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From the Clinical Research Centers |
Department of Medicine (C.C.-C., K.S.P.), University of Chicago, Chicago, Illinois 60637; and Department of Nutritional Sciences (D.A.S.), University of Wisconsin–Madison, Madison, Wisconsin 53706
Address correspondence and requests for reprints to: Dale A. Schoeller, Nutritional Sciences, University of Wisconsin–Madison, 1415 Linden Drive, Madison, Wisconsin 53706. E-mail: dschoell{at}nutrisci.wisc.edu
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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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As of yet, it is not fully understood how human leptin levels are regulated and which metabolic functions leptin modulates. It does not seem that leptin modulates energy expenditure because leptin levels correlate neither with resting metabolic rate (9) nor total energy expenditure (TEE) (10) in humans. However, leptin is modulated by energy balance. Protracted extreme caloric restriction or excess to induce changes in weight have demonstrated that leptin levels increase and decrease accordingly and that the observed changes exceed those expected from changes in fat mass (11, 12). Furthermore, these changes in leptin preceded changes in body weight. To date, only one study has been performed that investigated the effects of typical day-to-day variations in energy balance (13). Although the amplitude of the nocturnal rise in leptin reflected energy balance, changes in average daily levels were not detected.
Studies in animal models indicate that leptin regulates intake (1, 2, 3), and this has been confirmed in humans lacking functional leptin (14) or its cognate receptor (6). However, attempts to correlate physiologic changes in leptin have not demonstrated any association with subsequent energy intake (15) or hunger (16). These studies did not characterize the subjects according to restrained eating, whereas previous studies of ingestive behavior have indicated that it may be important to differentiate between restrained and nonrestrained eaters because the former may dissociate energy intake from physiologic hunger and satiety signals (17).
It is also not evident whether short-term changes in leptin levels reflect current energy status and, thus, will return to normal once the individual consumes a diet equal to expenditure; or if they indicate cumulative energy balance and, thus, will not return to normal until the subject consumes a diet that repays the acute energy deficit or surfeit. We hypothesized that leptin levels acutely respond to caloric excess or insufficiency, thus reflecting the body’s current energy state in nonobese, nonrestrained eaters. By signaling energy balance, leptin plays a role in regulating hunger and satiety, enabling the maintenance of normal weight. To test this hypothesis, 24-h leptin levels were measured as individuals underwent a series of 3-day periods of eucaloric feeding (100% TEE), moderate underfeeding (70% TEE), and overfeeding (130% TEE). In addition, changes in ad libitum intake were compared to changes in leptin levels in nonrestrained eaters.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We studied six healthy, nonobese (BMI, 18–25
kg/m2) males between the ages of 18 and 39 yr.
Their clinical characteristics are shown in Table 1
. Subjects were normolipemic
(cholesterol <2 g/L and triglycerides <1.55 g/L), had normal thyroid
function as determined by thyroid-stimulating hormone level (0.4–3.6
mU/L), and had scores 
6 on the restriction scale on the Eating
Attitudes Test (17). Because of the volume of blood to be drawn over
the duration of the study, inclusion criteria also included normal iron
stores, as determined by serum iron (0.5–1.6 mg/L) and serum ferritin
(15–200 µg/L), and normal total iron binding capacity (2.5–4.0
mg/L), in conjunction with normal hemoglobin (135–175 g/L). We
excluded individuals who had a history of metabolic disease such as
diabetes, hypertension, or liver disease, or were taking prescription
medications or over-the-counter substances such as melatonin. Subjects
who exercised regularly or who did not eat three meals a day including
breakfast (an early morning meal) were also excluded. The study
protocol was approved by the Institutional Review Board at the
University of Chicago, and all subjects provided written informed
consent. The study was performed at the Clinical Research Center (CRC)
at the University of Chicago Hospital.
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The subjects’ energy requirements were individually determined by measuring TEE using the doubly labeled water method (18) during a 2-week maintenance period (no biologically significant changes in weight) 4–10 weeks before the feeding study. This value defined the eucaloric state/diet for each individual. The average TEE was 12.5 ± 1.7 MJ/day (2980 ± 410 kcal/day).
The 12-day study consisted of four consecutive treatment periods of 3
days each with varying caloric intakes; a diagrammatical representation
of the study protocol is shown in Fig. 1.
During the first treatment period, subjects were fed a eucaloric diet
equal to 100% of their baseline TEE. During the second 3-day period
subjects were fed either 70% or 130% of their energy requirements.
During the third treatment period between the overfeeding and
underfeeding periods, the subjects’ intake was returned to 100% of
their energy requirement. During the fourth treatment period subjects
received the complementary dietary treatment from period 2. The order
of overfeeding and underfeeding during the second and fourth periods
was randomized in a crossover design. In other words, the three
subjects who received dietary intakes of 70% TEE during the second
treatment period (days 4–6) received dietary intakes increased to
130% TEE during the fourth treatment period (days 10–12). Meanwhile,
the other three subjects (who received dietary energy intakes increased
to 130% TEE during days 4–6) received dietary energy intakes
decreased to 70% TEE during days 10–12. As shown in Fig. 2, this treatment protocol yielded a
counterbalanced study such that the deficit or surfeit energy balance
that was established during the second period was not restored until
completion of the fourth period.
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Subjects were instructed to continue all habitual activities and to maintain a consistent activity level throughout the study, avoiding any prolonged vigorous activities (i.e. exercise). Subjects were also instructed to go to bed at 2300 h. Intravenous cannulas were placed in the forearm vein for blood withdrawal. Blood draws were conducted prior to every meal, with the exception of a packaged late-evening snack. On every 3rd day of each treatment period (days 3, 6, 9, and 12) additional blood samples were drawn after every meal and subjects were admitted to the CRC for an overnight visit. During this inpatient stay, hourly blood samples were drawn from 1800 h to 0800 h the following morning. From 2200–0700 h, blood samples were drawn using a 15-foot catheter through an opening in the wall to allow nighttime sampling without interruption of sleep.
Experimental measurements
Energy requirements for eucaloric feeding were determined by measuring TEE with doubly labeled water. Water containing 0.2 g O-18 labeled water and 0.14 g deuterium labeled water per kilogram estimated total body water (TBW) was administered by mouth. Spot urine specimens were collected before and 2, 3, and 6 h and 14 days and 14 days + 2 h after the dose. The specimens were decolorized with dry carbon black, and the stable isotope abundances were measured by isotope ratio mass spectrometry, as described previously (19). The isotope dilution spaces and elimination rates were determined and the energy expenditure was calculated, as described previously (18). The respiratory ratio was assumed to be 0.86. The TBW was calculated as the average of the deuterium dilution space/1.041 and the O-18 dilution space/1.007 (20). Percent body fat was calculated as: %BF = 1001(W-TBW/0.73)/W, where W is body weight.
At all time points described above, leptin levels were measured in serum in duplicate by RIA (Linco HL-81K, modified—a double antibody technique; Linco Research, Inc., St. Charles, MO). Results from the 3rd day of each dietary treatment period were subjected to analysis of diurnal variation, as described below. In addition, every 3rd day sample was analyzed for insulin, as well. Insulin levels were measured in serum by a double antibody technique (21). The lower limit of detection was 20 pmol/L, and the average intra-assay coefficient of variation was 6%. All 0800-h fasting blood samples were tested for triglyceride levels. The 0800-h fasting blood samples from the day after each dietary period (days 4, 7, 10, and 13) were analyzed for T3 levels.
Data analysis
Chronobiological parameters.The daily variation in each individual leptin profile was quantitatively evaluated by building a best-fit curve, using a program that repeatedly calculates periodograms method based on repeated periodogram calculations described in detail previously (22). Briefly, the periodogram method consists of fitting a sum of sinusoidal components on the series of data and of selecting those that contribute significantly to the observed variations. The significant components in the low frequency range are summed to render the best-fit curve for the determination of the standard chronobiology parameters. This procedure allowed the objective comparisons of the parameters and their timing. The zenith is defined as the time of occurrence and maximum in the best-fit curve. Although the nadir (minimum) of the leptin profile has been reported to take place during the afternoon (23), our sampling protocol could not include hourly leptin levels during the daytime and, therefore, we were unable to accurately identify the nadir. Daytime sampling was limited to minimize alterations in the subjects’ normal daily activity and, thus, maintain TEE. The leptin mesor (average) was calculated from the weighted mean of the leptin levels on the 3rd day of each treatment period at 0800, 0900, 1300, and 1400 h and hourly from 1800 h to 0800 h the following morning. The amplitude was calculated by subtracting the mesor from the zenith. The insulin mesor was calculated using the same method as stated above for the leptin mesor. All results are expressed as means ± SD.
Statistical analysis.To test the primary hypothesis that leptin levels reflect the current day’s energy balance, ANOVA with repeated measures was performed on the mesor of the 3rd day of each period. As a second test of the primary hypothesis, we compared the difference between the two eucaloric period mesors (periods 1 and 3), as well as the differences between the first and last period (period 4) mesors using a paired two-tailed t test. If the primary hypothesis was correct, then the mesors of the two eucaloric periods should not differ at all, whereas the changes in the mesors between periods 1 and 4 should differ with respect to treatment order. These analyses were repeated for the zenith and amplitude. For the second test, results are expressed as the percentage of the baseline value measured on the 3rd day of the first eucaloric period.
Because leptin mesors did indicate an effect of treatment order, we also tested whether within-subject leptin levels increased or decreased progressively from days 1, 2, and 3 within the overfeeding, underfeeding, and eucaloric periods. For this comparison, the three daily premeal levels (0800, 1300, and 1800 h) were available for analysis. We compared leptin levels within each treatment period (before each meal and also the average of all three premeal values) using ANOVA to test for changes with time within each dietary treatment period.
Linear correlation was calculated as the Pierson product. Individual leptin levels for each time point were plotted against the corresponding insulin level to find any correlation between these two putative energy indicators. We also compared changes in average leptin levels to changes in ad libitum intake during breakfast buffet for each dietary treatment period to determine whether there was any correlation between this putative energy indicator and a quantitative measure of hunger. The statistical significance of differences was assessed at the 5% level.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Leptin levels were measured on the 3rd day of each of four treatment periods. The diurnal variation in leptin levels was significant (P < 0.01) in 24 of the 24 test periods (four periods each in six subjects). During the initial eucaloric period, the serum leptin mesor averaged 2.8 ± 1.8 ng/mL. The zenith occurred at 0200 h ± 2:05 h and averaged 3.7 ± 2.3 ng/mL, and the amplitude averaged 31 ± 8%. The leptin mesor during this first eucaloric period was correlated with percent body fat (r = 0.90; P = 0.02) and trended with fat mass (r = 0.79; P = 0.06), as demonstrated previously by Considine (7).
The zenith of the leptin profiles behaved in a similar manner as the
mesors (Table 2). When the
participants returned to eucaloric intake levels during period 3, the
leptin zeniths differed depending on treatment order. Those who were
underfed earlier had leptin zeniths that averaged 93 ± 26% of
the first eucaloric period, and those who were overfed earlier had
leptin zeniths that averaged 142 ± 20% of the first eucaloric
period (P = 0.07 with respect to feeding order). At the
end of period 4, when the participants had finally returned to
cumulative energy balance, the zenith of those who were first underfed
averaged 110 ± 28% of the baseline eucaloric period [not
significant (n.s.)], and those who were first overfed averaged
102 ± 11% of the baseline eucaloric period (n.s.)
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however, the effects of feeding order did not reach significance at the
end of the second period, perhaps because one of the subjects (who were
initially underfed) demonstrated an increase in amplitude during the
decreased intake treatment period (first underfed = 27 ±
11% vs. overfed first = 39 ± 10%; n.s.).
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The order of the treatments had a significant effect on the leptin
mesor (Table 4 and Fig. 3, A and B). Rather than return to
baseline levels when energy intake was returned to the eucaloric level
in period 3 as hypothesized, the leptin mesor remained unchanged from
the previous period (average change, -0.26 ± 0.32 ng/mL; n.s.).
Expressed as a percentage of the baseline leptin mesor value, the
leptin levels on the 3rd day of returning to eucaloric intake levels
(period 3) differed with respect to dietary treatment order (+35
± 22% after overfeeding vs. -12 ± 16% after
underfeeding; P = 0.03). The effect of feeding order,
however, disappeared by the 3rd day of period 4 when the energy deficit
or surfeit effected during period 2 was repaid by the complementary
dietary treatment during period 4 (Fig. 2
). Expressed as a percentage
of the baseline mesor, the leptin levels on the 3rd day of period 4
averaged 104 ± 21% (n.s.) of baseline for those who were
initially overfed vs. 106 ± 16% (n.s.) for those who
were initially underfed.
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). Decreasing intakes by 30% of the TEE decreased the mesor by
0.75 ± 0.71 ng/mL (-26 ± 17%; P = 0.01),
and increasing intakes by 30% of the TEE increased mesor by 0.53
± 0.24 ng/mL (+21 ± 8%; P = 0.001). Again, the
other chronobiological parameters behaved in a similar manner (Tables 3 and 4). The leptin zenith exhibited an average decrease of 1.2 ±
1.1 ng/mL (-30 ± 21%; P = 0.02) after
decreasing intake by 30% of the TEE and an average increase of
0.72 ± 0.45 ng/mL (21 ± 12%; P = 0.01)
after increasing intake by 30% of the TEE. The amplitude demonstrated
little trend. The time of the zenith did not change with underfeeding
or overfeeding. It was observed, on average, at 0200 h ± 2:05 h
during the first eucaloric period; 0100 h ± 1:15 h during the
second eucaloric period; 0110 h ± 1:28 h during underfeeding; and
2350 h ± 1:10 h during overfeeding. In addition to the frequent blood sampling on the 3rd day of each dietary period, blood was collected before each meal on all 3 days of each treatment period. The daily specimens were analyzed for leptin to determine whether daily leptin levels changed progressively during the treatment. When just the morning fasting values (0800 h) were compared, leptin levels trended with the direction of the dietary treatment, but these differences did not reach statistical significance. Expressed as a percentage of the 3rd day of the previous eucaloric mesor, fasting leptin levels averaged 92%, 88%, and 80% on the 1st, 2nd, and 3rd days of underfeeding, and 89%, 98%, and 102% on these respective days of overfeeding. When all three of the daytime leptin levels (0800, 1300, and 1800 h) were averaged for each participant and then compared in a similar manner, daily leptin levels during underfeeding decreased systematically (104 ± 22%, 84 ± 20%, and 79 ± 21%; P = 0.03). The leptin levels did not change systematically during the 3 successive days of overfeeding (98 ± 15%, 105 ± 25%, and 96 ± 18%; n.s.).
Comparison to energy balance indicators
The responses in body weight, triglyceride, triiodothyronine, and
insulin throughout the study are shown in Table 5. Changes in daily body weight as
well as fasting triglyceride and triiodothyronine levels trended with
changes in energy balance, but only weight loss during underfeeding
reached statistical significance. On the other hand, mesor insulin
levels decreased during underfeeding (average change, -45 pmol/L;
P = 0.02), increased during overfeeding (average
change, 81 pmol/L; P = 0.02), and returned to baseline
levels when energy intake was returned to the eucaloric level in period
3 (average change, 11 pmol/L; P = 0.47). These changes
in mesor insulin levels were not affected by feeding order (and
subsequently cumulative energy balance) as observed with the changes in
leptin levels, but were instead the result of changes in daily caloric
intake. Furthermore, hourly insulin levels (average insulin profiles
are shown in Fig. 4, A and B) did not
correlate with hourly leptin levels (data not shown), nor did changes
in insulin between treatments correlate with changes in leptin
levels.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, A and B, where the fourth period profiles are
superimposable with the first period profiles, regardless of treatment
order. These findings extend the observations of others (11, 12) who
reported that 24-h average leptin levels decreased or increased from
baseline levels after participants were exposed to either fasting or
8 MJ/day overfeeding and those of van Aggel-Leijssen et
al. (13), who demonstrated that leptin levels also respond to
modest changes in energy intake. In our study, the leptin response was detected in the 24-h average (mesor) and the zenith. We could not detect this response in the morning fasting level, however, this could be a type 2 error. Both the mesor and zenith include a significant averaging of multiple leptin levels, and, thus, variability due to assay or pulsatile secretion is reduced. When averaged over the three blood specimens drawn within each day, we did detect a systematic daytime change in leptin levels during underfeeding, suggesting that the daytime levels also responded to cumulative energy balance; however, this was not detected during overfeeding. This may still be a type 2 error, but it is consistent with the suggestion by Flier (8) that leptin levels may be more responsive to negative energy balance than positive energy balance.
The response of leptin to positive and negative cumulative energy balance in the present study is consistent with a recent report (13) that also measured 24-h leptin patterns with roughly 30% changes in energy balance, resulting from exercising and manipulations in diet. The authors, however, reported significant changes in the amplitude of the 24-h leptin profile, but only trends in the mesors. In contrast, we found that the mesors were significantly different, whereas the amplitudes only trended. The 24-h patterns and absolute changes in leptin levels, however, are qualitatively quite similar between the studies. Thus, it is likely that that these differences are type 2 errors because both studies involved a modest number of subjects.
With the exception of insulin, the comparison of other energy balance indicators to leptin levels was inconclusive. Nonetheless, we do not assume this to indicate that the subjects were either breaching protocol or that the dietary intake and energy expenditure calculations were not accurate. There are a number of probable reasons as to why there was poor correlation between these energy balance indicators and leptin levels. For example, triglyceride and triiodothyronine results did not vary with changes in energy intake, perhaps due to the infrequency of sampling.
We were unable to replicate the observations of others that there is a high degree of correlation between peripheral insulin and leptin levels (24). Changes in mesor insulin levels were affected by changes in daily caloric intake, whereas leptin levels seemed to reflect cumulative energy balance. Although this is not inconsistent with a regulatory control of leptin by insulin, it does indicate that under conditions of changing energy intake, the simple correlation of leptin and insulin is lost. Leptin is known to affect energy intake in rodent models (1, 2, 3) and beagles (25). It has also been shown to have decrease energy intake in nonhuman primates, but only when directly administered into the hypothalamic region (26).
The role of peripheral leptin in the acute regulation of human energy intake has been previously thought to be minor (8). We found, however, that changes in intake during the ad libitum breakfast negatively correlated with changes in 24-h average leptin levels, indicating a possible relationship between acute changes in leptin levels and hunger as first hypothesized on leptin’s discovery. When leptin levels increased, ad libitum intake decreased, and when leptin levels decreased, ad libitum intake increased. Although this correlation in and of itself does not prove causality between leptin levels and intake, it does indicate a consistent relationship between these two variables in male nonobese, nonrestrained eaters. More studies are needed to determine whether this relationship is limited to nonobese, nonrestrained eaters.
The physiologic role of the diurnal variation in circulating leptin is still not fully understood. In a previous study, we demonstrated that the nocturnal rise was entrained to the meal pattern during the day (27). The current study and the study by van Aggel-Leijssen et al. (13) demonstrates that leptin levels throughout the entire day are altered by changes in energy balance. We speculate that the nocturnal rise may be important in leptin role’s action on energy intake. Thus, in future human studies involving leptin administration to moderate energy intake, it may be important to provide leptin in the evening as opposed to the morning.
In cross-sectional studies, it is clear that body fat significantly contributes to leptin levels (7). In the present study, we demonstrate that the average 24-h leptin level and zenith increase and decrease in response to moderate changes in dietary energy intake. These observed changes, however, are larger than would be predicted by increases and decreases in body fat. Even if the entire excess (or deficit) in energy intake were stored (or used) as body fat during the overfeeding (or underfeeding) period, the change in fat would be only 0.3 kg (11.3 MJ/39.8 MJ'kg). This is <2% of the baseline body fat, yet the average leptin levels increased by 17% during overfeeding and decreased by 24% during underfeeding. Thus, we interpret this observation as an indication that leptin levels are responding to the cumulative energy balance in addition to body fat. The mechanisms underpinning this action are uncertain at this date.
In summary, the results of this study add to the increasing body of evidence that leptin levels reflect cumulative energy balance and also demonstrate an association between leptin levels and hunger. Taken together, these results suggest that leptin provides a signal that could be used by the metabolic regulatory center to maintain energy homeostasis by modulating intake in healthy nonobese, nonrestrained individuals.
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Acknowledgments |
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Footnotes |
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Received December 30, 1999.
Revised April 10, 2000.
Accepted May 14, 2000.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
); 2, underfed (
); 3,
eucaloric (
); 4, overfed (
). Leptin levels decreased after
underfeeding, increased after overfeeding, and did not change
significantly after eucaloric feeding relative to the preceding
treatment period. Data are the mean of the three subjects who underwent
each treatment order protocol.
