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Robert H Eckel, Teri L Hernandez, Melanie L Bell, Kathleen M Weil, Trudy Y Shepard, Gary K Grunwald,
Teresa A Sharp, Coni C Francis, and James O Hill
KEY WORDS
Carbohydrate balance, dietary fat, dietary carbohydrate, metabolic predictor, weight gain, fat mass gain, body
composition, energy balance, insulin sensitivity, obesity, indirect
calorimetry
INTRODUCTION
several metabolic predictors of obesity, such as lower basal metabolic rates (6, 7), reductions in nonexercise activity thermogenesis (NEAT) (8), increases in carbohydrate (CHO) oxidation (9,
10), insulin sensitivity (SI) (1113), low concentrations of leptin
(14), and reduced levels of sympathetic nervous system activity
(15, 16), were reported. A better understanding of these metabolic factors could be useful in identifying obesity prevention
interventions for those at greater risk.
Exposing persons to an interval of positive energy balance
could elucidate metabolic differences in the propensity for
weight gain. The standard energy balance equation, by definition, indicates equality between energy intake (EI) and energy
expenditure (EE; EI EE). Conversely, positive energy balance
indicates that EI exceeds EE (EI EE), which sets the stage for
weight gain. Energy balance can also be quantified for each of the
macronutrients (protein, fat, and CHO), such that CHO balance
is the rate of CHO intake minus the rate of CHO oxidation,
reflecting a change in CHO stores. Thus, the term positive CHO
balance reflects storage of CHO in the body (17).
The purpose of the present study was to investigate the effect
of diets on the degree to which the components of energy balance
and SI predict long-term changes in weight and body composition. Here, we address the question of whether prospective differences in energy balance on a high-CHO diet compared with a
high-fat diet during 1 day of physical inactivity could predict
weight or adipose tissue gain over 4 y.
SUBJECTS AND METHODS
Subjects
The Colorado Multiple Institutional Review Board at the University of Colorado at Denver and Health Sciences Center
1
Am J Clin Nutr 2006;83:803 8. Printed in USA. 2006 American Society for Nutrition
803
ABSTRACT
Background: The prevention and treatment of obesity is a public
health challenge.
Objective: We investigated the effects of dietary composition, insulin sensitivity (SI), and energy balance on predicted changes in
body composition.
Design: In a randomized crossover design study, 39 normal-weight
(n 23), overweight (n 8), and obese (n 8) men and women
(aged 2536 y) each followed a 15-d isocaloric high-fat (HF; 50%
fat) and high-carbohydrate [HC; 55% carbohydrate (CHO)] diet
with a 4 6-wk washout period during the first year. During each
treatment, energy balance was measured while the subjects were
inactive by using indirect calorimetry on day 15, and SI was measured by using a euglycemic clamp study (40 mU m2 min1) on
day 16. Weight and body composition were then measured annually
for 4 y. The outcomes for fat mass, percentage body fat, and weight
were measured by using a linear 2-stage mixed model.
Results: CHO balance (day 15) and SI (day 16) on the HC diet were
highly and significantly correlated (r 0.55, P 0.001). On the HC
diet, the subjects who had a higher positive CHO balance (day 15)
gained less fat mass (P 0.001), percentage body fat (P 0.006),
and weight (P 0.024) over time. When adjusted for SI, CHO
balance remained a significant predictor of changes in fat mass (P
0.021) and percentage body fat (P 0.025).
Conclusions: On a HC diet, the subjects who had a higher positive
CHO balance on day 15 while they were inactive gained less fat mass
during 4 y, a predictive effect independent of SI. As suggested in
rodents, the capacity to expand the glycogen pool might reduce
energy intake and protect against fat and weight gain.
Am J Clin
Nutr 2006;83:803 8.
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ECKEL ET AL
TABLE 1
Baseline characteristics of subjects1
Age (y)
Sex (M/F)
Weight (kg)
BMI (kg/m2)
RMR (kcal/d)
RQ, fasting
Glucose (mg/dL)
Insulin (U/mL)
SI (GIR; mg m2 min1)
Normal-weight subjects
(n 23)
Overweight subjects
(n 8)
Obese subjects
(n 8)
28 32
14/9
68 12
21.5 2.0
1629 315
0.82 0.06
88.5 8
5.7 2.2
355 126
30 4
6/2
85 114
26.9 1.33
1850 226
0.77 0.05
87.6 9
8.0 3.3
323 184
33 13
2/6
108 235
37.1 6.64
2138 5075
0.79 0.07
93.4 11
20.3 13.3
145 453
n 39. RMR, resting metabolic rate; RQ, respiratory quotient; SI, insulin sensitivity; GIR, glucose infusion rate.
x SD (all such values).
35
Significantly different from normal-weight subjects (t tests with Bonferroni adjustment): 3P 0.0001, 4P 0.001, 5P 0.01.
Procedures
Diets
The HC diet provided a macronutrient content of 55% of
energy as CHO, 25% as fat, and 20% as protein. The HF diet
provided 30% of energy as CHO, 50% as fat, and 20% as protein.
During the calorimeter stay, the subjects consumed 3 meals and
2 snacks. All foods were weighed, and the diets were analyzed by
using a computer program (FOOD PROCESSOR PLUS; ESHA
Research, Salem, OR).
for valid RMR was a minimum of 15 min of steady state, determined as 10% fluctuation in minute ventilation and oxygen
consumption and 5% fluctuation in RQ.
Insulin sensitivity
On day 16 of each diet phase, a 3-h 40 mU m2 min1
hyperinsulinemic euglycemic clamp study was performed to
measure SI (19). The euglycemic goal was measured as the fasting blood glucose concentration measured on the morning of day
16 of diet phase 1. The individual SI with each diet was then
measured as the mean glucose infusion rate (in mg m2 min1)
over the last hour of the infusion study (120 180 min). Therefore, the glucose infusion rate is an expression of SI. Fasting
serum insulin concentrations were also considered to be an indicator of relative SI (24). The female subjects were each studied
in the early follicular phase of their menstrual cycle.
Physical activity index
(1)
Data analysis
The goal of the analysis was to estimate the degree to which
baseline responses to the HC and HF diets predicted changes in
outcomes of body weight, fat mass, and percentage fat during the
next several years. Candidate predictor variables were 24-h energy balance, CHO and fat oxidation and balance, and SI on each
diet. Associations of candidate variables individually with
changes in outcomes separately were estimated by using a
2-stage mixed model (32). All mixed models included a fixedeffect intercept, a fixed effect for time (which represented the
population mean change in outcome), and random effects for
subject-specific intercepts and slopes. Each model also included
a fixed effect for one candidate predictor as well as an interaction
between the predictor and time. The interaction estimates and
tests the association of the predictor with change in outcome.
This analysis is similar to first regressing each subjects outcome
on time to obtain a slope (rate of change of outcome), then
regressing this slope on the predictor, but it is preferred in the
presence of missing data. Two of the 39 subjects had only initial
measurements of weight and fat mass, so these measurements
were omitted from all analyses of changes in weight and fat mass.
Results were similar with the regression approach. Fixed effects
for sex and baseline BMI and their interactions with time were
included in all models to adjust for these characteristics. Analyses were also repeated with adjustment for estimated baseline
physical activity outside the calorimeter. Two forms were considered: PAI (25) and NEAT (8).
(2)
(3)
RESULTS
Physical activity level was estimated by calculating the physical activity index (PAI) (25). This index is the ratio of total EE
to basal EE. In the present study design, actual EE was not
measured during each 14-d feeding phase before the calorimeter
stay. However, each feeding period was highly controlled and
monitored; the subjects were weight-stable within 1 kg and were
therefore in energy balance. PAI was calculated as follows:
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ECKEL ET AL
TABLE 2
Results from the indirect calorimeter stay on both the high-carbohydrate
(HC) and high-fat (HF) diets1
Outcome
Carbohydrate balance (kcal)
Fat balance (kcal)
24-h RQ
Energy expenditure (kcal)
SI (mg m2 min1)
HC diet
HF diet
P2
642 85
4 112
0.815 0.010
2516 98
305 24
350 80
415 127
0.775 0.009
2391 117
278 23
0.0033
0.0017
0.0076
0.1618
0.1712
1
All values are x SEM. n 36. RQ, respiratory quotient; SI, insulin
sensitivity.
2
A paired t test was used for the difference between diets.
TABLE 3
Effects of carbohydrate (CHO) balance and insulin sensitivity (SI) with a high-CHO diet at baseline measurement on changes in fat and weight over 4 y
Outcome
Effect of CHO balance
Weight change (kg y1 100 kcal1)
Fat mass change (kg y1 100 kcal1)
Percentage fat change (% y1 100 kcal1)
Effect of SI
Weight change [(kg/y)/100 mg m2 min1)]
Fat mass change [(kg/y)/100 mg m2 min1)]
Percentage fat change [(%/y)/100 mg m2 min1)]
1
2
P1
Adjusted for
sex, baseline
BMI, and SI
0.081 0.0372
0.097 0.033
0.097 0.036
0.038
0.007
0.013
0.30 0.10
0.22 0.11
0.15 0.12
0.008
0.051
0.23
P1
P1
0.038 0.038
0.082 0.037
0.095 0.041
0.32
0.037
0.029
0.26 0.11
0.13 0.11
0.051 0.12
0.027
0.25
0.68
A 2-stage mixed model was used to determine predictors of future changes in body composition.
x SEM (all such values).
balance and weight gain for both diets (P 0.053 for HC diet;
P 0.058 for HF diet). Fat balance on the HF diet was also
inversely related to weight gain (P 0.038) but was otherwise
not a significant predictor for any of the outcomes on either
diet (P 0.25). CHO balance and SI on the HF diet were not
predictive of future gains in any of the 3 outcomes (P 0.30
for all). Adjustment for usual physical activity as quantified
by PAI or NEAT did not substantially change any of these
results; additionally, no relation was observed between either
measure of physical activity and weight or fat gain over 4 y for
either diet (P 0.1 for all). Specifically, no relation was
observed between the PAI at the beginning of year 1 and the
change in fat mass (r 0.2, P 0.2) (Figure 1), weight
(r 0.2, P 0.3), or percentage body fat (r 0.12,
P 0.4) over 4 y.
The strongest and most consistent predictors of future weight
and fat change were CHO balance and SI after the HC diet. On the
HC diet, the subjects who had a higher positive CHO balance
(day 15) gained less fat mass (P 0.001), percentage body fat
(P 0.006), and weight (P 0.024) over time. When adjusted
for SI, CHO balance remained a significant predictor of changes
in fat mass (P 0.021) and percentage body fat (P 0.025). The
effects of CHO balance and SI on each of the 3 outcomes, adjusted for sex and baseline BMI, are shown in Table 3. Both
predictors were consistently and inversely related to the outcomes (with the exception of SI for fat mass change, P 0.051),
and all were significant except SI for percentage body fat. For
example, for each additional 100 kcal/d in CHO balance, the
subjects gained a mean (SEM) 0.081 0.037 kg/y less weight
(P 0.038) and 0.097 0.033 kg/y less fat (P 0.007). For each
DISCUSSION
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ECKEL ET AL
and energy balance experiment require confirmation, and mechanisms need to be pursued.
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