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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 6 2672-2677
Copyright © 2004 by The Endocrine Society

Obesity: Original Article

Leptin Hormonal Kinetics in the Fed State: Effects of Adiposity, Age, and Gender on Endogenous Leptin Production and Clearance Rates

Shekman L. Wong, Alex M. DePaoli, Jennifer H. Lee and Christos S. Mantzoros

Departments of Pharmacokinetics and Drug Metabolism (S.L.W.) and Clinical Research (A.M.D.), Amgen Inc., Thousand Oaks, California 91320; and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine (J.H.L., C.S.M.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Christos S. Mantzoros, M.D., D.Sc., Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Stoneman 816, Boston, Massachusetts 02215. E-mail: cmantzor{at}bidmc.harvard.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Leptin is an adipocyte-secreted hormone that regulates energy homeostasis and neuroendocrine function. Replacement therapy with recombinant methionyl human leptin (r-metHuLeptin) improves obesity, insulin resistance, hyperlipidemia, and neuroendocrine dysfunction associated with low-leptin states. We administered three doses of r-metHuLeptin (0.1, 0.3, and 1.0 mg/kg) to healthy subjects to determine r-metHuLeptin pharmacokinetics in the fed state, to determine endogenous leptin production and clearance rates, and to study the effects of age, body mass index, gender, and race on r-metHuLeptin pharmacokinetics.

We detected no dose-dependent effects on elimination half-life (t1/2), dose-normalized area under the curve (nAUC0–{infty}), total body clearance (CL), or volume of distribution at steady state. The mean t1/2, CL, and volume of distribution at steady state of r-metHuLeptin are 3.4 ± 1.5 h, 79 ± 16 ml/kg·h, and 150 ± 39 ml/kg, respectively. Older subjects have a higher nAUC0–{infty} (P = 0.003) and tend to have a decreased leptin production rate (Rsyn) and CL (P = 0.01). Increased body mass index is associated with higher baseline endogenous leptin levels (P < 0.0001), higher Rsyn (P < 0.0001), and longer t1/2 (P = 0.008). Females have significantly greater baseline endogenous leptin levels and Rsyn than males (P < 0.0001).

In summary, the leptin production rate is increased in females and with increasing adiposity, whereas leptin clearance is decreased with increasing adiposity, and nAUC0–{infty} is increased with age. Elucidation of leptin pharmacokinetic parameters allows the accurate calculation of exogenous leptin replacement doses for humans in the fed state.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
LEPTIN IS AN adipocyte-derived hormone that is secreted into the circulation in proportion to the amount of energy stored in fat and activates specific leptin receptors in the hypothalamus to regulate appetite, energy expenditure, and neuroendocrine function (1, 2, 3, 4, 5). Congenital leptin deficiency results in morbid obesity, and treatment with low-dose recombinant methionyl human leptin (r-metHuLeptin) results in significant weight loss and improvement in the metabolic dysfunction associated with this condition (6, 7, 8). In addition, low-dose r-metHuLeptin replacement improves hyperlipidemia and insulin resistance associated with severe lipodystrophy and hypoleptinemia (9), normalizes energy expenditure and thyroid hormone levels in patients with sustained weight reduction and relative hypoleptinemia (10), and restores short-term starvation-induced neuroendocrine changes in healthy humans (11). Although r-metHuLeptin continues to be used for these and other interventional studies (12, 13), the pharmacokinetics of r-metHuLeptin as well as the characteristics of endogenous leptin production and clearance remain largely unknown. A greater understanding of r-metHuLeptin pharmacokinetics is important for improved design of clinical trials and may increase our understanding of the physiology and pathophysiology of leptin by elucidating differences in production and clearance rates in different physiologic states.

We have thus conducted a study in healthy subjects to investigate the influence of age, body mass index (BMI), gender, and race on leptin pharmacokinetics in the fed state. By administering known doses of r-metHuLeptin, we first determined the production and clearance rates of endogenous leptin. We then determined the differences in leptin levels between lean and obese subjects as well as between men and women after r-metHuLeptin administration. Finally, we calculated the appropriate doses for r-metHuLeptin administration in the fed state.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study design and description

This was a single-center study conducted at MDS Harris Laboratories (Lincoln, NE) to evaluate the pharmacokinetics of r-metHuLeptin after single-dose administration and to assess the differences in leptin kinetic disposition between males and females of varying BMI. Subjects were assigned randomly to one of three dose cohorts (0.1, 0.3, and 1.0 mg/kg), reflecting the dose of r-metHuLeptin administered iv. Within each dose cohort, subjects were stratified on the basis of BMI: group 1 for BMI less than 25.0 kg/m2, group 2 for BMI 25.0–30.0 kg/m2, and group 3 for BMI greater than 30.0 kg/m2.

Serial blood collection from a peripheral vein for the measurement of serum leptin concentrations was performed at 0 (baseline or predose), 5, 15, 30, and 45 min and 1, 3, 6, 9, 12, and 24 h after 0800 h r-metHuLeptin dosing. Approximately 5 ml of whole blood were drawn for each time point, and the serum was frozen for shipment to the analytical laboratory. Subjects fasted for at least 8 h before dosing and were allowed to discontinue fasting after the collection of the 3-h postinjection blood sample.

Subjects

Sixty-three healthy men and women between the ages of 19 and 65 yr (inclusive) with BMIs ranging from 20.1–37.2 kg/m2 were recruited for the study. Women had to be postmenopausal or have had a hysterectomy and/or bilateral tubal ligation at least 6 months before screening; men agreed to practice adequate methods of contraception. Before entering the study, subjects signed an informed consent, which was in compliance with U.S. Food and Drug Administration regulations and approved by the Institutional Review Boards of Amgen Inc. and MDS Harris Laboratories.

r-metHuLeptin administration

The active ingredient in the formulation is the protein hormone r-metHuLeptin produced in Escherichia coli, into which a plasmid containing the human leptin gene has been inserted. The recombinant protein (r-metHuLeptin) is composed of 146 amino acids plus an amino-terminal methionine. r-metHuLeptin is a lyophilized formulation supplied in glass vials and requires reconstitution with sterile water before administration. The study drug was administered iv using a standard slow iv push at an approximate rate of 1 ml/min for the 0.1, 0.3, and 1.0 mg/kg cohorts and was not injected into the limb from which blood samples were drawn for pharmacokinetic analysis.

Leptin/r-metHuLeptin assay

All pharmacokinetic samples, including baseline (predose) leptin values, were assayed using an ELISA that was described previously (12) and that does not distinguish between endogenous leptin and r-metHuLeptin. The limit of quantification of the assay was 0.02 ng/ml with the linear range only up to 10 ng/ml. Dilution of samples was performed when necessary. For the assay to be acceptable, the standard curve had to have a correlation coefficient greater than or equal to 0.99, and the controls had to be within 80–120% of expected value, with an intraassay coefficient of variation of less than or equal to 20%. Samples were run in duplicate wells, and if the coefficient of variation exceeded 20%, the sample was repeated.

Pharmacokinetic analysis

The pharmacokinetic parameters of r-metHuLeptin were estimated using noncompartmental pharmacokinetic methods (14). All pharmacokinetic analyses were performed using serum leptin concentrations corrected for the subject’s baseline leptin level before r-metHuLeptin dosing. For the analysis of these studies, we considered that endogenous leptin and r-metHuLeptin had equal immunoreactivity in the ELISA assay used herein.

The terminal elimination rate constant ({lambda}z) was determined by linear regression of the natural logarithms of the last two to four measurable concentrations during the terminal phase. The terminal phase elimination half-life (t1/2) was calculated as ln(2)/{lambda}z. The areas under the serum leptin concentration vs. time curve from time zero to infinity (AUC0–{infty}) were calculated using the linear trapezoidal method and extrapolated to infinity. Dose-normalized AUC0–{infty} was defined as AUC0–{infty} /dose of r-metHuLeptin administered. The total body clearance (CL) of r-metHuLeptin was defined as the ratio of the actual dose administered to AUC0–{infty}. The volume of distribution at steady state (Vss) was calculated using standard noncompartmental methods (14). The analysis was performed using WinNonlin Professional (version 3.3; SCI, Pharsight Corp., Mountain View, CA).

Endogenous leptin kinetics analysis

The endogenous leptin level was assumed to be at steady state before r-metHuLeptin administration and can be described by the following differential equation:

(1)
In equation 1Go, [L], Rsyn, and CLout represent the amount of leptin in the body, endogenous leptin production rate, and clearance of endogenous leptin, respectively, and (L) defines the serum concentration of leptin. During steady state (before r-metHuLeptin administration), when there is no change of endogenous leptin levels (d[L]/dt = 0), equation 1Go can be simplified to:

where (L0) is the baseline serum concentration of endogenous leptin at time zero. After injection of r-metHuLeptin, it is assumed that r-metHuLeptin and endogenous leptin are eliminated from the body with the same kinetic disposition and via the same pathway (CL of r-metHuLeptin = CLout). Thus, the endogenous production rate of leptin (Rsyn) can be solved by using the pharmacokinetic data from this study.

Statistical analysis

One-way ANOVA was used to test for differences between the three dose cohorts with respect to the age of the subject, weight, height, and BMI. We also used ANOVA to test for differences in t1/2, dose-normalized AUC0–{infty}, CL, and Vss between the three doses administered. We then used analysis of covariance (ANCOVA) to evaluate the effect of dose, age, BMI, gender, and race as predictors of t1/2, dose-normalized AUC0–{infty}, CL, Vss, L0, and Rsyn. The ANCOVA models were built with all variables (dose, age, BMI, gender, and race) added at the same time. In addition, ANOVA was used to assess for differences in L0, Rsyn, CLout, and t1/2 between males and females for each BMI group, as well as between BMI groups for males and females separately. Bivariate analysis was also performed to evaluate the relationship between BMI and L0, Rsyn, CLout, and t1/2, first in the entire group and then stratified by gender. All analyses were performed using JMP (version 3.2.2; SAS Institute Inc., Cary, NC). After Bonferonni adjustment for multiple comparisons was performed, a level of 0.01 was used as the cutoff point for statistical significance for ANOVA and ANCOVA tests. P < 0.05 was considered statistically significant for bivariate analysis.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A total of 43 men and 20 women participated in the study. Demographic data are summarized in Table 1Go. The age, weight, and BMI of the subjects enrolled in this study ranged from 19–65 yr (mean, 36), 55.4–119 kg (mean, 81.8), and 20.1–37.2 kg/m2 (mean, 27.1), respectively. There was no significant difference in age, weight, height, or BMI among the three different r-metHuLeptin-treated groups.


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  		TABLE 1. Demographic information

 
Tolerance and adverse events

r-metHuLeptin was well tolerated by the study subjects, and no serious adverse events occurred during the treatment. The most prevalent treatment-related events were injection site reactions, including mild redness, itching, and swelling. No clinically significant changes were noted in vital signs, physical examination, or electrocardiogram. In addition, there were no clinically significant changes in routine clinical laboratory results, including red blood cell counts, hemoglobin, and liver enzymes (alanine aminotransferase or aspartate aminotransferase).

Pharmacokinetics of r-metHuLeptin

Figure 1Go shows the mean r-metHuLeptin serum concentration, adjusted for baseline endogenous leptin levels, plotted against time in hours. As expected, there was a dose-proportional increase in r-metHuLeptin concentrations and AUC values. The mean (±SD) noncompartmental pharmacokinetic parameters of r-metHuLeptin for each dose cohort are summarized in Table 2Go. Using ANOVA, we found no dose-dependent effects on t1/2, dose-normalized AUC0–{infty}, CL, or Vss, indicating r-metHuLeptin is absorbed and eliminated from the body similarly among the different study doses administered. The overall mean t1/2, CL, and Vss of r-metHuLeptin are 3.4 ± 1.5 h, 79 ± 16 ml/kg·h, and 150 ± 39 ml/kg, respectively.



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  		FIG. 1. Mean (±SD) r-metHuLeptin serum concentration-time profile.

 

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  		TABLE 2. Mean (±SD) pharmacokinetic parameters of r-metHuLeptin

 
Effects of age, BMI, gender, and race on r-metHuLeptin pharmacokinetics

ANCOVA was then performed to test the effects of age, BMI, gender, and race on t1/2, dose-normalized AUC0–{infty}, CL, Vss, L0, and Rsyn. Older subjects had higher dose-normalized AUC0–{infty} (P = 0.003) and tended to have both lower Rsyn (P = 0.01) and lower CL (P = 0.012) values. Age also tended to be negatively correlated with L0, but this association was not statistically significant (P = 0.06).

Higher BMI values were associated with higher L0 (P < 0.0001) and higher Rsyn (P < 0.0001) and tended to be associated with higher dose-normalized AUC0–{infty} (P = 0.015). Similarly, BMI was associated with longer t1/2 (P = 0.008) and decreased CL (P = 0.013), reflecting slower elimination of r-metHuLeptin with increasing BMI.

Female gender was positively associated with higher L0 (P < 0.0001) and Rsyn (P < 0.0001), whereas race had no effect on these parameters. There were no gender or racial differences for t1/2, dose-normalized AUC0–{infty}, CL, or Vss, indicating that male and female subjects of different races absorb and eliminate r-metHuLeptin similarly.

Endogenous leptin kinetics

Table 3Go outlines the mean leptin kinetic parameters by gender for each BMI group. Again, as expected, women had significantly greater baseline endogenous leptin levels than men (see L0 values). Analysis of L0 in relation to BMI, for men and women separately, showed that leptin levels were higher with increasing BMI for both genders (P < 0.001 for males and P = 0.007 for females). Figure 2Go illustrates the strong correlation between baseline endogenous leptin levels and BMI and the steeper regression line slope observed for women compared with men.


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  		TABLE 3. Mean (±SD) leptin kinetic parameters by BMI group

 


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  		FIG. 2. Individual baseline leptin levels vs. BMI.

 
We then analyzed the Rsyn rates, CL rates, and t1/2 of leptin in men and women after stratification for BMI (Table 3Go), to assess whether the difference in baseline leptin levels between genders is due to differences in endogenous production or clearance, assuming CL of r-metHuLeptin = CLout. We found statistically significant differences in Rsyn between men and women (Table 3Go), with women having higher rates than men (P < 0.0001) for all BMI groups. There were no statistically significant differences in clearance rates or t1/2 between males and females for each BMI group (Table 3Go).

We then evaluated Rsyn, CL, and t1/2 by ANOVA in relation to BMI groups shown in Table 3Go after stratification for gender to see whether the increases in baseline leptin levels with increasing BMI may be due to differences in production, clearance, or t1/2. Leptin production significantly increases with BMI in both males and females (P < 0.001 and P = 0.004, respectively). In addition, leptin clearance tends to decrease with BMI in both males and females (Table 3Go), but due to the smaller sample size, this difference does not achieve statistical significance at the Bonferonni adjusted P = 0.01 level when the analysis is performed in the subgroups of men and women separately (P = 0.04). Lastly, although t1/2 in males tends to be greater in the greater than 30.0 kg/m2 BMI group compared with the lower BMI groups (P = 0.04), there is no significant difference in t1/2 between BMI groups for females (P = 0.48).

Finally, we explored the relationship between BMI and L0, Rsyn, CLout, and t1/2 by bivariate analysis, in the entire group as a whole as well as after stratification by gender. We again found that BMI is positively associated with L0 in the entire group (ß = 1.75; P < 0.001) as well as in males (ß = 0.58; P < 0.0001) and females (ß = 3.47; P < 0.0001) separately. The leptin production rate is similarly positively associated with BMI in all subjects (ß = 117.7; P < 0.0001) as well as in males only (ß = 38.3; P < 0.0001) and females only (ß = 236.9; P < 0.0001). We also confirmed a negative association between BMI and clearance that achieved statistical significance in the entire group (ß = –1.34; P = 0.003) and in males (ß = –1.14; P = 0.03) but failed to reach statistical significance in females (ß = –0.80; P = 0.35). Lastly, we found a positive relationship between BMI and t1/2 that, again, achieved statistical significance in the entire group (ß = 0.13; P = 0.004) and in males (ß = 0.15; P = 0.01) but failed to reach significance in females (ß = 0.08; P = 0.28).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we determined the pharmacokinetic parameters of r-metHuLeptin administration in lean and obese humans and provide important contributions to the understanding of endogenous leptin kinetics. We confirm that females and increasing fat mass are associated with higher baseline leptin levels and endogenous production rates. We further demonstrate that, despite correction for baseline endogenous leptin levels, older subjects and individuals with increased adiposity have higher serum leptin levels after r-metHuLeptin administration (dose-normalized AUC0–{infty}), which are related to decreased leptin clearance.

This study provides several important insights into the relationship between leptin and adiposity, gender, and age. The fact that serum leptin levels correlate highly with percentage of body fat, increasing exponentially with increasing BMI (15, 16, 17, 18), raises the question of whether leptin synthesis and/or clearance change with increasing adiposity. Using a direct pharmacokinetic approach, we found not only that endogenous leptin production rate (Rsyn) is increased with adiposity but, unlike the study by Klein et al. (19), that leptin elimination tends to be slower (decreased clearance and increased t1/2) with increased adiposity. The discrepancy between the two studies may reflect methodological differences (direct measurement of whole body kinetics vs. indirect method), the larger subject population in this study, or that the previous study examined males only. The kidney is the main site of leptin clearance in rodents (20, 21, 22) and humans (23, 24, 25), and the short isoform of the leptin receptor, which is responsible for leptin clearance, has been demonstrated to be down-regulated in the kidney of hyperleptinemic male overweight cafeteria-fed rats (26). Thus, it is possible that leptin receptor expression or function may also be decreased in kidneys of obese subjects, leading to relatively decreased clearance in this setting. Future studies are needed to further elucidate whether leptin receptor expression, density, and/or function are regulated by adiposity in humans.

With regard to gender, our data are in agreement with other studies indicating that women have higher baseline endogenous leptin levels than men and that the slope of the correlation between serum leptin concentration and BMI is steeper in women (15, 17, 18, 27, 28). In agreement with previous studies showing increased leptin mRNA expression and secretion in adipose tissue in women (28, 29), we show that leptin synthesis rate is significantly greater in women across all BMI groups, whereas clearance rate and t1/2 are similar in males and females. Although leptin production is greater in sc than visceral fat (30, 31, 32, 33) and women have a higher sc to visceral fat ratio than men, this cannot fully account for the difference in the leptin synthesis rate between genders. Lastly, although women have higher circulating leptin levels and endogenous leptin synthesis rates, we found no gender differences in r-metHuLeptin pharmacokinetics (t1/2, dose-normalized AUC0–{infty}, CL, or Vss), indicating that men and women absorb and eliminate leptin similarly. It is possible, however, that there is an interaction between gender and BMI in predicting pharmacokinetic parameters because by bivariate analysis, the effect of BMI on CLout and t1/2 achieves statistical significance in the entire group and in males but fails to reach statistical significance in females. Given that the number of females (n = 20) is less than half the number of males (n = 43), however, it remains unclear whether the lack of statistical significance in females represents a true sexual dimorphism or may be simply related to the small sample size in females. This will need to be examined further in larger studies.

We also found that older subjects have higher dose-normalized AUC0–{infty} and lower clearance rates after r-metHuLeptin administration. This is most likely predominantly related to decreased renal function and creatinine clearance associated with increasing age. Additionally, we found that older subjects tend to have lower endogenous leptin production rates, but this finding might be due to changes in fat mass and distribution with aging. These hypotheses remain to be further explored in the future.

Finally, in addition to important pathophysiologic and physiologic knowledge gained from this study, we have provided practical information relevant to exogenous administration of r-metHuLeptin to humans in the fed state. We find that r-metHuLeptin is absorbed and eliminated similarly in the three different doses studied, which encompass physiologic to high pharmacologic doses of leptin. The mean t1/2 is 3.4 ± 1.5 h, CL is 79 ± 16 ml/kg·h, and Vss is 150 ± 39 ml/kg. Moreover, one can use the information presented herein to calculate the dose of exogenous r-metHuLeptin needed to increase circulating leptin levels by "X" ng/ml in men and women in the fed state. The infusion rate of exogenous r-metHuLeptin required to produce a target concentration of leptin can be calculated using the following equations (depending on iv or sc administration, respectively): 1) infusion dose (ng/kg·h) = [target concentration – (L0)] x CLout, for iv administration; and 2) infusion dose x F (ng/kg·h) = [target concentration – (L0)] x CLout, for sc administration, where F is the bioavailability, or fraction of drug that reaches the systemic circulation. Thus, to achieve an "X" ng/ml increase in leptin concentration, the infusion dose required is calculated as: (X ng/ml) x CLout for iv administration and [(X ng/ml) x CLout]/F for sc administration. Given that CLout tends to decrease with BMI (Table 3Go), the calculated infusion dose will vary with BMI. In contrast, because there are no major differences in CLout between males and females, the infusion dose will be similar between males and females.

Although the state-of-the-art technique for measurement of production rate is infusion of a labeled compound and measurement of isotopic dilution at steady state, because of technical and ethical limitations this was not performed in this study. Thus, current assay methodology does not allow discrimination between endogenous and exogenous leptin. Therefore, whether there is rapid equilibrium between endogenous and exogenous leptin, and whether exogenous leptin infusion inhibits endogenous production, remains to be shown by future studies in the fed and fasting state, which will also incorporate detailed assessment of total and regional fat mass.

In conclusion, our study of leptin pharmacokinetics using r-metHuLeptin administration in the fed state in humans provides the basis for accurate calculations of r-metHuLeptin doses to be administered in the fed state and shows that increased adiposity is correlated with increased serum leptin levels secondary to increased production rate and decreased elimination. In addition, the differences between males and females in baseline endogenous leptin levels appears to be due to differential leptin synthesis rates, whereas the elimination of leptin between males and females is similar. Lastly, older patients have higher dose-normalized AUC0–{infty} due to altered production and elimination, but there is no racial difference in t1/2, AUC0–{infty}, or clearance after r-metHuLeptin administration in the fed state.


   Footnotes
 
This work was supported by Amgen Inc., National Institutes of Health (NIH) Grant RO1-58785 (to C.S.M.), NIH Training Grant 5T32DK07516-18 (to J.H.L.), and an Eli Lilly and Co. fellowship award.

S.L.W. and A.M.D. contributed equally to this work.

Abbreviations: ANCOVA, Analysis of covariance; BMI, body mass index; CL, total body clearance; CLout, clearance of endogenous leptin; L0, baseline serum concentration of endogenous leptin; nAUC0–{infty}, dose-normalized area under the curve; r-metHuLeptin, recombinant methionyl human leptin; Rsyn, endogenous production rate of leptin; t1/2, elimination half-life; Vss, volume of distribution at steady state.

Received November 7, 2003.

Accepted March 1, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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