showed that leptin reduction could not be solely explained by the estrogen decline. Other researchers have shown that estrogen administration in menopausal women has no effect on circulating leptin and excluded that estrogens are responsible for the gender differences (28, 45). Thus, it has been proposed that the sexual dimorphism in leptin concentrations might be male related and due to androgens.
Several cross-sectional studies have reported that in men testosterone is associated negatively with serum leptin independently of body fatness (46, 47, 48, 49). However, in these in vivo studies a direct linkage between testosterone and leptin cannot be established, because leptin levels reflect fat mass, which is reduced by testosterone administration. Also, because of the concomitant correlation among testosterone, insulin, and BMI, no firm conclusions on causalities in the leptin-testosterone association can be drawn. In in vitro studies Wabitsch et al. (50) showed a direct long term inhibitory effect of testosterone on leptin production from human adipocytes in culture. Conversely, excessive leptin has been shown to exert receptor-mediated inhibitory actions on hCG-stimulated testosterone secretion from rat Leydig cells in culture (51, 52) and possibly have an inhibitory influence on testosterone production in men (53). It is important to note that in most previous clinical studies, the size of the effect of testosterone on serum leptin was small, indicating that it may only be detectable in a large sample of men. In addition, there may be a threshold level for serum testosterone that is necessary for the suppression of leptin. Our study showed that there was an inverse relationship between testosterone and leptin in obese and nonobese men, confirming previous results (53). Multiple regression analysis showed that in males the age-related decline in circulating leptin was independent from the reduction in testosterone, indicating that, as in women, other variables are involved in leptin reduction during the aging process. In summary, our data support the idea that sex hormones, in particular estradiol in women and testosterone in men (54), may be important contributors to the variations in serum leptin concentrations, but do not explain the age-related decline in leptin levels. Also, we found that the gender difference in serum leptin concentrations could not be fully explained by gender differences in sex hormones, BMI, or any other investigated variable, thus supporting the hypothesis of a genetic origin of the sexual dimorphism in circulating leptin (42).
Concerning the other hormones, body fat content is also influenced by the activity of the somatotropic hormonal axis, which is known to decrease progressively with age (55, 56). In the present study GH was significantly lower in obese compared to normal weight subjects, but it was not correlated with leptin or BMI in either gender. Fasting GH and IGF-I were negatively correlated with age in both sexes, but, as observed in other studies, they did not emerge as significant independent determinants of serum leptin levels (57, 58, 59).
Several animal studies have shown that insulin may modulate serum leptin levels. In humans, it has been found that serum leptin correlates with fasting insulin (6, 7) and indexes of insulin resistance (8). Recently, it has been demonstrated that supraphysiological (9) and physiological (10) insulin concentrations have acute stimulatory effects on serum leptin. However, in humans, other studies have been unable to detect an effect of insulin on leptin (60); furthermore, the presence of diabetes does not affect leptin (61). In our study fasting insulin, FIRI, and C peptide were positively correlated with serum leptin in obese subjects of both genders. However, these correlations were strictly associated with body weight and lost significance when adjusted for the influence of BMI and age.
Finally, as repeatedly observed, the adrenal androgen DHEA was negatively correlated with age in both sexes (58, 62, 63, 64). Although there was no relationship between leptin and DHEAS after univariate analysis, an inverse relationship emerged after multivariate analysis in women, but not in men. However, in this case forward multiple regression analysis showed that DHEAS was not an independent contributor to the age-related decline in leptin levels. The possibility remains that DHEAS might play a role in the gender difference in leptin levels, which needs to be further explored.
In conclusion, our data show that serum leptin concentrations in humans gradually decline during aging. The aging-related reduction is higher in women than in men, but it is independent from BMI and other hormones. The inclusion of several hormones in our regression model showed that only testosterone in men and estradiol and DHEAS in women were independent contributors to serum leptin levels, possibly accounting for part of the leptin sexual dimorphism. None of the hormonal parameters studied abolished the negative correlation between leptin and age, indicating that the age-related reduction in leptin is independent from other major endocrine changes. Future studies examining the effect of gender or hormonal status on serum leptin should consider the independent and inverse role of age on circulating leptin levels.
Received October 27, 1999.
Revised January 5, 2000.
Accepted January 12, 2000.
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, solid line) and 98
postmenopausal (
, dotted line) women. B, Relation
between leptin and BMI in 150 men.
