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Original Studies |
Department of General Internal Medicine, and Center for Human Drug Research (J.B., R.C.S., A.F.C.), and the Department of Radiology, Leiden University Medical Center (J.D.), Leiden, The Netherlands
Address all correspondence and requests for reprints to: J. G. Langendonk, M.D., Department of General Internal Medicine, Leiden University Medical Center, C1-R51, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: langendonk{at}rullf2.medfac.leidenuniv.nl
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The metabolic profile of an adipocyte appears to be dependent upon its location in the various fat depots (7). Therefore, it is conceivable that leptin is secreted in different amounts by visceral adipocytes compared to sc adipocytes. Several in vitro studies have addressed the issue of the site specificity of ob gene expression. Some revealed higher levels of ob messenger ribonucleic acid (mRNA) in rat adipocytes from intraabdominal compartments (8), whereas others have documented increased expression in human sc compared to human visceral adipocytes (2, 3, 4, 5, 6, 7, 8, 9). As leptin delivers its message to the brain via the circulation, it is of obvious importance to establish whether site-specific differences in gene expression translate into different plasma levels. Waist circumference or waist to hip ratio were reported to be positively correlated to the plasma concentration of leptin in a number of clinical studies (10, 11). However, the sizes of visceral and sc fat depots were not measured in these studies. Two recent studies reported that visceral fat mass is not independently correlated with the circulating fasting leptin concentration in humans (12, 13).
The plasma leptin concentration appears to follow a circadian rhythm (5, 14, 15, 16, 17, 18). The biological rhythm of various hormones affecting metabolism is of major importance for their biological effect (19). The present study was performed to establish whether the 24-h plasma leptin profile is 1) different in normal weight compared to obese humans with respect to its circadian rhythm, 2) different in obese subjects with upper body obesity (UBO) compared to body mass index (BMI)-matched subjects with lower body obesity (LBO), 3) dependent upon the size of visceral and sc (abdominal and/or femoral) adipose tissue depots, or 4) affected by weight loss. Finally, as the fasting leptin concentration was measured to represent plasma leptin levels in almost all studies of leptin in humans to date, the agreement between fasting levels and 24-h profile characteristics were studied.
Because plasma leptin levels are strongly correlated with BMI and influenced by gender (20), we studied two groups of obese women who were closely matched for BMI while exhibiting a widely different distribution of their body fat, as evidenced by their waist to hip ratio (WHR).
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Subjects and Methods |
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Sixteen healthy obese and eight normal weight (NW) premenopausal
women were asked to participate through an advertisement in local
newspapers. The obese subjects were categorized as UBO (WHR, 
0.89) or
as LBO (WHR, 
0.81). The waist circumference (centimeters) was
measured half-way between the lower costal margin and the iliac crest;
the hip circumference was measured at the maximum circumference of the
hip with the subjects in the standing position (21). The two groups of
obese women were matched for BMI, and all women were matched for age.
All women had normal menstruation. They did not take any medication,
including oral contraceptives. Those with hemoglobin A1C
levels above 6.7% and smokers were excluded. According to their
medical history, all women had a stable body weight for at least 3
months before the study.
Written informed consent was obtained from all subjects. The study was approved by the ethics committee of Leiden University Medical Center.
Study design and protocol
This study was designed as an open observational study of three matched groups and was performed as part of a large project in which GH profiles were studied. The results of these studies will be published separately. The subjects were admitted to the research center at 0800 h after an overnight fast. All women were studied within 7 days after the first day of the menstrual period. They were instructed to follow a diet [total of 8.3 megajoules (MJ)/day] consisting of Modifast (2 MJ/day; macronutrient composition per 100 g: protein, 41 g; fat, 6 g; carbohydrate, 40 g; Sandoz Nutrition, Veenendaal, The Netherlands) and Nutridrink (6.3 MJ/day; macronutrient composition per 100 mL: protein, 5 g; fat, 6.5 g; carbohydrate, 17.9 g; Nutricia, Zoetermeer, The Netherlands) for 3 days before admission. On study days, these food products were served as meals at 0930, 1300, and 1830 h. The subjects were allowed to walk around inside the research center during the day. Lights went off at 2330 h.
After obtaining a 24-h hormone profile, all obese women started using a hypocaloric diet, which consisted of 2 MJ/day (Modifast). After they had lost 50% of their overweight, a second 24-h hormone profile was obtained according to the same protocol. This design was chosen to maintain BMI matching between both obese groups after weight loss.
Blood sampling
A 20-gauge cannula was placed in an antecubital vein. Starting 1 h after the insertion of the cannula, blood was drawn through a nonthrombogenic catheter, inserted through the cannula, and connected to a constant withdrawal pump (Conflo, Carmeda, Taeby, Sweden) (22). The withdrawal rate was 7.8 mL/h, and the reservoir tubes were changed every 10 min for a 24-h period. Plasma leptin concentrations were measured every 20 min. Blood samples were collected in heparinized tubes. All samples were centrifuged within the hour of sampling, and plasma was stored at -40 C until assay.
Leptin assay
Plasma human leptin concentrations were determined with a standardized RIA (Linco Research, St. Charles, MO); the limit of sensitivity was 0.5 µg/L. The limit of linearity for human leptin was 100 µg/L. The intraassay coefficients of variation ranged from 6–7% over the leptin concentration range of 3–80 µg/L, and the interassay coefficients of variation were 10.2%, 5.3%, and 7.2% for concentrations of 3.9, 11.3, and 63.8 µg/L. All samples of one 24-h profile were processed in the same assay procedure.
Body composition
Body fat mass and percentage were measured by bioelectrical impedance analysis (Bodystat, Ltd., Douglas, Isle of Man, UK). The impedance measurements were obtained on the morning of the study after the subjects had voided and while they were fasting and resting in bed (23).
Magnetic resonance imaging (MRI) measurement
Visceral and sc adipose tissue areas were assessed with MRI scanning in all groups before and after weight loss, using a Gyroscan-T5 whole body scanner (0.5 Tesla, Phillips Medical Systems, Best, The Netherlands) with a multislice fast spin echo sequence, a repetition time of 200 ms, and an effective echo time of 30 ms. The echo train length was three, and the number of signals averaged was four. Data from all images were acquired on a 256 x 180 matrix within a 40 x 40-cm field of view. Images were displayed on a 256 x 256 matrix. Transverse abdominal scans were made at three levels, consisting of six scans (a left and a right scan at each level), with each scan 10 mm thick and a gap of 2 mm between levels. The highest abdominal scan was at the level of the cranial intervertebral facies of the fourth lumbar vertebra. Similar scans were taken at the level of the hip, with the upper scan taken at the superior border of the trochanter major. The total acquisition time was approximately 30 min.
Analysis of the images was performed on a SUN workstation (SUN, Palo Alto, CA), using software developed at the Department of Biomedical Engineering at the Free University Hospital (Amsterdam, The Netherlands) (24). Image acquisition artifacts were corrected interactively by the observers. Image analysis of each slice was performed in triplicate by two observers unaware of subject-specific information, such as name and anthropometric data. The intra- and interobserver correlations were excellent (r = 0.984–0.998; P < 0.001). Visceral, abdominal sc, femoral sc, and total sc adipose tissue area and the ratio of visceral fat divided by abdominal sc fat were measured.
Calculations
The average 24-h leptin concentration (avgL) was calculated as the area under the curve divided by 24 h. The diurnal rhythm of each leptin profile was quantitatively described with cosinor analysis, as described previously (25). Cosinor analysis was implemented using nonlinear regression, using the NLR procedure in SPSS/PC+ (SPSS, Chicago, IL), to estimate the parameters of a cosine function using normal additive residual error. No corrections were made for an asymmetrical shape of individual curves. In short, a cosine curve with a fixed period (the duration of one complete rhythmic cycle) of 1440 min was fitted through all data to obtain individual parameter estimates, and the following chronobiological parameters were obtained: acrophase (the time between reference time and time of peak value), amplitude (half of the total predictable change in a rhythm), and mesor (the average value of a cosine curve fitted to the data; the mesor and the average 24-h leptin concentration are equivalent).
The percentage of overweight was calculated as 100 x (weight/ideal body weight) - 100. Ideal body weight for height was determined according to the Metropolitan Life Insurance tables for median build/frame (1983).
Statistical analysis
Paired t tests were used to compare parameters within groups before and after weight loss. Unpaired t tests were used to compare parameters between groups. Changes due to weight loss (before minus after) were compared in UBO and LBO women using unpaired t tests. The significance level was set at 5%. No corrections for multiple comparisons were implemented. All results are presented as the mean ± SD and 95% confidence intervals (CIs) of the difference unless otherwise indicated.
Correlations between parameters were calculated using Pearson’s correlation coefficient (separately for before and after weight loss). Most important predictors of outcome parameters were determined using stepwise multiple regression.
Calculations were performed using SPSS/PC+ V4.0.1 and SPSS for Windows, version 6.1.
The comparison between fasting plasma leptin levels and the average 24-h leptin concentration was made using a statistical method for assessing agreement between two methods (26).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The characteristics of the subjects included in the study are
shown in Table 1
. The obese women were
closely matched for BMI and percent body fat, whereas WHR and waist
circumference were higher in UBO than in LBO women (95% CIs, 0.15,
0.23 and 8.9, 23.3, respectively). The amount of visceral fat was
1.9-fold higher in the UBO group (95% CI, 95, 464), whereas their
total sc fat area was comparable to that in the LBO group (95% CI,
-336, 843).
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The circadian rhythm of plasma leptin concentration could
adequately be described by a cosine (Fig. 1). The cosine fit of a 24-h leptin
profile had a similar time course in obese and NW subjects (Table 2). The avgL in obese women was 4.2-fold
higher than that in NW women. Also, avgL expressed per kg fat mass was
1.9-fold higher in the obese group.
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No statistically significant difference between UBO and LBO was
observed with respect to the average 24-h leptin concentration or
acrophase (Table 2
). The absolute amplitude of the cosine fit was 3.5-
and 1.9-fold increased in LBO and UBO women, respectively, compared to
that in NW controls (95% CI, 3.5, 11.8, and 0.7, 5.6, respectively).
The absolute amplitude was 1.7-fold increased in LBO compared to that
in UBO women (95% CI, 0.24, 8.7). In contrast, the amplitude,
expressed as a percentage of the avgL or the relative amplitude, was
smaller in obese subjects (26 vs. 34% in NW group).
Comparison of the relative amplitude between UBO and LBO women revealed
that this difference was mainly due to a substantially smaller relative
amplitude in UBO women (22% vs. 34%; 95% CI, 2.9, 21.6),
whereas in LBO women the relative amplitude was only slightly smaller
than that in the NW controls (LBO, 29% vs. 34%; 95% CI,
-3.5, 13.9).
Correlations of the avgL with visceral and sc adipose tissue depots
Table 3 shows the correlation
coefficients for the avgL and various parameters related to body fat
storage. BMI, the absolute amount of body fat, and the amount of fat
expressed as a percentage of total body weight were strongly correlated
with avgL. There was a significant correlation between waist
circumference, but not WHR, and avgL. Multiple regression analysis
indicated that the total sc fat area was the best predictor of the
avgL. Visceral fat was not an independent predictor of avgL. The ratio
of visceral over sc fat area also did not correlate with leptin
levels.
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One subject in the LBO group failed to complete her weight loss program. One subject in the UBO group did lose sufficient weight, but plasma sampling could not be performed due to a technical problem with the blood withdrawal system. Therefore, each group comprised 7 women after completion of the weight loss protocol, and the statistical analysis of differences induced by weight loss includes data for these 14 women only.
BMI, fat percentage, waist circumference, total sc fat area, and
visceral fat area decreased significantly during hypocaloric dieting in
both groups. WHR did not change in LBO women, but decreased in UBO
women (Table 4).
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and 6). Weight loss was associated with a
significant decrease in avgL and avgL per kg fat
mass. The
estimated amplitudes of leptin profiles decreased by nearly 50% after
weight loss, whereas the amplitude as a percentage of the avgL did not
change. These changes were similar in UBO and LBO women. After weight
loss, the avgL was still correlated with BMI, absolute amount of body
fat, and body fat as a percentage of body weight (Table 3). Also, the strong correlation between
avgL and total sc fat area, abdominal sc fat, and femoral sc fat
remained. Multiple regression analysis indicated that the femoral sc
fat together with the BMI were the best predictors of the avgL after
weight loss (r = 0.85; P < 0.001).
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The fasting plasma leptin concentration measured at 0900 h was strongly correlated with avgL (r = 0.97) and with the amplitude of the cosine fit of its circadian rhythm (r = 0.69; P < 0.01). The limits of agreement between a fasting leptin level and avgL were -3.6 (95% CI, -5.92, -1.28) and 12.8 µg/L (95% CI, 10.48, 15.12). The limits of agreement between the average of three single measurements, the plasma leptin levels of 0900, 1800, and 0200 h averaged, and avgL were -3.2 (95% CI, -4.02, -2.36) and 2.7 µg/L (95% CI, 1.86, 3.52).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Differences in the distribution of body fat over upper body and lower body fat stores, as determined by the WHR, did not affect the average 24-h plasma leptin concentration or its circadian rhythm to a major extent. The results of this study suggest that the sc, be it femoral or abdominal, as opposed to visceral location of adipocytes, is a more important determinant of leptin’s plasma level. This might be due to the simple fact that the bulk of adipose tissue was located in sc areas. On the other hand, several studies have shown that ob mRNA expression is enhanced in sc located adipocytes compared to visceral adipocytes (2, 3, 4, 5, 6, 7, 8, 9). In fact, women were found to have an almost 6-fold higher ob gene expression in sc compared to omental adipocytes (9). Taken together, these data suggest that sc adipocytes mainly contribute to plasma leptin levels in women. The visceral fat depot contains readily available triglycerides, used by the liver to meet the energy (glucose) needs of peripheral tissues and the brain. Both its location and the extraordinary sensitivity to lipolytic stimuli that characterize visceral fat are in keeping with this idea (7). In contrast, sc fat is less lipolytically active and probably contains fat stores to cover long term energy needs. Thus, the finding that leptin’s plasma levels are mainly determined by the size of the sc fat depot is in line with all data gathered to date that suggest that leptin is involved in the long term regulation of the size of the body’s energy stores. Interestingly, it has been observed that sc adipocytes in women are less sensitive to epinephrine and more sensitive to insulin than visceral adipocytes (29, 30), which might contribute to the difference in ob mRNA expression between these cells, because insulin increases and epinephrine decreases leptin secretion. Also, sc adipocytes tend to be larger than visceral ones in women (31), and fat cell size has been reported to correlate positively with ob gene expression and leptin secretion (28, 32).
The relative amplitude (as opposed to the absolute amplitude) of the cosine fit of the circadian rhythm of leptin was lower in obese women than in their normal weight controls. Analysis of the two obese groups separately revealed that the difference was mainly due to a substantially lower relative amplitude in UBO women, whereas the relative amplitude in LBO women did not differ significantly from that in normal weight women. Interestingly, even after losing 50% of their overweight, UBO women exhibited significantly lower relative amplitudes than normal weight women. Although the physiological importance of this observation remains to be elucidated and requires further study of leptin levels in UBO women after reduction of their body fat mass to completely normal levels, it could suggest that this phenomenon is a trait characteristic of UBO women.
The concentrations of hormones in plasma are governed by their specific kinetic features, i.e. production rate, distribution volume, and clearance characteristics. To date, there is no clue as to what specific feature might cause the diurnal variation in plasma leptin levels. There are no data on (variations in) the distribution volume and clearance of leptin. As far as production is concerned, several factors have been shown to affect ob gene expression in cultured adipocytes. Although diurnal variations in fat cell size are unlikely, some studies have suggested that fat cell size is involved in the regulation of ob gene expression (28, 32). The secretion rate of insulin is governed by the concerted action of the plasma concentrations of various nutrients superimposed upon diurnal and ultradian rhythms (33, 34). The plasma insulin concentration reaches its peak during the day and levels off during the night to reach its nadir in early morning. Although in vitro studies indicate that insulin stimulates leptin secretion (35, 36), in vivo studies have shown that it takes at least 4–5 h after initial exposure of adipose tissue to insulin for leptin levels to increase (37, 38). Therefore, the delay between peak levels of insulin and leptin makes it unlikely that insulin stimulates leptin secretion during the night. Cortisol has also been shown to increase leptin secretion by cultured human fat cells (36). Furthermore, plasma leptin levels are increased in patients with glucocorticoid excess (39). As 24-h cortisol levels peak in the early morning (40), cortisol is not a likely candidate to increase nighttime leptin levels. Finally, although it seems more likely that some other, as yet unknown, regulatory hormone or intrinsic feature of adipocytes governs leptin’s circadian pattern, the decreased epinephrine concentrations during the night (41) could allow leptin levels to rise, as epinephrine suppresses ob gene expression in mouse adipose tissue (42). Recently, strong evidence was found to indicate that one of the factors entraining the circadian rhythm of leptin in humans is meal timing. The light/dark cycle does not appear to affect leptin’s rhythm in any way (18). Furthermore, the average 24-h leptin level was shown to be influenced by chronic hyperinsulinemia (17).
Fasting leptin levels at 0900 h were strongly correlated to avgL. The statistically significant limits of agreement between fasting leptin levels and avgL were -3.6 and 12.8 µg/L, which means that the avgL may be 3.6 below or 12.8 µg/L above the fasting leptin levels. This indicates that a fasting leptin level is probably not an acceptable indicator of avgL. If, however, three separate single measurements were averaged (plasma leptin levels at 0900, 1800, and 0200 h), the agreement was much better with the avgL. These limits of agreement were small enough (2.7 and -3.2) to allow the use of only these three leptin measurements to get an idea of the average leptin measured over 24 h.
In summary, this study shows that the time course of the diurnal rhythm of leptin is not different in obese and NW women. Furthermore, body fat distribution over upper body and lower body fat depots does not affect the avgL or its circadian rhythm to a major extent. The relative amplitude appears to be smaller in UBO women, even after substantial weight loss. Although the physiological significance of this observation is uncertain, it might be a trait characteristic of UBO subjects. The sc fat area, as opposed to the visceral fat area, is the major determinant of variations in avgL.
Received October 6, 1997.
Revised December 19, 1997.
Accepted January 6, 1998.
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