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Original Research Communications |
1 From the McGill Nutrition and Food Science Centre, Royal Victoria Hospital, Montréal, Canada, and Hoffmann-La Roche, Inc, Nutley, NJ.
2 Supported by grants from the Canadian Diabetes Association and Servier Canada (to RG and EBM).
3 Address reprint requests to R Gougeon, McGill Nutrition and Food Science Centre, Royal Victoria Hospital, 687 Pine Avenue West, Montréal, Québec, Canada, H3A 1A1 E-mail: rgougeon{at}rvhmed.lan.mcgill.ca.
See corresponding editorial on page 305.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: We tested the interactions between energy intake and fat loss on plasma leptin during prolonged moderate and severe energy restriction, with a view to understanding mechanisms of control.
Design: Postabsorptive leptin was measured with an enzyme-linked immunosorbent assay specific for the human peptide in 21 obese women aged 41 ± 3 y (weight: 102 ± 4 kg; 48 ± 1% body fat) after 1 wk of a weight-maintaining diet and then weekly for 4 wk during a total fast (group 1); a 1.9-MJ/d all-protein, very-low-energy diet (VLED) (group 2); or a low-energy, balanced-deficit diet (BDD) providing 50% of maintenance energy (group 3). In groups 1 and 2, leptin was also measured after 1 wk of refeeding with a diet equivalent to the BDD.
Results: Mean leptin decreased markedly by up to 66% (P < 0.001) at week 1 of energy restriction and then gradually thereafter. The change in leptin per kilogram fat mass correlated with that in glucose concentrations [r = 0.538 (P = 0.012) at week 1 and r = 0.447 (P = 0.042) at week 4] but not with that in fat mass. During refeeding postfasting, leptin increased (P = 0.008), despite an ongoing loss of fat mass and correlated positively with changes in resting energy expenditure. At times with comparable cumulative energy restriction and fat loss between diets, the percentage change in leptin paralleled that in glucose.
Conclusions: In obesity, changes in energy intake over days to weeks are a primary modulator of plasma leptin concentrations that are related to the change in glycemia and are able to override the regulatory influence of fat mass.
Key Words: OB gene • obesity • leptin • energy restriction • refeeding • fasting • ketones • lipolysis • resting energy expenditure • women
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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With exceedingly rare exceptions, obese humans appear to have a normal OB gene (10) and normal leptin and leptin receptors. Plasma leptin concentrations in humans correlate closely and positively with indexes of body fat mass (10–13). Consumption of diets with moderate energy deficits is associated with decreases in plasma leptin (14–17), which appear to parallel changes in weight and fat mass (14), especially in men (17). Subjects who subsequently regain weight show corresponding increases in their plasma leptin concentrations (18).
Plasma leptin decreases markedly during short-term total fasting (18, 19), not in proportion to the loss in fat mass, and returns to baseline concentrations with refeeding (18). The cellular mechanism whereby fasting decreases leptin concentrations is as yet poorly defined, but correlates with markers of lipolysis (19). Plasma leptin concentrations correlate with serum insulin concentrations in weight-stable individuals, and both concentrations decrease in parallel after weight loss (20). The same findings were found in fed and fasted mice (21). If glucose and insulin are both "clamped" at basal concentrations, the decline in leptin with fasting is prevented (19). Four-day fasts are associated with a rapid decline in leptin concentrations that correlates best with that of insulin concentrations (22). Insulin does not increase leptin release by cultured rat adipocytes if glucose uptake is blocked (23), whereas intravenous glucose acutely increases concentrations of serum leptin (22). Taken together, these results suggest that insulin-mediated glucose availability may play a role in the control of leptin synthesis by adipocytes (24).
In the present study, we determined leptin concentrations in 3 groups of obese women undergoing different degrees of dietary energy restriction for 4 wk as well as after 1 wk of refeeding. We hypothesized first that the initial change in energy intake would cause a decline in leptin concentrations over a period of days in response to the changes in hormone-fuel milieu and concurrent fat loss. The second hypothesis was that for comparable fat masses lost, independent of duration of energy restriction, decreases in plasma glucose, insulin, or both would parallel those in plasma leptin. Third, we postulated that leptin would increase during hypoenergetic refeeding in which energy intake is increased relative to that in the preceding period, but that net fat mobilization would continue.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Each subject was informed of the nature, purpose, and possible risks of the study and consent was obtained; the protocols were approved by the hospital's Human Ethics Committee. Clinical and laboratory evaluations showed no evidence of gout or of hepatic, thyroid, cardiovascular, renal, or pulmonary dysfunction. The subjects did not smoke during the study, nor did they exercise, except for walking in the hospital ward. Results of studies of protein turnover in these subjects were published previously (25).
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1.5 L/d. Subsequently, 3 different levels of energy restriction were imposed for 4 wk. Eight subjects underwent total fasting. Six subjects consumed a mainly protein, very-low-energy diet (VLED) (Bariatrix International Inc). The protein formula provided 95 g protein, 10–15 g carbohydrate, 2 g fat, and 1.9 MJ/d. Seven other subjects received a low-energy, balanced-deficit diet (BDD) that provided 50% of individual weight-maintenance energy requirements and provided 5.5 ± 0.3 MJ/d with 30 ± 1% of energy as protein, 53 ± 1% as carbohydrate, and 17 ± 1% as fat. The diet was composed of a commercial meal-replacement product (Boost; Mead Johnson Canada, Belleville, Canada), a bran cereal (AllBran Cereal; Kellogg Canada Inc, Etobicoke, Canada), milk, and a casein-soy protein supplement (Bariatrix International Inc) to maintain a protein intake the same as that of the isoenergetic diet. All subjects were given one tablet of a multivitamin-multimineral supplement (Centrum Forte; Cyanamid Canada Inc, Montréal) daily and, with the total fast or the VLED, 20 mmol K as KCl (K-Dur; Key, Schering Canada Inc, Pointe-Claire, Canada). After 4 wk of fasting or of the VLED, subjects were refed for 1 wk a diet providing 3.35 MJ/d initially. The diet was composed of regular foods and had a low carbohydrate content to minimize water retention. Carbohydrate was increased stepwise by 30 g every 3 d over 8 d to 100 g/d, and total energy to 4.2 MJ/d.
Weight was measured on a balance calibrated to 0.1 kg (Scale-Tronix digital scale; Ingram and Bell-Meditron, Le Groupe Inc, Don Mills, Canada). Initial body composition was assessed with a 4-terminal bioimpedance analyzer (BIA-103; RJL Systems, Detroit) by using the procedures, anatomic sites, and equation described by Lukaski et al (26). Body circumference measurements were taken at the site giving the minimal value between the xiphoid process and the iliac crest for the waist and at the level of maximal protuberance in the trochanteric region for the hips.
Resting energy expenditure (REE) was measured with a ventilated-hood indirect calorimeter (Deltatrac Metabolic Monitor; Sensormedics Corporation, Anaheim, CA) weekly in the morning, on awakening, in a quiet environment with a room temperature averaging 22°C. Data were collected while the subjects breathed under the plastic canopy for 20 min. The average result from the last 15 min of calorimetry was used to calculate 24-h REE according to the de Weir equation (27). Overnight fasted blood samples were taken for determinations of serum glucose, electrolytes, calcium, phosphate, uric acid, and lipid concentrations; for liver and kidney function tests; and for complete blood counts. An electrocardiograph was performed weekly in all subjects.
Venous blood samples were drawn with minimal stasis after an overnight fast at the end of the isoenergetic diet, then weekly at 0800 in all subjects. Heparin-containing plasma was collected with aprotinin (Trasylol, 10000000 Kallikrein inhibiting U/L; Bayer, Etobicoke, Canada). These samples were cooled, centrifuged at 2000 x g at 4°C for 15 min, and stored at -20°C until assayed for leptin (see below) and for insulin by using an anti-beef insulin antiserum, purified human insulin standards, [125I]pork insulin (Linco Research Inc, St Charles, MO), and dextran-coated charcoal separation. This immunoassay gives immunoreactive insulin results slightly lower than that of an assay (Linco Research Inc) specific for insulin that excludes proinsulin (R Gougeon, M Giroux, and EB Marliss, unpublished observations, 1991). Plasma values were corrected for dilution by aprotinin, based on concurrently determined hematocrit values. Perchloric acid supernates of deproteinized whole blood were assayed for 3-hydroxybutyrate with an enzymic microfluorometric method (28). Circulating total leptin concentrations were measured by using the human OB protein-specific enzyme-linked immunosorbent assay: samples were added to monoclonal anti-human OB–coated plates, then polyclonal rabbit anti-human OB was added to the plates and the complexes were detected by using horseradish peroxidase–labeled goat anti-rabbit immunoglobulin G. Optical density of the labeled reaction was measured at a wavelength of 450 nm in a plate reader (Titertek Multiscan MC; Eflab OY, Helsinki) (29, 30).
Daily urinary urea nitrogen and creatinine were determined with an autoanalyzer and daily ammonium nitrogen was measured by using a specific ion electrode (Orion Research Inc, Cambridge, MA). Total urinary nitrogen was measured with an automated micro-Kjeldahl technique by using a single-channel autoanalyzer (Technicon, Tarrytown, NY) (31) or by chemiluminescence (Antek Pyro-chemiluminescent Nitrogen System, Houston). All determinations were made in duplicate or triplicate. Daily nitrogen balance was calculated on the basis of measured intake minus the sum of 1) measured urinary total nitrogen, 2) pooled fecal nitrogen from subjects in similar studies (during weight maintenance: 0.8 g N/d, n = 9; during the VLED: 0.3 g N/d, n = 3; during fasting: 0.1 g N/d), and 3) estimated skin, hair, and secretion (5 mg N/kg body wt) losses (32).
Weekly fat (triacylglycerol) losses were calculated by using the following equation:
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| (1) |
where energy expenditure is REE (measured) + energy expended in daily activity (estimated as 50% of baseline REE) and energy from protein oxidation is nitrogen excretion (g N) x 6.25 (g protein/g N) x 4 (kcal/g protein). (To convert kcal to kJ, multiply by 4.184.) The thermic effect of food was estimated to be 7% and was considered part of the energy expended in daily activity. Because the fasting group had no dietary intake, 7% was subtracted from total energy expenditure.
Statistical analyses
Statistical analyses were carried out by using the PRIMER BIOSTATISTICS program (McGraw-Hill Inc, New York) and the SPSS for WINDOWS software package (release 6.0; SPSS Inc, Chicago). Data were analyzed by using repeated-measures analysis of variance (ANOVA): one factor (group) between and one factor (time) within subjects. When an interaction among groups was found with repeated measures, a one-way ANOVA was done to detect differences among groups at each point and the significant differences (P < 0.05) were identified by Bonferroni adjustment. Linear correlations were calculated by using Pearson correlation coefficients. Data are presented as means ± SEMs.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Plasma leptin concentrations in the 3 groups of subjects are shown in Figure 1A. Baseline values on day 7 of isoenergetic feeding were not significantly different between groups and correlated positively with fat mass (r = 0.724, P = 0.0002), REE (r = 0.501, P = 0.025), fasting plasma insulin (r = 0.503, P = 0.020), and triacylglycerol (r = 0.517, P = 0.03) and negatively with the nonprotein respiratory quotient (NPRQ) (r = -0.633, P = 0.005). However, in stepwise linear multiple regression analyses, only fat mass correlated significantly with initial plasma leptin concentrations (r = 0.786, P = 0.0003; n = 16). Leptin decreased significantly in all 3 groups in the first week (P < 0.001), with values correlating with baseline values (r = -0.625, P = 0.002), and continued to decrease but less dramatically so through week 4. At week 4, concentrations also correlated with baseline values (r = -0.843, P < 0.001). The percentage decline in baseline values is shown in Figure 1B. Differences were greatest between the fasting and BDD groups and were significant at all time points. Thus, there was a trend for greater declines in leptin with greater energy deficits. Leptin concentrations adjusted per kilogram fat mass are shown in Figure 1C. The decrease in the BDD group was significantly lower than that in the fasting group from weeks 1 to 4 (P = 0.026). After 1 wk of refeeding (week 5), leptin increased significantly (P = 0.002) in the fasting group.
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, respectively. Fat mass decreased significantly (P < 0.001) from baseline in all 3 groups at week 1: 1.63 ± 0.06 kg in the fasting group, 1.48 ± 0.13 kg in the VLED group, and 0.87 ± 0.07 kg in the BDD group. The rates of loss remained constant in each subsequent week, up to week 4. The amount of fat lost during refeeding (1.1 ± 0.1 kg) was significantly different from the amount of fat lost during the preceding weeks of the study (P < 0.001). The amount of fat lost reflected the energy deficits, with the fasting and VLED groups losing more fat than the BDD group (both P < 0.001); differences in the amount of fat lost were not significant between the fasting and VLED groups.
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, respectively. Plasma glucose concentrations decreased significantly in both the fasting and VLED groups (P < 0.05), significantly more so in the fasting group, whereas concentrations did not decline in the BDD group (Figure 3A). Concentrations in the fasting group were significantly different from those in the VLED and BDD groups from weeks 1 to 4. The percentage change in plasma glucose from initial concentrations was significant (P < 0.001) in the VLED and fasting groups, greatest in the fasting group and intermediate in the VLED group (Figure 3B). With refeeding, glucose increased significantly from weeks 4 to 5 in the fasting and VLED groups.
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). However, the percentage change from baseline during the BDD was significantly less than that during fasting and the VLED (Figure 4B). Insulin increased significantly with refeeding (from weeks 4 to 5) in the fasting group, in absolute terms (Figure 4A) and as a percentage change from baseline (Figure 4B).
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, respectively. REE decreased significantly (P < 0.002, repeated-measures ANOVA) with time: by week 1 in the VLED group, by week 2 in the fasting group, and by week 3 in the BDD group. With refeeding, REE increased (NS) by 3.3% from weeks 4 to 5. The positive correlation between percentage changes in leptin (per kg fat lost) and percentage changes in glucose at week 4 in the BDD group and at week 2 in the VLED group are shown in Figure 6.
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. The percentage change in leptin correlated positively with the change in glucose, NPRQ, and fat mass at week 1; with the change in glucose and fat mass at week 4; and with the change in REE from weeks 4 to 5. We performed stepwise multiple linear regression with the percentage change in leptin concentrations from baseline as a dependent variable and the change in glucose, NPRQ, and fat mass at week 1 and the change in glucose and fat mass at week 4 as independent variables. Only glucose entered as a significant independent variable. At week 1, it explained 49% and at week 4, 63% of the variation in the percentage change in leptin. At week 5, 50% of the variation in the percentage change in leptin was explained by the change in REE.
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). With refeeding, the change in leptin from weeks 4 to 5 correlated with that in REE and that in triacylglycerol. With stepwise linear multiple regression analysis, only REE was a significant independent variable, explaining 45% of the change in leptin.
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. There were significant differences between the BDD and fasting groups in the percentage change in leptin, the percentage change in leptin per kilogram fat mass lost, and the percentage change and change in absolute values of glucose. There was also a significant difference between the VLED and fasting groups in the percentage change and change in absolute values of glucose. There was no significant effect of age nor of group on baseline leptin concentrations or on leptin concentrations adjusted per kilogram fat mass (by simple-factorial ANOVA). Within the fasting group, of which half the subjects were aged <30 y, age had no significant effect on leptin responses (P = 0.650, repeated-measures ANOVA).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We found that the magnitude of the decrease in leptin related to that of its baseline value. However, the decrease in leptin at weeks 1 and 4 did not correlate with baseline values when expressed as a percentage change or when corrected per kilogram fat mass. Thus, we analyzed the response in change from baseline by adjusting leptin per kilogram fat mass to correct for the variability at baseline and found a significant correlation with the change in glucose at weeks 1 and 4. The change in glucose at weeks 1 and 4 did not correlate with baseline values. Furthermore, we pooled the data of subjects after comparable cumulative energy deficits and fat losses and found that per kilogram of fat lost, the percentage decline in leptin correlated with the change in glucose concentrations (Figure 6
). These results support those of others (24) that a close relation exists between changes in leptin and glucose during energy restriction and suggest an effect of glucose availability on leptin secretion (19). Our results are consistent with the finding that insulin-mediated glucose uptake and utilization by isolated adipocytes are determinants of leptin expression and secretion (23). Studies in insulin-deficient diabetic rats showed that plasma leptin concentrations decreased proportionally to those of insulin and inversely to those of glucose, independent of weight loss, consistent with the decrease resulting from decreased glucose transport into cells (35).
However, other factors change acutely in response to changes in energy balance, which precede major modifications in body composition (34). We also found a significant decline in the concentration of substrates such as triacylglycerol and cholesterol and of hormones such as insulin and increases in circulating nonessential fatty acids and 3-hydroxybutyrate (25). Although 3-hydroxybutyrate concentrations rose in proportion to the decline in leptin, the percentage change in 3-hydroxybutyrate did not correlate with that of leptin. Ketone bodies per se do not trigger changes in leptin concentrations (18).
Some (36, 37) but not all (13) studies have shown a significant association of leptin with insulin and proinsulin concentrations (37) after adjustment for body mass index and waist-to-hip ratio. Higher concentrations of leptin suggest a resistance to the effect of leptin with hyperinsulinemia (37). We found that when corrected per kilogram fat mass, baseline leptin values with isoenergetic feeding correlated with no other variables, including insulin concentrations. However, relative insulin deficiency in obese, poorly controlled diabetic subjects was associated with lower leptin concentrations (38, 39), which increased with insulin treatment (39). Insulin mediates glucose uptake in adipose tissue and decreases lipolysis. The decline in insulin with fasting or poorly controlled type 2 diabetes leads to a change in adipocyte fuel uptake that could regulate leptin synthesis and release. However, we found no correlation between percentage changes in leptin and changes in insulin. By contrast, a role for glucose in a nutrient-sensing pathway that regulates leptin gene expression in muscle and fat has been suggested; this pathway's end product, UDP-N-acetyl glucosamine, stimulates leptin messenger RNA and protein, and, in turn is stimulated when there is hyperglycemia (40). Improvements in insulin resistance with troglitazone administration to nonobese type 2 diabetic subjects was associated with a decrease in leptin, glucose, and insulin concurrently with an increase in body mass index. The decrease in leptin, despite weight gain, was attributed to the decrease in insulin concentrations (41). These effects of troglitazone were not seen in obese nondiabetic subjects (42).
In studies in which normal-weight subjects were submitted to comparable energy deficits, no correlation was reported between changes in leptin and changes in percentage fat mass at day 7 of a fast supplemented with protein (24). We also found no correlation between decreases in leptin and percentage changes in fat mass, with a large range of energy deficits by day 7. Others also found no correlation between decreases in leptin and percentage changes in fat mass with 50% energy reductions, but reported a positive correlation with reductions in dietary carbohydrate intakes (43). Our results showed a greater decrease in percentage changes in leptin and in leptin adjusted per kilogram fat mass in the fasting group than in the VLED group by week 4, although neither group consumed carbohydrates. Declines in leptin concentrations corresponded to those in glucose concentrations, which were also significantly different between those who fasted and those who received the VLED—2 treatments that induced comparable fat losses. When we corrected for cumulative energy deficits and fat losses by looking at the results of subjects given a BDD at week 4 and of those who fasted and then were given a VLED at week 2, both percentage changes in leptin and glucose concentrations differed significantly between the BDD and fasting groups, but changes in insulin did not (Table 4). The greatest decrease in glucose concentrations was associated with the greatest decrease in leptin per kilogram fat lost. This finding (all data pooled) supports a role for glucose and its availability to adipose tissue in determining circulating leptin concentrations. We present results from women only because their responses to energy deficits 1) differ from those of men (24, 44), 2) result in smaller percentage decreases in insulin and glucose than in men (24), and 3) result in higher leptin concentrations than in men. Thus, our results cannot be extrapolated to men.
Our refeeding diet had greater effects in subjects after fasting than after the VLED: leptin, insulin, and glucose concentrations increased significantly after refeeding in the fasting group, whereas only glucose increased in the VLED group. Ketone bodies decreased considerably in both groups after refeeding (data not shown); the corresponding increase in leptin was explained only by the increase in REE. This finding suggests that despite continuous fat mobilization associated with the low-energy refeeding, leptin increases and may stimulate energy expenditure. The increment represented 3.3% of REE, 199 kJ, or the oxidation of 5 g fat. Döring et al (45) reported that energy expenditure in food-restricted mice was higher with leptin than with saline treatment, suggesting that leptin attenuated the suppression of thermoregulatory energy expenditure. By contrast, Rosenbaum et al (46) found no correlation between changes in leptin and energy expenditure when refeeding humans 21–33 MJ/d to maximize the rate of weight gain.
In conclusion, we showed that prolonged changes in energy intake override the regulation of leptin concentrations by the fat mass. Our results support the premise that insulin-mediated glucose uptake by adipocytes primarily modulates leptin concentrations. Furthermore, after a fast, refeeding a diet providing energy intakes considerably below requirements increases leptin concentrations and energy expenditure even with ongoing fat mobilization.
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ACKNOWLEDGMENTS |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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