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Original Studies |
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 |
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| Introduction |
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| Subjects and Methods |
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This study included 31 healthy subjects (17 men, 14 women),
36 ± 2 (mean ± SEM) yr old (range 1855) with
a body mass index (BMI) of 27.5 ± 1.0 kg/m2 (range
19.940.7). 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 1
).
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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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 68 and 57% 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 (20000540 h) to day (06001940 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 |
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| Discussion |
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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 47 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 210 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 23 h to become evident. In addition, other studies
showed that infusion of insulin or glucose could increase plasma leptin
concentration in 46 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 5
). 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 23 h after meals (Fig. 5
). 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 leptins 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 |
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| Footnotes |
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Received July 11, 1997.
Revised September 16, 1997.
Revised October 3, 1997.
Accepted October 14, 1997.
| References |
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