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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 2 453-459
Copyright © 1998 by The Endocrine Society

Original Studies

Diurnal and Ultradian Rhythmicity of Plasma Leptin: Effects of Gender and Adiposity1

Mohammed F. Saad, Maggy G. Riad-Gabriel, Arshad Khan, Alok Sharma, Ragui Michael, Sujata D. Jinagouda, Rima Boyadjian and Garry M. Steil

The Department of Medicine (M.F.S., M.G.R.-G., A.K., A.S., R.M., S.D.J., R.B.), University of Southern California Medical School, Los Angeles, California 90033; and Joslin Diabetes Center (G.M.S.), Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Mohammed F. Saad, M.D., 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. E-mail: saad{at}hsc.usc.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Plasma leptin shows a nocturnal rise and a pulsatile pattern. This work was undertaken to determine the effects of gender and obesity on this pattern. Twenty-four-hour leptin profiles were evaluated in 31 subjects [17 male, 14 female; age: 36 ± 2 yr (mean ± SEM); body mass index: 27.5 ± 1.0 kg/m2]. Plasma leptin profiles were higher in obese (body mass index > 27 kg/m2) than in lean subjects and higher in women than in men, regardless of fat mass. Leptin showed diurnal rhythmicity with peaks between 2200–0300 (median: 0120) and nadirs between 0800 and 1740 (median: 1033). Spectral analysis revealed 2 components (periodicities: 24 and 12 h) with higher relative amplitudes in lean than in obese subjects. The relative diurnal amplitude also was higher in men than in women, controlling for adiposity. Insulinemia, female sex, and age were negative determinants of diurnal rhythm relative amplitude. Pulse analysis revealed 3.6 ± 0.3 pulses/24 h, occurring mostly 2–3 h after meals. Pulse frequency correlated negatively with fat mass and insulinemia (Spearman’s r = -0.54 and -0.37, respectively; P < 0.05 for each). Thus, obesity is associated not only with higher leptin levels but also with blunted diurnal excursions and dampened pulsatility. This abnormal rhythmicity may contribute to leptin resistance in obesity. The significance of the sexual dimorphism in the diurnal amplitude is unclear, but it may be related to leptin’s putative role as a metabolic signal to the reproductive axis.


   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). Leptin is thought to be a lipostatic signal to brain centers controlling energy homeostasis. It could contribute to body weight regulation through modulating feeding behavior and/or energy expenditure (1, 2, 3, 4, 5, 6, 7). Fat mass and gender are major determinants of plasma leptin concentration in man (8, 9, 10, 11, 12, 13). Leptin levels are higher in the obese (8, 9, 10, 11, 12, 13, 14), reflecting leptin resistance, possibly caused by reduced transport into the cerebrospinal fluid (15, 16) or defective postreceptor signaling (17). Fasting plasma leptin is higher in women than in men, regardless of fat mass (10, 11, 12, 13). The mechanism and significance of this sexual dimorphism are unknown, but leptin may have a reproductive function (18, 19, 20, 21, 22). Leptin shows a nocturnal rise (23, 24) and a pulsatile secretory pattern (25). Little is known, however, about the determinants of this pattern. This work has been undertaken to evaluate the effects of gender and obesity on the 24-h leptin profile.


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

This study included 31 healthy subjects (17 men, 14 women), 36 ± 2 (mean ± SEM) yr old (range 18–55) with a body mass index (BMI) of 27.5 ± 1.0 kg/m2 (range 19.9–40.7). None was taking any medications. Obesity was defined by a BMI > 27 kg/m2 (26). Thus, subjects were divided into 4 groups by gender and obesity (Table 1Go). The study was approved by the Institutional Review Board of the University of Southern California, and all subjects gave informed consent.


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  		Table 1. Characteristics of subjects

 
Experimental protocol

Subjects had an oral glucose tolerance test, with a 75-g glucose, to rule out diabetes. Body composition was determined by underwater weighing (27). Subjects were subsequently admitted to the Clinical Research Center for 3 days and were kept on a weight-maintenance diet. On the third day and after a 10- to 12-h overnight fast, an iv catheter was placed at 0500 h. Blood was collected for determination of plasma glucose, insulin, and leptin concentrations every 20 min for 24 h, starting at 0600 h. Breakfast, lunch, and dinner were served at 0800 h, 1300 h, and 1800 h, respectively. The caloric distribution was 20% for breakfast, 40% for lunch, and 40% for dinner. Only water was allowed between meals. Subjects did not nap or sleep until 2300 h, when lights and television were turned off.

Biochemical analyses

Plasma glucose was determined by the glucose oxidase method. Insulin and leptin were determined by RIA with reagents from Linco Research (St. Louis, MO), with detection limits of 12 pmol/L and 0.5 ng/mL, respectively. The interassay coefficients of variation were 6–8 and 5–7% for insulin and leptin assays, respectively. All samples from a single participant were measured in triplicate in the same assay. Plasma testosterone and estradiol were measured in fasting samples (at 0800 h), in duplicate, with kits from Diagnostic Products Corporation (Los Angeles, CA).

Data analysis

The 24-h leptin profiles were analyzed for peak (single highest) and nadir (single lowest) values and for several indices, for the extent of the diurnal change. These included 24-h excursion (peak-nadir/24 h mean) expressed as a percent, the coefficient of variation around the 24-h mean (24-h CV), and the night/day ratio (ratio of average leptin levels during the night (2000–0540 h) to day (0600–1940 h). In addition, spectral and pulse analyses were performed.

Spectral analysis was done with MLAB (Civilized Software, Inc., Bethesda, MD) using a power-of-two fast Fourier transform (FFT). Fourier transform analysis is a mathematical technique that assesses the contribution of oscillations of different periodicities to total oscillatory activity in a data set (28). Because of gender- and obesity-related differences, leptin levels were first normalized by calculating percent of change at different time points in relation to the 24-h mean. The amplitude of the oscillations (square root of the spectrum) and phase spectrum were calculated from FFT of the normalized data. FFT results also were used to predict a theoretical time course using 1, 2, and 3 principal harmonics (equivalent to cosinar analysis with periods of 24, 12, and 8 h). Residuals (data - FFT predicted curve) were subjected to autocorrelation analysis; spectral components that did not reduce the oscillatory nature of the autocorrelation function were not considered significant. Time profiles consistent with a diurnal rhythm (period = 24 h) and a diurnal plus a 12-h component were identified. Estimated time profiles of higher-order spectral components were not significant, and the R2 values for fits involving the first two cosines were 86 ± 2%. The estimated phase was used to calculate the time-to-peak value of the first two cosine components (the peak of the diurnal and the first peak of the 12-h components).

Pulse analysis was performed with the pulse-identification program, ULTRA (29, 30). The general principle of this program is the elimination of all peaks of plasma concentration for which either the increment (difference between peak value and the preceding nadir) or the decrement (difference between peak value and the next nadir) does not exceed a certain threshold related to measurement error. Peaks that do not meet threshold criteria are eliminated from the data set using an iterative process, leaving a clean series in which all remaining peaks are assumed to represent significant pulses. The intraassay coefficient of variation of leptin assay was less than 5%, and therefore, the threshold for pulse detection was set at 10%. Each pulse was characterized in terms of total duration and absolute (difference between levels at the peak and at the preceding trough) and relative (percent increase above the trough) increments.

Statistical analyses

Data are expressed as means ± SEM or as means with 95% confidence interval. Insulin and leptin concentrations were log-transformed to normalize the distribution. Statistical analyses were performed with programs of SPSS, Inc., Chicago, IL (31). Two-way ANOVA was used to evaluate the effects of gender and obesity on different variables. Linear regression and/or Pearson product moment correlations (unless otherwise specified) were used to evaluate the relations among different variables. Multiple linear regression, with a backward-stepwise procedure, was used to define the variables most predictive of 24-h leptin concentration and of the amplitudes of the two spectral components.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Plasma glucose, insulin, and leptin concentrations were higher in obese than in lean subjects. Whereas no sex difference was observed in glucose or insulin (Fig. 1Go), leptin profiles were higher in lean and obese women than in their male counterparts (Fig. 2Go). Mean 24-h plasma leptin concentration and the 24-h area under the curve (AUC) correlated strongly with BMI, percent body fat, and fat mass in men and women (Table 2Go). Nevertheless, women had higher 24-h mean leptin and AUC at any BMI, percent body fat, or fat mass (Fig. 3Go). Leptin AUC correlated with the waist/hip ratio in men but not in women (Table 2Go). After adjusting for fat mass, the relation was significant in neither men nor women. Leptin and insulin AUC were correlated in men (r = 0.65, P = 0.005) and women (r = 0.54, P = 0.056), but these relations became insignificant after controlling for adiposity. Leptin AUC was not significantly correlated to plasma testosterone or estradiol in men (r = -0.33, -0.28 respectively) or women (r = 0.38, 0.03). Multiple regression showed that fat mass and gender explained 86% of the variance in 24-h leptin AUC (Table 3Go).



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  		Figure 1. Plasma glucose (lower panels) and insulin (upper panels) 24-h profiles in lean and obese subjects.

 


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  		Figure 2. Plasma leptin 24-h profiles in lean and obese subjects. Lower panels, raw values; upper panels, normalized profiles (the percent change around the 24-h mean) and their cosine fits (dashed lines for men; solid lines for women) obtained from the spectral analysis.

 

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  		Table 2. Correlation between plasma leptin and different anthropometric parameters

 


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  		Figure 3. The relation between 24-h leptin AUC and BMI (left) and fat mass (right) in men (solid circles) and women (open circles). Slopes of the regression lines are similar (P > 0.1), but the intercepts are different (P < 0.001) in both panels.

 

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  		Table 3. Determinants of 24-h leptin concentration (multivariate regression analysis)

 
Plasma leptin showed diurnal variations with a peak between 2200–0300 (median 0120) and a nadir between 0800 and 1740 (median 1033). The average peak and nadir leptin levels were higher in women than in men, and in obese than in lean subjects. Gender and obesity had no effect, however, on their timing. The magnitude of the relative diurnal change in leptin (estimated as the 24-h excursion, the 24-h CV, or the night/day ratio) was highest in lean men, followed sequentially by lean women, obese men, and obese women (Table 4Go).


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  		Table 4. Parameters of the diurnal and pulsatile changes in leptin

 
Spectral analysis of normalized leptin profiles revealed two major frequency components at 0.042 and 0.083 cycles/h (corresponding to periodicities of 24 and 12 h, respectively). The relative amplitude of the diurnal (24-h) component was higher in men than in women, and in lean than in obese subjects (Fig. 4Go). Gender had no effect on the relative amplitude of the 12-h component, which was higher in lean individuals (Table 4Go). The peak of the diurnal component occurred between 2140 and 0140 (median 0020). The first peak of the 12-h component occurred between 1240 and 2240 (median 1400) and the second peak, 12 h later, i.e. between 0040 and 1040 (median 0200). Neither gender nor obesity had an effect on the time of the peak of either component. Multiple regression showed that 24-h insulin AUC, female sex, and age were negative determinants of the relative amplitude of the diurnal component, explaining 31% of its variance (Table 5Go). The same type of analysis indicated that age was a weak negative determinant of the relative amplitude of the 12-h component, explaining 8% of its variance (P = 0.055); none of the other variables were significant.



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  		Figure 4. Spectral analysis of the normalized 24-h leptin time series in the four groups of subjects. The inset shows the cosine fit of the data (the same as in the upper panels of Fig. 2Go) to facilitate comparisons. SE is not shown, to simplify the figure. P < 0.05 for the effects of both gender and obesity.

 

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  		Table 5. Determinants of the amplitude of the diurnal change in leptin concentration (multivariate regression analysis)

 
Pulse analysis showed the presence of 1–9 irregular pulses/24 h per individual (mean: 3.6 ± 0.3, median: 3) with a duration of 372 ± 41 min (median 293). Prominent pulse activity occurred in the time periods 1000–1400 h, 1500–1800 h, and 2000–0100 h (18, 21, and 44% of total pulses in all subjects, respectively). Thus, major pulse activity seemed to follow meals and the associated increase in insulin levels by 2–3 h (Fig. 5Go). Pulses were less frequent in obese than in lean subjects, but no sex differences were detected (Table 4Go). Pulse frequency was inversely related to fat mass and the 24-h insulin AUC (Spearman’s r = -0.54 and -0.37, respectively; P < 0.05 for each). Absolute pulse increments were higher in women than men and in obese individuals. Neither gender nor obesity had an effect, however, on the relative increments (Table 4Go).



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  		Figure 5. The temporal relation between the 24-h insulin profile and the frequency distribution of leptin pulses, as detected by the program ULTRA. The mean insulin levels and the frequency distribution of leptin pulses in all subjects are shown. SEM insulin values are not shown, to simplify the figure. Insulin is represented on the left y-axis, and leptin on the right.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our data show that adiposity and gender are the major determinants of plasma leptin concentration and its secretion pattern. Fat mass was strongly and directly associated with absolute leptin level and negatively related to its relative diurnal excursion and ultradian pulse frequency. Thus, obesity was characterized not only by high absolute leptin levels but also by blunted relative diurnal excursions and dampened pulsatility. Gender had a considerable impact on leptinemia, because women had higher absolute 24-h leptin profiles and relatively lower diurnal excursions than men, regardless of fat mass. These findings could have important physiological and pathophysiological implications regarding leptin’s putative role in energy homeostasis and reproduction.

Diurnal leptin rhythmicity does not seem to be controlled by the endogenous circadian clock. Schoeller et al. (32) have recently shown that day/night reversal produced a rapid phase shift that was dissociated from the change in cortisol. Meal time and insulin apparently play a major role, because delaying meals for 6.5 h caused a 4–7 h shift in nadir and peak leptin levels (32). Other hormones that show diurnal changes and can influence plasma leptin, such as neuropeptide Y (33), corticosteroids (34), and catecholamines (35), could also modulate its diurnal rhythm. In addition, circulating leptin is bound to one or more binding proteins (36, 37) that may modulate its plasma pattern.

Insulin could be the major determinant of leptin secretory pattern. Although several studies showed that insulin infusions for 2–10 h had no effect on plasma leptin concentration (38, 39, 40, 41, 42), our preliminary data show that insulin, in concentrations well within the physiologic range, could increase plasma leptin by approximately 50% and that such an effect takes 2–3 h to become evident. In addition, other studies showed that infusion of insulin or glucose could increase plasma leptin concentration in 4–6 h (43, 44, 45). It is plausible, therefore, that repeated daytime postprandial insulin release could induce increases in leptinemia that become apparent in the afternoon and during the night. Conversely, the nocturnal postabsorptive diminution in insulinemia could cause a decline in leptinemia that becomes manifest in the early morning hours. Thus, insulinemia could influence the magnitude of the diurnal leptin excursion (Table 5Go). Meanwhile, postprandial insulin excursions could cause fluctuations in plasma leptin, which are reflected as episodic pulsations. This is supported by the occurrence of prominent leptin pulsatility 2–3 h after meals (Fig. 5Go). Moreover, an insulin infusion that kept its level constantly elevated at twice that of basal completely eliminated pulsatility for 9 h (unpublished observations). Thus, the insulin secretory pattern seems to modulate the 24-h leptin profile.

Hyper and hypoinsulinemia could perturb leptin rhythmicity. In obesity, the fasting and postprandial hyperinsulinemia could continuously up-regulate leptin production and thereby buffer the daytime decline and limit the fluctuations in its plasma concentration, resulting in decreased diurnal excursion and dampened pulsatility. Our data show that 24-h insulin AUC correlated negatively with leptin’s diurnal rhythm amplitude and its pulse frequency (Spearman r = -0.34 and -0.37, respectively; P < 0.05 for each). Furthermore, hyperinsulinemia usually reflects insulin resistance, which can diminish the stimulatory effect of postprandial insulin release on leptin production and consequently decrease the diurnal rhythm amplitude. Hypo-insulinemia also could lead to the same result but through down-regulating leptin production. Laughlin and Yen (24) showed that the diurnal variations in leptin were absent in amenorrheic women athletes with low postprandial insulin excursions. The pathophysiological significance of impaired leptin secretory pattern in hyper and hypoinsulinemic states is unknown but merits further evaluation.

Absolute plasma leptin levels were higher in the obese, who could be leptin resistant because of decreased cerebrospinal transport (15, 16) or defective postreceptor signaling (17). Blunted relative diurnal excursions and dampened pulsatility also could contribute to leptin resistance in obesity. Although the effectiveness of pulsatile vs. steadily infused leptin has not been evaluated, continuous hormone delivery can produce a weaker effect or induce resistance. Conversely, pulsatile hormonal stimuli seem to maintain receptor sensitivity and enhance tissue responsiveness (46). For example, pulsatile insulin (47) and glucagon (48) administration has a greater effect on glucose metabolism, whereas continuous delivery of GnRH desensitizes the pituitary to its actions (49). It is conceivable, therefore, that the diurnal and pulsatile changes in plasma leptin improve its transport across the blood-brain barrier or maintain end organ sensitivity. Hence, abnormal leptin rhythmicity could play a role in leptin resistance and, consequently, contribute to the development or worsening of obesity.

We (13) and others (10, 11, 12) have described sexual dimorphism in fasting plasma leptin concentrations. The current report extends these observations and shows sexual dimorphism not only in the 24-h leptin profile but also in the relative amplitude of its diurnal rhythm. The mechanism of this sexual dimorphism is unclear. Sex hormones do not seem to play a major role, because the sex difference exists in neonates (50) and young prepubertal children (51). Nevertheless, androgens might account for some of the difference, because testosterone was found to decrease leptin level in hypogonadal men (52) and ob expression in vitro in adipocytes (53). Differences in fat distribution may play a role. Two studies showed that ob messenger RNA (mRNA) expression is higher in sc than in intraabdominal adipose tissue (54, 55). Thus, central (visceral) android adipose tissue may produce less leptin than peripheral (sc) gynecoid fat, accounting for the differences between men and women. Nevertheless, female adipose tissue, whether sc or visceral, was found to have 2- to 3-fold higher leptin mRNA expression than in men (55, 56). Moreover, this study and others found no significant association between fat distribution and leptin, independent of total adiposity (13, 57, 58, 59, 60). Taken together, these data indicate that differences in body fat distribution and, consequently, the amount of sc fat could contribute to, but cannot completely explain, the higher leptin levels in women.

A further possibility is a sex difference in the hypothalamic regulation of leptin production. Sainsbury et al. (33) showed that intracerebroventricular administration of neuropeptide increased ob gene expression in adipose tissue of normal rats. Sexual dimorphism characterizes several hypothalamic nuclei (61), as well as neuropeptide gene expression and secretion (62). Finally, female adipose tissue is more sensitive to insulin (63), which can lead to chronic up-regulation of leptin production with subsequent blunting of diurnal rhythmicity. The significance of the sexual dimorphism in leptin concentration and rhythmicity is unclear, but several studies suggested that leptin serves as a metabolic signal to the hypothalamic centers involved in the coordination of the reproductive axis (18, 19, 20, 21, 22).

In conclusion, plasma leptin shows diurnal and ultradian rhythmicity, which is modulated by fat mass, gender, and insulinemia. Obesity is associated not only with higher absolute leptin levels but also with blunted relative diurnal excursions and dampened pulsatility. Abnormal leptin rhythmicity may contribute to leptin resistance thought to occur in obesity. Women have higher absolute leptin levels and lower relative diurnal amplitude than men at any fat mass. The significance of the sexual dimorphism in leptin is unclear, but leptin may act as a metabolic signal to the reproductive axis.


   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. We also thank Dr. E. Van Cauter for providing the ULTRA program.


   Footnotes
 
1 This work was supported by grants from the American Diabetes Association and by Grant M01-RR-43 from the General Clinical Research Branch, National Center for Research Resources, NIH. Back

Received July 11, 1997.

Revised September 16, 1997.

Revised October 3, 1997.

Accepted October 14, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. 1994 Positional cloning of the mouse obese gene and its human homologue. Nature. 372:425–432.[CrossRef][Medline]
  2. 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]
  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. 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]
  5. Stephens TW, Basinski M, Bristow PK, et al. 1995 The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature. 377:530–532.[CrossRef][Medline]
  6. 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]
  7. 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.
  8. 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. Nat Med. 1:1155–1161.[CrossRef][Medline]
  9. 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]
  10. Rosenbaum M, Nicolson M, Hirsch J, et al. 1996 Effects of gender, body composition, and menopause on plasma concentrations of leptin. J Clin Endocrinol Metab. 81:3424–3427.[Abstract]
  11. Ostlund Jr RE, Wang JW, Klein S, Gingerich R. 1996 Relation between plasma leptin concentration and body fat, gender, diet, age, and metabolic covariates. J Clin Endocrinol Metab. 81:3909–3913.[Abstract/Free Full Text]
  12. Havel PJ, Kasim-Karakas S, Dubuc GR, Mueller W, Phinney SD. 1996 Gender differences in plasma leptin concentrations. Nat Med. 2:949–950.[Medline]
  13. Saad MF, Damani S, Gingerich RL, et al. 1997 Sexual dimorphism in plasma leptin concentration. J Clin Endocrinol Metab. 82:579–584.[Abstract/Free Full Text]
  14. Zimmet P, Hodge A, Nicolson M, et al. 1996 Serum leptin concentration, obesity, and insulin resistance in Western Samoans: cross sectional study. BMJ. 313:965–969.[Abstract/Free Full Text]
  15. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte Jr D. 1996 Cerebrospinal fluid leptin levels: relationship to plasma levels, and to adiposity in humans. Nat Med. 2:589–593.[CrossRef][Medline]
  16. Caro JF, Kolaczynski JW, Nyce MR, et al. 1996 Decreased cerebrospinal fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet. 348:159–161.[CrossRef][Medline]
  17. Rohner-Jeanrenaud F, Jeanrenaud B. 1996 The discovery of leptin and its impact in the understanding of obesity. Eur J Endocrinol. 135:649–650.[Medline]
  18. Chehab FF, Lim ME, Lu R. 1996 Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet. 12:318–320.[CrossRef][Medline]
  19. Barash IA, Cheung CC, Weigle DS, et al. 1996 Leptin is a metabolic signal to the reproductive system. Endocrinology. 137:3144–3147.[Abstract]
  20. Chehab FF, Mounzih K, Lu R, Lim ME. 1997 Early onset of reproductive function in normal female mice treated with leptin. Science. 275:88–90.[Abstract/Free Full Text]
  21. Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS. 1997 Leptin accelerates the onset of puberty in normal female mice. J Clin Invest. 99:391–395.[Medline]
  22. Cheung CC, Thornton JE, Kuijper JL, Weigle DS, Clifton DK, Steiner RA. 1997 Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology. 138:855–858.[Abstract/Free Full Text]
  23. Sinha MK, Ohannesian JP, Heiman ML, et al. 1996 Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J Clin Invest. 97:1344–1347.[Medline]
  24. Laughlin GA, Yen SSC. 1997 Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. J Clin Endocrinol Metab. 82:318–321.[Abstract/Free Full Text]
  25. Sinha MK, Sturis J, Ohannesian J, et al. 1996 Ultradian oscillations of leptin secretion in humans. Biochem Biophys Res Commun. 228:733–738.[CrossRef][Medline]
  26. Burton BT, Foster WR, Hirsch J, Van Itallie TB. 1985 Health implications of obesity: an NIH consensus development conference. Int J Obes. 9:155–170.[Medline]
  27. Keys A, Brozek J. 1953 Body fat in adult man. Physiol Rev. 33:245–325.[Free Full Text]
  28. Bloomfield P. 1976 Fourier analysis of time series: an introduction. New York: John Wiley & Sons, Inc.
  29. Van Cauter E. 1988 Estimating false-positive and false-negative errors in analysis of hormonal pulsatility. Am J Physiol 254:E786–E794.
  30. Van Cauter E. 1990 Diurnal and ultradian rhythms in human endocrine function: A minireview. Horm Res. 34:45–53.[Medline]
  31. SPSS. 1993 User’s Guide. Release 6.1. Chicago.
  32. Schoeller DA, Cella LK, Sinha M, Caro J. 1996 Entrainment of the diurnal variation in plasma leptin levels. Obes Res. [Suppl 1]4:38S.
  33. Sainsbury A, Cusin I, Doyle P, Rohner-Jeanrenaud F, Jeanrenaud B. 1996 Intra-cerebroventricular administration of neuropeptide Y to normal rats increases obese gene expression in white adipose tissue. Diabetologia. 39:353–356.[Medline]
  34. Berneis K, Vosmeer S, Keller U. 1996 Effects of glucocorticoids and of growth hormone on serum leptin concentration in man. Eur J Endocrinol. 135:663–665.[Abstract]
  35. Trayhurn P, Duncan JS, Rayner DV. 1995 Acute cold-induced suppression of ob (obese) gene expression in white adipose tissue of mice: mediation by the sympathetic system. Biochem J. 311:729–733.
  36. Sinha MK, Opentanova I, Ohannesian JP, et al. 1996 Evidence of free and bound leptin in human circulation. J Clin Invest. 98:1277–1282.[Medline]
  37. Houseknecht KL, Mantzoros CS, Kuliawat R, Hadro E, Flier JS, Kahn BB. 1996 Evidence for leptin binding to proteins in serum of rodents and humans: modulation with obesity. Diabetes. 45:1638–1643.[Abstract]
  38. Dagogo-Jack S, Fanelli C, Paramore D, Brothers J, Landt M. 1996 Plasma leptin and insulin relationships in obese and nonobese humans. Diabetes. 45:695–698.[Abstract]
  39. Muscelli E, Camastra S, Masoni A, et al. 1996 Acute insulin administration does not affect plasma leptin levels in lean or obese subjects. Eur J Clin Invest. 26:940–943.[Medline]
  40. Vidal R, Auboeuf D, Vos PD, et al. 1996 The expression of ob gene is not acutely regulated by insulin and fasting in human abdominal subcutaneous adipose tissue. J Clin Invest. 98:251–255.[Medline]
  41. Kolaczynski JW, Nyce MR, Considine RV, et al. 1996 Acute and chronic effects of insulin on leptin production in humans. Studies in vivo and in vitro. Diabetes. 45:699–701.[Abstract]
  42. Boden G, Chen X, Kolaczynski JW, Polansky M. 1997 Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects. J Clin Invest 100:1107–1113.
  43. Utriainen T, Malmström R, Mäkimattila S, Yki-Järvinen H. 1996 Supraphysiological hyperinsulinemia increases plasma leptin concentrations after 4 h in normal subjects. Diabetes. 45:1364–1366.[Abstract]
  44. Havel PJ, Aoki TT, Grecu EO, Stern JS, Kasim-Karakas S. 1996 Leptin/adiposity relationships in intensively treated IDDM and NIDDM and increased plasma leptin after 6 hours of high dose insulin infusion. Obes Res. [Suppl 1]4:15S.
  45. Sonnenberg GE, Krakower GR, Hoffmann RG, Maas DL, Hennes MMI, Kissebah AH. 1996 Plasma leptin concentrations: effects of extended fasting and stepwise increases in glucose infusions. Obes Res. [Suppl 1]4:13S.
  46. Weigle DS. 1987 Pulsatile secretion of fuel-regulatory hormones. Diabetes. 36:764–775.[Medline]
  47. Matthews DR, Naylor BA, Jones RG, Ward GM, Turner RC. 1983 Pulsatile insulin has greater hypoglycemic effect than continuous delivery. Diabetes. 32:617–621.[Abstract]
  48. Weigle DS, Goodner CJ. 1986 Evidence that the physiological pulse frequency of glucagon secretion optimizes glucose production by perifused rat hepatocytes. Endocrinology. 118:1606–1613.[Abstract]
  49. Belchetz PE, Plant TM, Nakai Y, et al. 1978 Hypophysial response to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone. Science. 202:631–633.[Abstract/Free Full Text]
  50. Matsuda J, Yokota I, Iida M, et al. 1997 Serum leptin concentration in cord blood: relationship to birth weight and gender. J Clin Endocrinol Metab. 82:1642–1644.[Abstract/Free Full Text]
  51. Garcia-Mayor RV, Andrade MA, Rios M, Lage M, Dieguez C, Casanueva FE. 1997 Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage. J Clin Endocrinol Metab. 82:2849–2855.[Abstract/Free Full Text]
  52. Sih R, Morley JE, Kaiser FE, Perry III HM, Patrick P, Ross C. 1997 Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 82:1661–1667.[Abstract/Free Full Text]
  53. Wabitsch M, Blum WF, Muche R, et al. 1997 Contribution of androgens to the gender difference in leptin production in obese children and adolescents. J Clin Invest. 100:808–813.[Medline]
  54. 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]
  55. Montague CT, Prins JB, Sanders L, Digby JE, O’Rahilly S. 1997 Depot- and sex-specific differences in human leptin mRNA expression. Implications for the control of regional fat distribution. Diabetes. 46:342–347.[Abstract]
  56. Lönnqvist F, Arner P, Nordfors L, Schalling M. 1995 Overexpression of the obese (ob) gene in adipose tissue of human obese subjects. Nat Med. 1:950–953.[CrossRef][Medline]
  57. Haffner SM, Gingerich RL, Miettinen H, Stern MP. 1996 Leptin concentrations in relation to overall adiposity and regional body fat distribution in Mexican Americans. Int J Obes. 20:904–908.
  58. Dua A, Hennes MI, Hoffman RG, et al. 1996 Leptin: a significant indicator of total body fat but not of visceral fat and insulin sensitivity in African-American women. Diabetes. 45:1635–1637.[Abstract]
  59. Weigle DS, Ganter SL, Kuijper JL, Leonetti DL, Boyko EJ, Fujimoto WY. 1997 Effect of regional fat distribution and Prader-Willi syndrome on plasma leptin levels. J Clin Endocrinol Metab. 82:566–570.[Abstract/Free Full Text]
  60. Shimizu H, Shimomura Y, Hayashi R, et al. 1997 Seum leptin concentration is associated with total body fat mass, but not abdominal fat distribution. Int J Obes. 21:536–541.
  61. Allen LS, Hines M, Shryne JE, Gorski RA. 1989 Two sexually dimorphic cell groups in the human brain. J Neurosci. 9:497–506.[Abstract]
  62. Sahu A, Phelps CP, White JD, Crowley WR, Kalra SP, Kalra PS. 1992 Steroidal regulation of hypothalamic neuropeptide Y release and gene expression. Endocrinology. 130:3331–3336.[Abstract]
  63. Jensen MD. 1995 Gender differences in regional fatty acid metabolism before and after meal ingestion. J Clin Invest. 96:2297–2303.



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