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Original Studies |
Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016
Address all correspondence and requests for reprints to: Christian Weyer, M.D., Clinical Diabetes and Nutrition Section, National Institutes of Health, 4212 N. 16th Street, Room 5-41, Phoenix, Arizona 85016. E-mail: cweyer{at}phx.niddk.nih.gov
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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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Differences in energy metabolism may play a role in long term body weight regulation and the pathogenesis of human obesity (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13). Several (2, 3, 4, 5, 6, 7), but not all (8, 9, 10), prospective studies have shown that a relatively low energy expenditure (2, 3, 4, 5) and a relatively high respiratory quotient, i.e. a low fat to carbohydrate oxidation rate (6, 7) predict body weight gain. Longitudinal studies, however, in which energy metabolism was assessed not only at baseline but also at follow-up, indicate that upon gaining weight, energy expenditure and fat oxidation increase (2, 6, 13). Metabolic propensity to obesity might thus depend not only on initial rates of energy expenditure and fat oxidation, but also on how these measures change in response to weight change (13).
Results from most overfeeding studies indicate that short term experimental weight gain is accompanied by an overcompensatory increase in energy expenditure, i.e. an increase in energy expenditure that is greater than predicted for the changes in body size and composition (14, 15, 16, 17, 18, 19, 20, 21, 22). Similarly, most underfeeding studies reveal that in the short term, intentional weight loss leads to a decrease in energy expenditure beyond predicted values (23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36). Such overcompensatory metabolic changes act to oppose further weight change and have thus been referred to as metabolic adaptation (13, 24, 37).
Although metabolic adaptation thus seems to occur in response to large perturbations in body weight over relatively short periods of time, it is unknown whether similar adaptive mechanisms also occur in response to spontaneous long term weight changes in free living conditions.
To examine this question, we analyzed data from an ongoing longitudinal study of the pathogenesis of obesity initiated in 1985 among the Pima Indians of Arizona, a population with a very high prevalence of obesity, in whom low rates of energy expenditure and fat oxidation predict body weight gain (2, 6). We present results from over 100 subjects in whom 24-h energy expenditure and 24-h substrate oxidation were repeatedly measured in a whole body respiratory chamber before and after an average follow-up of 3.6 yr during which changes in body weight varied widely. The aims of this study were 1) to test whether metabolic adaptation in 24-h energy expenditure and 24-h substrate oxidation occur in response to spontaneous long term weight change, 2) to quantify and explain the variability in these changes among individuals, and 3) to determine the relationship between changes in energy expenditure and substrate oxidation in response to weight gain and weight loss.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Since 1985, Pima Indians have been admitted to the metabolic
ward of the Clinical Diabetes and Nutrition Section of the NIH in
Phoenix, Arizona, for an ongoing longitudinal study of the pathogenesis
of obesity that includes the repeated assessment of 24-h energy
expenditure and 24-h substrate oxidation in a whole body respiratory
chamber. Subjects with diabetes mellitus and subjects who were not in
energy balance (energy intake ±20% of expenditure during the stay in
the chamber) or who had participated in studies involving diet,
exercise, or any other interventions affecting body weight or energy
metabolism, were excluded from the analysis. Among the 491 subjects
meeting these criteria, 102 subjects had been studied on at least 2
occasions. In subjects studied more than twice, the visit with the
greatest weight change was selected for follow-up. Among the 102
subjects, 31 subjects had lost weight and 71 had gained weight at
follow-up. All subjects were between 18–50 yr of age at baseline and
follow-up, healthy according to a physical examination and routine
laboratory tests, and did not smoke or take medications at baseline or
follow-up (Table 1
).
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Body composition
Body composition was estimated by underwater weighing, with determination of residual lung volume by helium dilution (39), or by total body dual energy x-ray absorptiometry (DPX-L, Lunar Corp., Madison, WI) (40). Percent body fat, fat mass (FM), and fat-free mass (FFM) were calculated as previously described (41), and a conversion equation (42) was used to make measurements comparable between the two methods. Waist and thigh circumferences were measured at the umbilicus and the gluteal fold in the supine and standing positions, respectively, and the waist to thigh ratio (WTR) was calculated as an index of body fat distribution (43).
Respiratory chamber
The measurement of energy expenditure and substrate oxidation in the respiratory chamber has previously been described (44) and did not differ at baseline and follow-up. In brief, volunteers entered the chamber at 0745 h after an overnight fast and remained there until 0700 h the following morning. Subjects were fed a standardized diet with the amount of calories calculated according to previously determined equations to achieve energy balance (45). Meals were provided at 0800, 1130, and 1700 h, and an evening snack was given at 2000 h. The rate of energy expenditure was measured continuously, calculated for each 15-min interval of the 23 h in the chamber, and then extrapolated to 24 h (24-h energy expenditure, 24-EE). Spontaneous physical activity (SPA) was detected by radar sensors and expressed as the percentage of time over the 24-h period in which activity was detected (44). Carbon dioxide production (VCO2) and oxygen consumption (VO2) were calculated at 15-min intervals, summed for the 23 h in the chamber, and then extrapolated to 24 h. The 24-h respiratory quotient (24-RQ) was calculated as the ratio of 24-h VCO2 and 24-h VO2 and adjusted for the 24-h energy balance (24-h energy intake - 24-EE during the stay in the chamber) in a multiple regression analysis. Based upon 24-RQ, 24-EE, and 24-h urinary nitrogen excretion, the rates of 24-h fat, carbohydrate, and protein oxidation were determined as previously described (46).
Statistical analyses
Statistical analyses were performed using the procedures
of the SAS Institute, Inc. (Cary, NC) (47). Results are
given as the mean ± SD. Data from the entire group of
491 subjects were used to assess the cross-sectional relationships
between 24-EE and 24-RQ vs. body weight (prediction line and
its 95% confidence interval) and to calculate the adjusted values of
24-EE (FFM, FM, WTR, age, and sex) and 24-RQ (percentage of body fat,
age, and sex; multiple linear regression). Changes in anthropometric
and metabolic parameters were assessed in the subset of 102 subjects
with follow-up measurements. Changes (
) in 24-EE and 24-RQ were
calculated as the difference between follow-up and baseline
measurements for both the unadjusted and the adjusted values. Paired
t tests were used to test whether measurements at follow-up
were significantly different from those at baseline. Pearson
correlation coefficients were calculated to assess the relation of the
changes in unadjusted and adjusted 24-EE and 24-RQ to the change in
body weight. Stepwise and general linear regression models were used to
assess determinants of 24-EE and 24-RQ, the percentage of
variance explained by these determinants (r2),
and the residual variance that remains after adjustment (
MSE =
root of the mean square error). The changes in 24-EE and 24-RQ
predicted for a 15-kg weight loss or 15-kg weight gain were determined
from the regression equation of the relationships between 24-EE and
24-RQ vs. weight. These changes were superimposed
onto the 95% confidence intervals of the prediction lines for the
cross-sectional relationships between 24-EE and 24-RQ vs.
body weight, as assessed in the entire study population of 491
subjects. The residuals of the relationships between 24-EE and
24-RQ vs. weight were calculated using general linear
regression models.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. The baseline anthropometric and
metabolic characteristics of the 102 subjects with repeated
measurements of energy metabolism were similar to those of the entire
study population. The follow-up duration ranged from 0.6–11.2 yr,
averaging 3.6 ± 2.7 yr. During this time, body weight changes
varied widely (ranging from -21 to +28 kg; Table 1). Cross-sectional analysis (n = 491)
In the entire population of 491 subjects, 24-EE was positively
related to body weight (r = 0.81; P < 0.0001;
Fig. 1C), whereas 24-RQ was negatively related to body weight (r =
-0.22; P < 0.0001; Fig. 2C).
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Changes in 24-h energy expenditure. There was a positive
linear correlation between the change in 24-h energy expenditure (
24-EE) and the change in body weight ( weight), but at any given
weight there was considerable interindividual variability in 24-EE
(SD, 192 Cal/day; Fig. 1A). The
correlation between 24-EE and weight remained significant when
baseline and follow-up 24-EE were adjusted for FFM, FM, WTR, age, and
sex (Fig. 1B). The SPA measured in the chamber was not related to
weight (r = 0.01; P = NS), and the correlation
between 24-EE and weight remained significant when baseline and
follow-up 24-EE was additionally adjusted for SPA (partial r =
0.23; P < 0.05). When the changes in 24-EE predicted
for a 15-kg weight loss and a 15-kg weight gain were superimposed onto
the cross-sectional relationship between 24-EE and body weight as
assessed in the entire population of 491 subjects, 24-EE fell below the
95% confidence interval after weight loss and above the 95%
confidence interval after weight gain (Fig. 1C). For these weight
changes, the calculated change in 24-EE (±244 Cal/day) was 16% (33
Cal/day) greater than that predicted from the cross-sectional
relationship between 24-EE and body weight (±211 Cal/day; Fig. 1C).
The weight alone explained 58% of the variability in 24-EE
(r2 = 0.58). In a multiple regression analysis,
the FFM, FM, WTR, and SPA were significant independent
determinants of 24-EE: 24-EE (Cal/day) = -25 + 14.9
FFM (kg) +16.5 FM (kg) + 22.2 WTR (decimal) + 9.7 SPA (%).
Together, these factors explained 63% of the variability in 24-EE,
reducing the variance from 192 to 118 Cal/day (MSE). Sex, age,
glucose tolerance status (normal or impaired), initial body weight, and
follow-up duration were not significant determinants of 24-EE.
Changes in 24-h respiratory quotient and substrate oxidation.
There was a negative linear correlation between 24-RQ and
weight, but for any given weight there was considerable
interindividual variability in 24-RQ (SD, 0.030; Fig. 2A). The correlation between 24-RQ and
weight remained significant when baseline and follow-up 24-RQ were
adjusted for percent body fat, age, and sex in addition to energy
balance in the chamber (Fig. 2B). When the changes in 24-RQ predicted
for a 15-kg weight loss and a 15-kg weight gain were superimposed onto
the cross-sectional relationship between 24-RQ and body weight, 24-RQ
fell above the 95% confidence interval after weight loss and below the
95% confidence interval after weight gain (Fig. 2C). For this weight
change, the calculated change in fat oxidation (±152 Cal/day) was 54%
(53 Cal/day) greater than predicted from the cross-sectional
relationship between fat oxidation and body weight (±99 Cal/day).
The weight alone explained only 9% of the variance in 24-RQ
(r2 = 0.09). In a multiple regression analysis,
the only additional independent determinant of 24-RQ was age at
baseline, explaining another 3% of the variance: 24-RQ =
-0.023 -0.001 weight (kg) + 0.001 age (yr) [residual variance
(MSE), 0.029]. Changes in percent body fat (P =
0.09) or WTR (P = 0.13) were not significant
independent determinants of 24-RQ, nor was sex, age, glucose
tolerance status, initial body weight, or follow-up duration.
Responses in energy expenditure vs. responses in substrate
oxidation. Based on the relationship between 24-EE and
weight (Fig. 1A), the changes in 24-EE can be divided into those that
were relatively high (positive residuals) and those that were
relatively low (negative residuals). The changes in 24-RQ (Fig. 2A) can
be divided in the same manner, but unlike 24-EE, positive residuals
indicate relatively low changes in fat oxidation, whereas negative
residuals indicate relatively high changes. In response to weight gain
there was a negative correlation between the residuals of 24-EE and
the residuals of 24-RQ (Fig. 3),
i.e. subjects with metabolic adaptation in 24-EE (positive
residuals) also tended to have metabolic adaptation in substrate
oxidation (negative residuals in 24-RQ) and vice versa. In
response to weight loss, the residuals in 24-EE and 24-RQ were
unrelated, i.e. metabolic adaptation in 24-EE did not tend
to be accompanied by metabolic adaptation in substrate oxidation (Fig. 3).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The results indicate that metabolic adaptation, i.e. changes in energy expenditure and substrate oxidation greater than predicted for the change in body size and composition, can occur in response to spontaneous long term weight changes. On the average, the metabolic changes were only slightly greater than predicted, but varied substantially among individuals. Finally, we found that in response to weight gain, adaptations in energy expenditure and substrate oxidation were related to one another, such that subjects with the most pronounced metabolic adaptation in energy expenditure also had the most pronounced metabolic adaptation in fat oxidation and vice versa. This was not the case for weight loss.
Most previous intervention studies have demonstrated metabolic adaptation in response to experimental short term weight change induced by controlled over- and underfeeding regimens (14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36). Whether similar overcompensatory changes in energy expenditure and fat oxidation occur in the natural history of weight changes has been a matter of contention (9, 10, 11, 12, 13, 16, 26).
The present study demonstrates, for the first time, that metabolic adaptation can occur in response to spontaneous long term weight changes, but also reveals that, on the average, these overcompensatory changes are small. We estimate that a 15-kg weight change is accompanied by a change in 24-h energy expenditure of 244 Cal/day, which is only 33 Cal/day greater than predicted from the cross-sectional relationship between 24-h energy expenditure and body weight (211 Cal/day). The change in 24-h fat oxidation after a 15-kg weight change was 53 Cal/day greater than predicted from the cross-sectional data. In practical terms, these adaptations translate into the caloric content of approximately one half of an apple, one fifth of a bagel, or one tenth of a cheeseburger (for the adaptation in 24-h energy expenditure) or the fat content of two teaspoons of peanut butter or seven potato chips (for the metabolic adaptation in 24-h fat oxidation), respectively.
These data indicate that in the long term, the defense mechanisms of the body to resist weight gain by an overcompensatory increase in energy expenditure and/or fat oxidation are relatively weak and easy to offset by small changes in food intake. The results also indicate that even a large decrease in body weight over several years is, on the average, not accompanied by a profound slowing of energy metabolism, as occasionally implied to explain the high rate of weight recidivism in the medical treatment of obesity. However, several aspects need to be considered in this respect.
First, it has been demonstrated that even small differences in energy expenditure and/or substrate oxidation that may appear trivial on a daily basis can have an important impact on body weight over the long term (2, 6). In a previous prospective study (2), we found that a difference in energy expenditure of only 70 Cal/day was associated with marked differences in subsequent weight gain.
Second, the present study was observational in design, which has both advantages and disadvantages. On the one hand, we have no information on the exact causes of the weight changes. In some individuals, weight loss might have been secondary to illness, although this is unlikely because subjects in our studies typically remain in close contact with the research unit and receive a comprehensive medical examination before each admission. An advantage of the observational design, on the other hand, is that it allows us to examine the metabolic responses to spontaneous long term weight changes that probably more closely resemble the typical pattern of weight change under free living conditions than imposed by over- and underfeeding regimens. The fact that the magnitude of metabolic adaptation in response to such gradual weight change was small, on the average, agrees with cross-sectional findings indicating that energy expenditure is only marginally reduced in formerly obese individuals who had returned to a normal body weight and had successfully maintained the weight loss over months or years (postobese individuals) (50). Some previous intervention studies suggest that the suppression in energy expenditure in response to weight loss might be larger shortly after a more rapid decrease in body weight (26, 27, 29, 31, 36).
It is also important to point out that energy expenditure in the present study was measured in the restricted environment of a respiratory chamber, which significantly reduces physical activity. Although nonexercise activity thermogenesis, of which spontaneous physical activity is a component, has recently been suggested to play an important role in the adaptation to overfeeding (21), our findings do not suggest a major role of spontaneous physical activity (i.e. fidgeting) in the metabolic response to long term weight change. To what extent changes in volitional physical activities such as exercise habits contribute to the overall metabolic responses to long term weight change remains unknown. Our study also provides no information on the role of spontaneous adaptations in energy intake. Because an increase in body weight of 15 kg resulted in an increase in energy expenditure of about 200–250 Cal/day, a similar increase in energy intake must have occurred to maintain the higher body weight. Thus, as with the metabolic adaptation in energy expenditure, small differences in the adaptation in energy intake may play an important role in determining whether body weight remains stable or continues to increase.
Although the adaptations in energy metabolism were small, on the
average, the present study reveals that the responses of both 24-h
energy expenditure (SD, ±192 Cal/day) and 24-h fat
oxidation (SD, ±286 Cal/day) to weight change vary
substantially among individuals. Thus, weight gain/loss is not
universally accompanied by small adaptive increases/decreases in energy
expenditure and/or fat oxidation. Rather, some individuals will
experience relatively large overcompensatory responses, whereas others
will have subnormal responses. Such interindividual variability in
metabolic responses has also been found in response to experimental
over- and underfeeding and has been used to explain why the amount of
weight gained or lost under standardized dietary regimens can differ
substantially among individuals (14, 19, 22, 26). The large number of
subjects in the present study allowed us to quantify the
interindividual variability in metabolic responses to weight changes
and to search for possible underlying determinants. We found that the
change in 24-h energy expenditure was explained not only by the changes
in FFM and FM, but also independently by the changes in body fat
distribution and spontaneous physical activity. The only additional
determinant of the change in 24-h respiratory quotient was age at
baseline. The effect of these additional factors was small, however,
and as much as 37% of the variability in 24-h energy expenditure
and 89% of the variability in 24-h respiratory quotient remained
unexplained. As only a small part of this variability can be attributed
to the variability of the method (2, 6, 44), other factors must be
involved. These may include, for example, changes in plasma thyroid or
sex hormone concentrations (49), autonomic nervous system activity (51, 52), mitochondrial uncoupling activity (53), plasma insulin and free
fatty acid concentrations, and glucose tolerance (54), each of which
was found to be related to energy expenditure and/or substrate
oxidation in cross-sectional studies. Moreover, there is strong
evidence from overfeeding studies in identical twins that the metabolic
responses to weight changes are in part genetically determined (55, 56).
Another interesting observation in the present study was that in response to weight gain, the changes in 24-h energy expenditure and 24-h substrate oxidation were related to one another, in that individuals with the most pronounced adaptation in energy expenditure also tended to have the most pronounced adaptation in fat oxidation and vice versa. Interestingly, this was not the case in response to weight loss, where adaptations in energy expenditure and substrate oxidation were unrelated.
The above findings may have important implications for our
understanding of the role of energy metabolism in the long term
regulation of body weight and the pathogenesis of human obesity. To
illustrate this, we have developed a schematic model that integrates
previous cross-sectional and prospective findings with those from the
present longitudinal study (Fig. 4).
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). Our present longitudinal data indicate that
upon gaining weight, the initially low rates of energy expenditure and
fat oxidation tend to normalize, on the average, but as with the
cross-sectional relationship, there is substantial interindividual
variability in these responses. Accordingly, the metabolic drive to
weight gain may soon diminish in some individuals, thereby limiting the
amount of weight gain (metabolic adaptation; arrow 1A),
whereas it may be sustained in others, who will thus be predisposed to
gain further weight (arrow 1B). Conversely, individuals with
relatively high rates of energy expenditure and/or fat oxidation are
predisposed to spontaneously lose weight, but the amount of weight loss
will depend upon the occurrence (arrow 2A) or not
(arrow 2B) of metabolic adaptation. Of note, these
considerations apply to spontaneous long term weight changes. If, for
instance, an obese individual decides to intentionally lose weight, his
or her initial energy expenditure and/or fat oxidation may fall below
rather than above the normal range. Further studies are needed to confirm the role of low energy expenditure and fat oxidation as predictors of weight gain and to formally test the effect of metabolic adaptation on further weight change. It will also be important to examine the role of adaptation in energy and substrate intake to weight change. These are probably complex and could include changes in the perception of hunger and satiation as well as in caloric intake and food preferences.
In summary, the results of this longitudinal study indicate that the changes in 24-h energy expenditure and 24-h respiratory quotient (i.e. in substrate oxidation) associated with long term weight changes 1) are greater than those predicted for the change in body size and composition, 2) vary substantially among individuals, and 3) are related to one another in response to weight gain.
We conclude that metabolic adaptation can occur not only in response to experimental short term perturbations in body weight, but also in response to spontaneous long term weight changes. These responses, albeit small on the average, vary substantially among individuals and may thus play a role in the long term regulation of body weight and the pathogenesis of human obesity.
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Acknowledgments |
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Received October 14, 1999.
Revised November 16, 1999.
Accepted November 23, 1999.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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quick decrease in the metabolic
drive