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Changes in Energy Expenditure and Substrate Oxidation Resulting from Weight Loss in Obese Men and Women: Is There an Important Contribution of Leptin?¹

Division of Kinesiology (E.D., S.S.P., P.M., A.T.), Departments of Food Sciences and Nutrition (N.A.) and Physiology and Anatomy (D.R.), Laval University, Ste-Foy, Quebec, Canada G1K 7P4

Address all correspondence and requests for reprints to: Dr. Angelo Tremblay, Physical Activity Sciences Laboratory, PEPS, Laval University, Ste-Foy, Quebec, Canada G1K 7P4. E-mail: angelo.tremblay{at}kin.msp.ulaval.ca

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The aim of the present study was to determine the impact of weight loss and its related metabolic and hormonal changes on resting energy expenditure (REE) and substrate oxidation. Forty subjects (16 men and 24 women) took part in a 15-week weight loss program that consisted of drug therapy (fenfluramine, 60 mg/day) or placebo coupled to an energy restriction (-700 Cal/day). Subjects were asked to come to the laboratory after an overnight fast for an indirect calorimetry measurement before and after weight loss. Fasting blood samples were also drawn and were analyzed for plasma glucose, insulin, leptin, and free fatty acid determinations. This program reduced body weight by 11% and 9% (P < 0.01) in men and women, respectively. Fat mass (FM) and fat-free mass (FFM) were also significantly reduced in both sexes. A significant decrease in REE (13%; P < 0.01) and fat oxidation (11%; P = 0.08) was observed in men in response to this program, whereas no significant differences were noted for these variables in women. In men, positive correlations were found between changes in FFM and energy-related variables, whereas the best predictor of changes in REE and substrate oxidation was the change in FM in women. The most important finding of this study is that in men, the association between changes in fasting plasma leptin and changes in REE (r = 0.50; P < 0.01) and fat oxidation (r = 0.63; P < 0.01) persist after correction for changes in body composition. These results suggest that a comparable weight loss is accompanied by a greater decrease in REE and substrate oxidation in men than in women, and that these changes are better explained by changes in leptinemia in men and by changes in FM in women.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
IT IS WELL recognized that weight loss is accompanied by a fall in energy expenditure, particularly in resting energy expenditure (REE). As this component accounts for approximately 70% of daily energy expenditure (EE), a small decrease can lead to substantial differences in daily energy balance (1). There is also evidence that reduced EE is a predictor of weight gain over time (2, 3), and that among individuals who have gone through weight loss therapy, the decline in REE resulting from such an intervention was associated with weight regain over time (4). These are troubling observations that need to be understood thoroughly if weight maintenance is to be achieved in the reduced obese state, as REE plays such an important role in the maintenance of energy balance.

Regardless of the fact that changes in body weight per se are predictive of changes in REE during weight loss, changes in body composition might also have an important role to play. Indeed, as fat-free mass (FFM) has been shown to be the best predictor of daily EE (1), a decrease in this compartment most certainly has considerable repercussions on body energy needs. Although fat mass (FM) and, more particularly, white adipose tissue have long been thought to be energetically not very demanding, recent results tend to show otherwise. In this context, Ferraro et al. (5) have shown that FM plays a significant role in the variance of daily EE. This is in agreement with recent results from our laboratory that have shown that EE and, more particularly, the sleeping metabolic rate were significantly associated with FM and even more closely related to abdominal adipose tissue mass (6).

Beyond the fact that REE seems to be largely dependent on body mass, numerous studies have drawn attention to the fact that changes in REE resulting from weight loss might be explained by factors other than weight loss per se. Indeed, weight loss triggers a decrease in sympathetic nervous system (SNS) activity (7). This observation might be explained by the concomitant fall in insulinemia (8, 9) and leptinemia (10) resulting from weight loss, two factors that have been shown to influence SNS activity (11, 12, 13, 14). This decrease in SNS activity resulting from body weight loss might also contribute to the decrease in fat oxidation observed in reduced obese individuals (15, 16), but might also be explained by the decrease in circulating free fatty acids (FFA) (17).

In-depth investigations into the role of leptin in the changes in energy metabolism that occur during weight loss have recently been conducted. In this sense, leptin levels have been shown to be lower in obese women who have undergone weight loss by energy restriction than in body mass index-matched controls (18). Moreover, Wadden et al. (19) reported that reductions in REE correlated significantly with changes in leptin after 40 weeks, even if such associations could not be found after 20 weeks, of energy restriction in obese women. Accordingly, it has also been reported that changes in leptin, FM, and FFM were significantly correlated with changes in REE in response to weight loss in women who had lost more than 7% of body weight (20). On the other hand, Rosenbaum et al. (21) reported that after a weight loss of 10% or 20% of initial body weight, only FFM and FM were still significantly associated with changes in REE (21). Hence, it still remains unclear whether changes in plasma leptin per se or changes in body weight and composition have the most influence on changes in energy metabolism-related variables in response to a therapeutic approach to obesity.

We thus aimed at investigating the impact of weight loss on changes in REE and substrate oxidation as well as their associations with changes in physiological and hormonal markers. More precisely, we investigated how changes in REE and fat and carbohydrate oxidation were related to changes in FM and FFM as well as changes in fasting plasma leptin, insulin, glucose, and FFA in response to a 15-week weight loss program. We also investigated whether a significant portion of the changes in REE and substrate oxidation was still explained by changes in plasma variables after correction for changes in body composition, i.e. FM and FFM.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Forty-six subjects took part in this study, which consisted of a 15-week drug therapy-energy restriction intervention. From these 46 subjects, 40 (16 men and 24 premenopausal women) for whom all variables were present were analyzed in the present study. Subjects were either given fenfluramine (60 mg; n = 12 and 19 men and women, respectively) daily or a placebo (n = 4 and 5 men and women, respectively) for the duration of the program. This pharmacological approach to treat obesity was coupled with a nonmacronutrient-specific energy restriction, which corresponded to a reduction in energy intake of approximately 700 Cal/day. To achieve this energy restriction, a nutritionist explained to each subject the Good Health Eating Guide (food exchange system) (22), which is an easy way for subjects to monitor their food intake. During this program, subjects had to come to our laboratory every 2 weeks for a control session during which they were weighed and asked about compliance. If subjects had lost less than 1 kg during this time period and this was not due to noncompliance on their part, the energy restriction was adjusted to insure a progressive weight loss throughout the duration of the program. This visit also served as a way to verify drug compliance and to renew a subject’s prescription when relevant. Subjects gave their written consent to participate in this study, which received approval of the Laval University medical ethics committee.

It is important to note that after the suspension of fenfluramine and dexfenfluramine due to a potential association with disturbances in cardiac valvular function (23, 24), all subjects (including placebos) were subjected to an echocardiogram. After this assessment, a detailed analysis of cardiac valvular function was performed by cardiologists who detected no abnormalities in response to the use of fenfluramine under these conditions (25).

Anthropometric measurements

Body weight was measured with a standard beam scale, whereas body density was determined by hydrodensitometry (26). The closed circuit helium dilution method (27) was used to assess the residual lung volume. The Siri formula (28) was used to estimate the percentage of body fat from body density, whereas FM and FFM were estimated from the derived percentage of body fat and total body weight.

Measure of REE and substrate oxidation

REE was measured by indirect calorimetry after a 12-h overnight fast. After a 15-min resting period, expired gas collection was achieved through a mouthpiece for 15 min while the nose was clipped during the entire sampling period. Oxygen and carbon dioxide concentrations were determined by nondispersive infrared analysis (Uras 10 E, Hartmann & Braun, Frankfurt, Germany), whereas pulmonary ventilation determination was assessed with an S-430A measurement system (Ventura, CA). The Weir formula (29) was used to determine the energy equivalent of oxygen volume. The determination of substrate oxidation was achieved through an adaptation of the calculations previously described by Frayn et al. (30) while assuming that protein oxidation contributed to 10% of the total EE measured under these conditions. It is important to note that subjects were measured before and 2–4 weeks after the interruption of treatment. Likewise, women were tested between days 5–12 of their menstrual cycle, because energy metabolism-related factors have been shown to be affected by sex steroid levels (31, 32).

Blood sampling

Blood samples were collected in tubes containing ethylenediamine tetraacetate and Trasylol (Miles Pharmaceutics, Rexdale, Canada) through a venous catheter from an antecubital vein. These samples were drawn early in the morning after a 12-h overnight fast 1–2 weeks before the beginning and 2–4 weeks after the end of the treatment. After the treatment, subjects were asked to maintain a stable weight until the posttreatment measurements.

Glucose and insulin concentrations

Plasma glucose was measured enzymatically (33), whereas plasma insulin was determined by RIA with polyethylene glycol separation (34).

Plasma leptin and FFA concentrations

Fasting plasma leptin concentrations were determined with a highly sensitive commercial double antibody RIA (Human Leptin Specific RIA Kit, Linco Research, Inc., St. Louis, MO) that detects relatively low leptin levels of 0.5 ng/mL and does not cross-react with human insulin, proinsulin, glucagon, pancreatic polypeptide, or somatostatin. Our coefficients of variation for the repeated assays ranged from 4.0–5.5% for the lower leptin concentrations and from 6.5–8.5% for higher plasma leptin concentrations (35). Fasting plasma FFA were determined by a colorimetric method (36).

Statistical analysis

Jump Software 3.1.6.2. from SAS Institute, Inc. (Cary, NC) was used for all analysis. Multivariate ANOVA for repeated measures was first performed on all variables to assess the effects of gender, treatment, time, and their interaction. As gender effects as well as gender x time interactions were observed, genders were analyzed separately. Paired t tests were performed to verify the effects of this intervention on subjects’ characteristics, energy metabolism-related variables, and hormonal and metabolic adaptations to weight loss. A stepwise multiple regression analysis was first performed to identify the nature of relations between energy metabolism-related variables and changes in FM, FFM, and fasting plasma glucose, insulin, leptin, and FFA. To further investigate these relations, Pearson’s correlation analysis was then performed between the variations of energy metabolism-related variables and changes in body composition as well as changes in fasting plasma glucose, insulin, leptin, and FFA in response to weight loss. Finally, changes in energy metabolism-related variables were then corrected for the contribution of changes in FM and FFM, and correlations were repeated between the residuals of energy metabolism-related variables and changes in fasting plasma glucose, insulin, leptin, and FFA in response to weight loss. All data are expressed as the mean ± SEM.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Table 1 presents the characteristics of subjects before and after the weight loss program. The 15-week weight loss intervention significantly reduced body weight (11% and 9%; P < 0.01), FM (25% and 12%; P < 0.01), FFM (2%, P < 0.05 and 5%; P < 0.01), percent body fat, and BMI in men and women, respectively.

View larger version (28K): [in this window] [in a new window]   Figure 1. Correlations between changes in leptin and changes in REE, fat, and carbohydrate oxidation corrected for changes in FM and FFM in men and women in response to 15 weeks of drug therapy coupled with energy restriction.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

It is a well known fact that weight loss is generally accompanied by a decrease in REE. Our results in men support these observations, because this weight loss program triggered a decrease in REE of 13%, which corresponds to the fall in EE expected after such an intervention (21). What is surprising is the fact that a 9% decrease in body weight in women was not sufficient to significantly alter REE even if this observation is concordant with that of Havel et al. (20), who reported no significant fall in REE in women who lost approximately the same amount of weight (7%). Although FM has been shown to be a minor, but significant, contributor to EE (5), it has been recently reported that this association might be better explained by changes in abdominal adipose tissue (6). Thus, it is possible that a decrease in FM in women, who do not generally present large amounts of abdominal fat, but, rather, have large depots of gluteo-femoral fat, which are also metabolically less active than abdominal fat (37), does not affect REE to the extent that it does in men.

The fact that weight loss triggers a decrease in plasma leptin (10, 18, 19, 20, 21) is now well recognized. As expected, there was a significant decrease in the ob gene product in response to weight loss in both men and women who took part in this study. The magnitude of the fall in plasma leptin in women is comparable to what was observed after a 10% decrease in body weight in a previous study (21). However, the same study reported that a 10% decrease in body weight in men was not accompanied by a concomitant fall in plasma leptin. This discrepancy between our results and those of Rosenbaum et al. (21) might be explained by the fact that their male subjects were nonobese individuals, and their weight loss was mostly explained by a decrease in FFM. Weight loss in our subjects triggered a decrease not only in absolute plasma leptin levels values but also in plasma leptin expressed per units of FM. This latter observation is in accordance with previously reported results (21). This is an important observation, because not only is there a decrease in leptin per se in response to weight loss, but there is also a decrease in leptin per units of FM. If leptin turns out to be an important regulator of energy balance in humans, as could be expected from animal studies, this finding might partly explain why weight stability is difficult to maintain once the reduced obese state is reached.

Beyond the fact that a decrease in leptin levels was observed in response to this therapeutic approach to obesity, the association between this decrease in leptin levels and changes in REE and substrate oxidation was not the same in men and women. In fact, changes in REE as well as changes in resting fat and carbohydrate oxidation were best predicted by changes in leptin in men, and these associations sustained corrections for known contribution of changes in FM and FFM to the variance in these variables. On the other hand, changes in REE in women were not predicted by changes in leptin but, rather, by changes in FM. This is surprising, because the decrease in nanograms per mL leptin was greater in women than in men. This raises the question of whether leptin sensitivity is similar in men and women. Indeed, it is possible that a decrease beyond a certain threshold has to be reached and/or female subjects have to be exposed to a much longer and more severe energy deficit for changes in leptin levels (considering that leptin levels are much higher in women than in men) to precipitate significant changes in energy metabolism-related variables. This could be a plausible explanation for the results observed by Wadden et al. (19), who reported that changes in leptinemia were not associated with changes in REE after 20 weeks of energy restriction, whereas after 40 weeks of intervention a positive relationship was observed. A plausible explanation for this gender dimorphism might be that leptin transport into the brain has been shown to be saturable. Evidence to this effect is available, because researchers have demonstrated that the transport of leptin into the central nervous system through the cerebrospinal fluid would seem to saturate around 20–25 ng/mL (38, 39). In this sense, as men in this study present leptin levels that are lower than 20–25 ng/mL both before and after weight loss, it would be expected that a decrease in the production of leptin would, thus, affect its transport to the brain and ultimately its effects on energy balance. Accordingly, the lack of association between changes in leptin levels and energy metabolism- related variables in women might be due to the fact that after weight loss, leptin levels in women were still above the saturating point of leptin transport to the central nervous system, thus hypothetically not affecting leptin levels in the brain.

Another important issue that needs to be addressed is whether posttreatment leptin levels were influenced by a continued state of energy restriction. In this sense, some investigators reported that in response to energy restriction the most striking decline in leptin levels is seen before any major change in adipose tissue stores occurs (19, 40). However, these studies also reported that after this early pronounced decline, leptin levels decreased at a slower rate even if the energy restriction was maintained. Hence, our integration of these results is that even if a small energy imbalance might have occurred between the end of our protocol and leptin measurements, it is very unlikely that this energy imbalance might constitute a factor explaining the main outcome of our study. Moreover, we also recently reported that subjects were still weight stable 4–6 weeks after the end of the protocol (41), thus giving the indication, through a gross index, that subjects were in energy balance during this time period.

It is somewhat intriguing to observe a negative association between changes in FM and changes in fat oxidation in women, especially because fat gain is thought to be a necessary adaptation to increase fat oxidation to permit the restoration of lipid balance (42, 43). In this context, fat loss would be expected to be associated with a decrease in fat oxidation. However, our results in women tend to show the opposite. This might be explained by the recent observation that moderate weight loss leads to greater adipose cell lipolytic efficiency (44). This situation might lead to an increase in circulating FFA, as it is the case for women in the present study. Ultimately, this situation could promote an increase in fat oxidation through an elevation of the gradient of circulating FFA (17, 45).

Weight-stable, reduced obese individuals not only present a reduced REE, but also an alteration of the fuel mix oxidized. Indeed, it has been reported that weight loss is accompanied by a decreased contribution of fat to energy production (15, 16). To our knowledge, this is the first study to report that the fall in plasma leptin levels precipitated by weight loss is associated not only with a decrease in REE, but also with a decrease in resting substrate oxidation. Indeed, in men the change in fasting plasma leptin was positively and significantly associated with changes in resting fat oxidation. Recent observations have shown that leptin administered to animals increases SNS activity (46, 47, 48) and fat oxidation (49). Moreover, leptin has been shown to be associated with SNS activity in humans (11). As fat oxidation is dependent upon ß-adrenergic stimulation (50, 51), it is not surprising to observe a positive association between the decrease in fat oxidation and the decrease in circulating plasma leptin.

In summary, the expected fall in REE resulting from weight loss seems to be more pronounced in men than in women after comparable weight losses. Moreover, the decrease in REE and substrate oxidation in men seems to be explained mainly by changes in circulating plasma leptin, whereas changes in FM seem to explain these changes in women.

	Footnotes

 
¹ This work was supported by grants from Servier Canada.

Received September 21, 1999.

Revised November 16, 1999.

Accepted December 10, 1999.

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