Am J Physiol Endocrinol Metab 298: E449–E466, 2010.
First published November 24, 2009; doi:10.1152/ajpendo.00559.2009.
Predicting metabolic adaptation, body weight change, and energy intake
in humans
Kevin D. Hall
Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
Submitted 8 September 2009; accepted in final form 16 November 2009
Hall KD. Predicting metabolic adaptation, body weight change,
and energy intake in humans. Am J Physiol Endocrinol Metab 298:
E449 –E466, 2010. First published November 24, 2009;
doi:10.1152/ajpendo.00559.2009.— Complex interactions between
carbohydrate, fat, and protein metabolism underlie the body’s
remarkable ability to adapt to a variety of diets. But any imbal-
ances between the intake and utilization rates of these macronu-
trients will result in changes in body weight and composition.
Here, I present the first computational model that simulates how
diet perturbations result in adaptations of fuel selection and energy
expenditure that predict body weight and composition changes in
both obese and nonobese men and women. No model parameters
were adjusted to fit these data other than the initial conditions for
each subject group (e.g., initial body weight and body fat mass).
The model provides the first realistic simulations of how diet
perturbations result in adaptations of whole body energy expendi-
ture, fuel selection, and various metabolic fluxes that ultimately
give rise to body weight change. The validated model was used to
estimate free-living energy intake during a long-term weight loss
intervention, a variable that has never previously been measured
accurately.
mathematical model; energy metabolism; macronutrient metabolism;
body composition
OVER THE PAST CENTURY, researchers in the fields of human metab-
olism and nutrition have accumulated an impressive body of
quantitative knowledge regarding how dietary changes impact
various aspects of metabolism, body weight, and body composi-
tion (12, 24, 38, 56, 68). But integrating this knowledge to make
quantitative predictions is a formidable task given the multiple
nonlinear interactions between various organ systems. Neverthe-
less, such an integrative approach is required to fully understand
both normal physiology as well as the derangements that underlie
conditions such as obesity, diabetes, and the metabolic syndrome.
Mathematical modeling and computer simulation are widely
used methodologies in the engineering and physical sciences for
integrating knowledge about complex systems and predicting
their behavior. This approach is beginning to gain traction in the
life sciences and forms a critical part of the systems biology
paradigm (20, 73). In the area of human energy metabolism and
body weight regulation, several mathematical models of weight
change have been proposed over the past few decades (3–5, 7,
16 –18, 33, 42, 44, 59, 60, 96, 110, 113). Previously, I presented
the first mathematical model of the metabolism of all three
macronutrients (i.e., carbohydrate, fat, and protein), and I used the
model to help understand the dynamics of semistarvation and
refeeding in healthy young men (42). Here, I extended my
previous model to apply to both obese and nonobese men and
Address for reprint requests and other correspondence: K. D. Hall, NIDDK/
NIH, 12 South Drive, Rm. 4007, Bethesda, MD 20892-5621 (e-mail: kevinh
@niddk.nih.gov).
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women and validated its behavior in response to several controlled
diet perturbations. The model was designed to quantitatively track
the metabolism of all three dietary macronutrients and their
interactions within the human body. In particular, the model
describes how diet perturbations result in adaptations of energy
expenditure, fuel selection, and various metabolic fluxes (e.g.,
lipolysis, lipogenesis, gluconeogenesis, ketogenesis, protein turn-
over, etc.) that ultimately give rise to changes of body weight and
composition on a time scale of days and longer. The main model
assumptions were that energy must be conserved and that changes
of the body composition result from imbalances between the
intake and utilization rates of fat, carbohydrate, and protein along
with intracellular and extracellular fluid changes. The model code
can be downloaded as a data supplement or at my website
(http://www2.niddk.nih.gov/NIDDKLabs/LBM/LBMHall.htm;
Supplemental Material for this article is available at the AJP-
Endocrinology and Metabolism website).
The model was developed using published human data from
more than 50 experimental studies (see APPENDIX) and was vali-
dated by comparing model predictions with the results from
several controlled feeding studies not used for model develop-
ment. In this validation process, I chose to simulate human studies
that carefully controlled food intake and measured changes in
body weight (BW) and body fat mass (FM) as well as total energy
expenditure (TEE) and resting metabolic rate (RMR). Requiring
this combination of measurements dramatically narrowed the
scope of possible validation studies and allowed for assessment of
not only the weight change predictions but also energy partition-
ing and energy expenditure changes. In all cases, the measured
food intake was used as a model input and included a wide range
of interventions, such as overfeeding and weight gain, weight loss
using a variety of diets, and adaptations of metabolic fuel selection
when the dietary macronutrient proportions were altered. These
validation studies were performed in several different subject
groups, including lean, overweight, and obese men and women.
Importantly, no model parameters were altered to fit the data other
than modifying the initial conditions appropriate for
modeling each subject group (e.g., initial BW and body FM).
Once the model was validated in situations where the food
intake was known, I proposed that the model could be used
to estimate the free-living energy intake changes underlying
observed changes of body weight. In particular, I used the
model to predict the energy intake required to result in the
typical trajectory of weight loss and regain observed during
an outpatient weight loss intervention (100). In addition to
providing a novel methodology for estimating the dynamics
of free-living human energy intake during weight loss and
regain, the model simulations addressed the relative role of
diet adherence vs. metabolic adaptation in explaining the
typically observed weight loss plateau after ⬃6 mo of
lifestyle modification.
E449
E450 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE

Glossary of Model Variables cases where one or more of these initial parameters was unknown, the
model used more common measurements of age, height, sex, and
BM Bone mineral mass in g physical activity level to estimate the initial parameter values using
BW Body weight in g published regression equations for body fat (50), RMR (72), and
CarbOx Rate of carbohydrate oxidation in kcal/day extracellular fluid (94). I also allowed for the possibility that the
CI Carbohydrate intake rate in kcal/day baseline diet may not result in a state of macronutrient balance.
DF Rate of endogenous lipolysis in g/day Rather, the parameters Fimbal, Gimbal, and Pimbal specified the initial
DG Rate of glycogenolysis in g/day imbalances of fat, glycogen, and protein, respectively. Other than
DNL Rate of de novo lipogenesis in kcal/day these initial parameter values, no other model parameters were ad-
DP Rate of proteolysis in g/day justed to simulate the validation experiments.
ECF Extracellular fluid mass in g To estimate the energy intake rate underlying the weight change
ECP Extracellular protein mass in g data of Svetkey et al. (100), I specified that the onset of the diet
EI Energy intake in kcal/day resulted in an immediate reduction of energy intake for a constant
FM Body fat mass in g period followed by a linear change of energy intake until another
FatOx Rate of fat oxidation in kcal/day constant period. The magnitude of the energy intake changes, along
with the duration of each period, was determined using a downhill
fC Carbohydrate oxidation fraction
simplex algorithm (78) implemented in the Berkeley Madonna soft-
fF Fat oxidation fraction
ware (version 8.3; http://www.berkeleymadonna.com) to minimize
FFM Fat-free body mass in g the sum of squares of weighted residuals between the simulation
FI Fat intake rate in kcal/day outputs and the BW change data.
fP Protein oxidation fraction
G Body glycogen mass in g
G3P Rate of glycerol 3-phosphate synthesis in kcal/day
GNGF Rate of gluconeogenesis from glycerol in kcal/day
GNGP Rate of gluconeogenesis from protein in kcal/day
ICS Intracellular solid mass in g
ICW Intracellular water mass in g
KetOx Rate of ketone oxidation in kcal/day
KTG Rate of ketogenesis in kcal/day
KUexcr Rate of ketone excretion in kcal/day
LCM Lean tissue cell mass in g
Nexcr Nitrogen excretion rate in g/day
NPRQ Nonprotein respiratory quotient
P Intracellular protein mass in g
PAE Physical activity energy expenditure in kcal/day
PI Protein intake rate in kcal/day
ProtOx Rate of protein oxidation in kcal/day
RMR Resting metabolic rate in kcal/day
RQ Respiratory quotient
SynthF Rate of fat synthesis in g/day
SynthG Rate of glycogen synthesis in g/day
SynthP Rate of protein synthesis in g/day
T Adaptive thermogenesis
TEE Total energy expenditure in kcal/day
TEF Thermic effect of feeding in kcal/day
TG Triacylglyceride
V̇CO2 Rate of carbon dioxide production in liters/day
V̇O2 Rate of oxygen consumption in liters/day
METHODS

The APPENDIX provides a detailed description of the mathematical

model along with the data and assumptions used in its development
and calibration. Briefly, the model comprises eight ordinary differen-
tial equations and uses dietary carbohydrate, fat, and protein as model
inputs. The model computes the various components of whole body
energy expenditure, rates of macronutrient oxidation, respiratory ex-
change, lipogenesis, ketogenesis, gluconeogenesis, and turnover of
Fig. 1. Adaptations of fuel selection following isocaloric exchange of dietary
fat, glycogen, and protein. Based on the computed macronutrient
carbohydrate and fat. A: 24-h respiratory quotient (RQ) in response to switch-
imbalances, along with sodium imbalances impacting extracellular ing from a 30 to a 60% fat diet. The simulated changes of RQ (dashed curve)
fluid, the model computes dynamic changes of BW and composition. along with the measured values () show a progressive approach to the food
To represent different initial conditions corresponding to different quotient (FQ; solid curve). B: simulated (dashed curve) and measured () 24-h
subject groups, parameter values were specified for initial BW, per- RQ changes in response to a diet switch from 37 to 50% fat corresponding to
cent body fat, total body water, RMR, and baseline food intake. In the depicted changes of FQ (solid curve). Data are presented as means ⫾ SD.

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 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE
RESULTS
Metabolic Fuel Selection
When the body is in a state of energy and macronutrient
balance, the intake of dietary carbohydrate, fat, and protein is
matched by their rates of utilization. A useful measurement of
the relative proportion of carbohydrate to fat being oxidized is
provided by the RQ, where a value of 1 reflects complete
reliance on carbohydrate oxidation for metabolic needs,
whereas RQ ⫽ 0.7 indicates state of pure fat oxidation and
intermediate values reflect a fuel selection mixture (27, 31, 37).
Macronutrient balance is achieved when the RQ is equal to the
food quotient (FQ), which represents the relative proportion of
macronutrients in the diet. Exchanging dietary carbohydrate
with fat while maintaining the same energy intake will result in
a state of macronutrient imbalance until fuel selection adapts to
the new FQ. Figure 1A depicts the model’s predicted change of
24-h RQ in response to a high-fat isocaloric diet that resulted
in a large decline of FQ. This diet perturbation was performed
by Schrauwen et al. (90), and the closed squares in Fig. 1A
show the measured RQ dynamics, which closely matched the
model predictions. Figure 1B shows the results from a similar
study performed by Smith et al. (95), with a less dramatic
change of FQ. Again, the model predictions agreed with the
data. Underlying these simulations were slow decreases of
glycogen as well as increased lipolysis due to the reduced
dietary carbohydrate (data not shown). These changes resulted
in altered substrate delivery to metabolically active tissues and
subsequent changes of fuel selection.
During overfeeding, the model predicts substantial changes
of various whole body metabolic fluxes, including suppression
of lipolysis and induction of de novo lipogenesis, that influence
overall fuel selection and macronutrient balance. The imbal-
ance between dietary macronutrients and their utilization rates
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E451
determined how the energy excess was partitioned in the
model. To test whether macronutrient oxidation changes were
simulated correctly during overfeeding, I used the data of Jebb
and colleagues (51, 52), who measured macronutrient oxida-
tion rates during 12 days of 33% overfeeding in healthy young
men that were continuously housed inside a metabolic cham-
ber. Figure 2A, left, shows the model predictions along with
the data for BW and body FM, whereas Fig. 2A, right,
depicts the simulated daily macronutrient oxidation rates
along with the data. The simulated gradual increase of carbo-
hydrate oxidation reached a plateau after several days as
glycogen approached a new steady state (data not shown).
These results closely matched the measured carbohydrate ox-
idation rate shown in the closed squares in Fig. 2A, right. The
simulated fat oxidation rate was suppressed at the onset of
overfeeding, which matched the measurements shown in the
open squares in Fig. 2A, right. The decrease of fat oxidation in
the simulation corresponded to a suppression of lipolysis as a
result of the increased carbohydrate intake (data not shown).
The simulated protein oxidation rate remained relatively un-
changed and corresponded to the measured rate shown in the
open triangles in Fig. 2A, right.
Jebb and colleagues (51, 52) also performed a complemen-
tary study where energy intake was decreased by 67% for 12
days, and these results are depicted in Fig. 2B along with the
corresponding model simulations. Again, the simulated
changes of body composition and macronutrient oxidation
rates closely matched the data and showed the opposite re-
sponse to overfeeding, whereas underfeeding suppressed car-
bohydrate oxidation while enhancing fat oxidation.
Underfeeding and Weight Loss
Although these results demonstrate that the model cor-
rectly simulated adaptations to short-term underfeeding in
Fig. 2. Metabolic fuel selection and body
composition and changes during over- and
underfeeding in healthy young men. A, left:
33% overfeeding resulted in the change of
simulated and measured body weight (BW;
solid curve and , respectively) along with
increased simulated and measured fat mass
(FM; dashed curve and □, respectively). A,
right: simulated and measured carbohydrate
oxidation rates (dashed curve and , respec-
tively) as well as fat oxidation (solid curve
and □, respectively) and protein oxidation
rates (dotted curve and
, respectively).
B: BW, FM, and macronutrient oxidation
rates in response to 67% underfeeding,
where the symbols are identical to A. Data
are presented as means ⫾ SD.
E452 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE

lean young men, longer-term underfeeding is required to
achieve significant weight loss in overweight people. A
recent 6-mo calorie restriction study investigated the meta-
bolic effects and weight changes in healthy, sedentary,
overweight men and women resulting from three strictly
controlled lifestyle interventions (45, 81, 82). Figure 3A
shows the effect of an 890 kcal/day very low-calorie diet
followed by a maintenance diet from 3 to 6 mo. The
imposed energy intake resulted in the drop of BW and FM
shown in Fig. 3A, left. The simulated TEE and RMR also
matched the data, which are depicted by closed and open
squares, respectively, in Fig. 3A, right. Figure 3B shows the
model simulations and data for a 25% reduction of calories
for 6 mo, and Fig. 3C shows the results for a 12.5% caloric
reduction plus a 12.5% increase of physical activity expen-
diture (PAE). Again, the model simulations matched the
body composition and energy expenditure data remarkably
well, although the initial simulated decrease in BW was
slightly more rapid than the data.
There has been much debate surrounding the metabolic
effects of weight loss diets that differ in macronutrient
content. Rumpler et al. (88) investigated this issue in obese
men by restricting energy intake by 50% for 4 wk using
diets with either 40 or 20% of energy from dietary fat.
Figure 4A, left, shows the model simulation and experimen-
tal results for the 40% fat diet, and Fig. 4B, right, shows the
results for the 20% fat diet. Figure 4, A and B, top,
demonstrates that the simulated body composition changes
corresponded reasonably well with the data, as did the TEE
and RMR changes shown in Fig. 4, A and B, middle. Figure
4, A and B, bottom, illustrates the very close agreement
between the simulated and measured 24-h RQ values, dem-
onstrating that the model appropriately represents fuel se-
lection during weight loss diets with differing macronutrient
composition in obese men.
The model also accurately simulated weight loss and
metabolic changes in obese women consuming 1,000 kcal/
day for an 8-wk period, as studied by de Boer et al. (19).
Figure 5A, left, demonstrates close agreement between the
simulated and measured body composition changes,
whereas Fig. 5A, right, shows that the simulated TEE and
RMR changes also matched the data quite well.

Fig. 3. Weight loss and metabolic effects of

caloric restriction for 6 mo. A, left: simulated
BW change (solid curve) along with the mea-
sured values () and the simulated FM
(dashed curve) and the measured FM (□)
changes resulting from a very low-calorie
liquid diet followed by a weight maintenance
diet. A, right: simulated (dashed curve) and
measured () total energy expenditure (TEE)
in response to the depicted changes of energy
intake (EI; solid gray curve). Simulated (solid
black curve) and measured resting metabolic
rate (RMR; □) along with the simulated
physical activity expenditure (PAE; dotted
curve). B: a sustained 25% reduction of EI
resulted in the simulated and measured
changes of BW and FM shown at left and the
corresponding TEE, RMR, and PAE changes
at right. C: a sustained 12.5% reduction of EI
along with a 12.5% increase of PAE resulted
in the simulated and measured changes of
BW and FM shown at left and the corre-
sponding TEE and RMR changes at right.
Data are presented as means ⫾ SD.

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 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE
Overfeeding and Weight Gain
Weight gain is the result of positive energy balance, but
predicting the magnitude of weight gain for a given change
of energy intake requires knowing how excess energy is
partitioned between deposition of body fat and fat-free
mass, which have dramatically different influences on en-
ergy expenditure and the subsequent magnitude of energy
imbalance. I tested the model predictions for weight gain by
simulating the 6-wk, 50% overfeeding study of Diaz et al.
(21), who measured body composition changes as well as
TEE and resting metabolic rate. Figure 5B, left, depicts the
simulated changes of BW and FM, which clearly matched
the body composition data, indicating appropriate energy
partitioning and weight gain. Figure 5B, right, shows that
the imposed energy intake resulted in simulated TEE and
RMR changes.
I also simulated the overfeeding study of Tremblay et al.
(103), who provided healthy young men with 1,000 kcal/day
above baseline energy requirements 6 days/wk for 100 days.
Prior to the overfeeding period, the average subject had BW ⫽
60.3 ⫾ 8.0 kg, FM ⫽ 6.9 ⫾ 3.5 kg, and RMR ⫽ 1,635 ⫾ 170
kcal/day. After 100 days of overfeeding, BW ⫽ 68.4 ⫾ 8.2 kg,
FM ⫽ 12.3 ⫾ 4.5 kg, and RMR ⫽ 1,793 ⫾ 190 kcal/day,
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E453
Fig. 4. Weight loss and metabolic changes in
obese men resulting from diets with differing
proportions of carbohydrate and fat. A, top:
simulated and measured changes of BW and
FM resulting from the 40% fat, 46% carbohy-
drate diet. A, middle: metabolic responses to
this diet, where the symbols are identical to
those in Fig. 3. A, bottom: simulated and
measured changes of RQ, where the symbols
are identical to Fig. 1. B, top: simulated and
measured changes of BW and FM resulting
from the 20% fat, 66% carbohydrate diet. B,
middle: metabolic responses to this diet. B,
bottom: simulated and measured changes of
RQ. Data are presented as means ⫾ SD.
which matched the following simulation results quite well:
BW ⫽ 69.7 kg, FM ⫽ 12.3 kg, and RMR ⫽ 1,850 kcal/day.
Estimating the Free-Living Energy Intake Underlying Weight
Loss and Regain
Maintenance of a reduced BW following weight loss is a
critical issue in the treatment of obesity (44, 46, 115, 116).
Most weight loss interventions result in a maximum amount of
lost weight after ⬃6 mo, with a gradual weight regain over the
subsequent several years. But what is the mechanism of the
weight loss plateau and subsequent regain? In particular, what
role does metabolic adaptation play in resisting further weight
loss after 6 mo?
Given that the mathematical model accurately simulates the
metabolic and body composition changes in response to known
changes of diet, I investigated what change of diet would be
required to simulate the average weight loss and regain pattern
in a group of 341 overweight and obese adults participating in
a self-directed weight loss program (100). Figure 6A, left,
shows the simulated weight loss and regain pattern (solid
curve) which closely matched the data (closed squares),
whereas the dashed curve is the predicted FM change. The
solid gray curve in Fig. 6A, right, is the predicted free-living
E454 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE
Fig. 5. Weight loss and weight gain. A, left:
simulated and measured changes of BW and
FM resulting from a 1,000 kcal/day diet for 8
wk in obese women. A, right: simulated and
measured changes of TEE, RMR, and PAE in
response to imposed changes of EI, where the
symbols are identical to those in Fig. 2. B, left:
simulated and measured changes of BW and
FM in response to 6 wk of overfeeding by
1,000 kcal/day in healthy young men. B, right:
changes of TEE, RMR, and PAE, where the
symbols are identical to those in Fig. 3. Data
are presented as means ⫾ SD.
energy intake underlying the observed weight loss and regain
trajectory, assuming no change of physical activity. At the
onset of the intervention, the model predicted a decrease of
energy intake by ⬃800 kcal/day, which was maintained for
only 6 wk. Subsequently, energy intake gradually increased
until ⬃10 mo, when it returned to the initial energy intake that
resulted in energy balance at the initial BW. The simulated
TEE is depicted by the dashed curve in Fig. 6A, right, and
shows that negative energy balance was achieved only for ⬃8
mo, after which time positive energy balance and weight regain
ensued.
Figure 6B shows the simulated changes of energy intake
required to maintain the weight loss achieved at 6 mo, which
was ⬃170 kcal/day less than the initial energy-balanced diet.
Figure 6C shows the BW and FM changes that were predicted
had the initial decrease of energy intake been maintained over
the entire 3-yr period. This simulation illustrates the very long
equilibration time for weight loss in obese subjects and dem-
onstrates that the weight loss plateau observed after 6 mo
cannot be a result of metabolic adaptation.
DISCUSSION
The ultimate goal of modeling is to provide physiological
insights and to help design novel experiments whose results
can then be integrated within the context of previous knowl-
edge, thereby improving both the model as well as our under-
standing of the system. Most systems biology models of
metabolism have been developed at the cellular level and are
aimed at calculating steady-state flux distributions through
complex metabolic networks in microorganisms (29, 30). Such
models are now beginning to be applied to human metabolism
(25, 92), and the model presented here represents a comple-
mentary dynamic approach to systems physiology at the level
of whole body human metabolism. Other than modifying the
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initial model parameters to represent the various subject
groups, no parameters were adjusted to simulate the validation
experiments. Rather, once the initial conditions were specified,
the model calculated the correct energy partitioning and met-
abolic adaptations required to simulate the physiological re-
sponses in lean, overweight, and obese men and women.
The model appears to accurately describe the physiology of
metabolism, fuel selection, and body composition change in
humans on time scales ranging from days to years. One
practical use of the model would be to computationally inves-
tigate the potential of various metabolic interventions for
treatment of obesity. Such a tool could help design key exper-
iments, focus resources on areas of likely success, and help
interpret experimental results. Of course, since the model
presently uses food intake as an input, any adaptive changes of
food intake as a result of a metabolic intervention would not be
automatically accounted for, but hypotheses regarding food
intake changes could be simulated.
Since the model responded accurately to known changes
of food intake, I proposed that known changes of body
weight and composition over long time periods could be
used to estimate the underlying changes of free-living en-
ergy intake. This is an important application of the model,
since free-living energy intake is notoriously difficult to
measure (117) and the gold standard doubly labeled water
method is valid only in situations of energy balance, when
the RQ is known (102). I used the model to estimate the
free-living energy intake changes underlying the typical
weight loss and regain trajectory observed in an outpatient
weight loss program. Surprisingly, the model predicted that
the initial reduction of energy intake was maintained for
only 6 wk, followed by a gradual return to baseline after 10
mo, where it remained for more than 2 years. This highlights
the importance of diet adherence for successful weight loss
 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE
and raises the question of why the estimated energy intake
has this pattern. In other words, what internal and external
factors contribute to this progressive loss of diet adherence?
Although the model presented here cannot answer these
questions, the ability to quantitatively predict the dynamics
of free-living energy intake during weight loss and regain
may have implications for the development of drug and
behavioral therapies for obesity.
An important caveat regarding the model estimate of
energy intake is that I assumed that the average physical
activity for the group was unchanged over the course of the
weight loss and regain trajectory. This does not mean that
the energy cost of physical activity was unchanged, since
performing the same physical activity at a different body
weight has a differing energy requirement, as was demon-
strated by the PAE curves in the validation simulations in
Figs. 3–5. Of course, the model can be simulated for any
assumed physical activity time course, and the energy intake
can be recalculated, thereby providing a range of estimates
for varying assumptions about physical activity. Future
work will investigate the sensitivity of the energy intake
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E455
Fig. 6. Weight loss and regain dynamics dur-
ing an outpatient lifestyle intervention. A, left:
a typical outpatient weight loss program re-
sults in the characteristic BW change trajec-
tory, where the symbols are identical to those
in Fig. 3. A, right: predicted free-living EI and
TEE underlying the observed BW loss and
regain trajectory. B: the model predicted that
maintenance of lost BW and FM (left) would
have been achieved if the EI over the last 2 yr
had been decreased by 170 kcal/day. C: had
the initial reduction of EI been sustained for
the 3-yr period, the model predicted a progres-
sive decrease of BW and FM shown at left and
the corresponding TEE changes shown at
right. Data are presented as means ⫾ SD.
estimates to various model parameters as well as the time
course of body weight change.
Much work remains for improving and expanding the
model. For example, although I have demonstrated that the
model behaves appropriately for different groups of sub-
jects, it is presently unclear whether individual subject
responses can be predicted given sufficiently detailed infor-
mation about their initial conditions. Furthermore, the
model now implicitly represents the effect of hormones such
as insulin, but an explicit representation of endocrine sig-
naling along with concentrations of hormones and metabo-
lites would be desirable, especially on shorter time scales, so
that the response to individual meals could be simulated.
Other additions to the model might include an explicit
representation of the possible contribution of human brown
adipose tissue to the overall energy expenditure and its role
in adaptive thermogenesis (80). Finally, it would be partic-
ularly interesting to “close the loop” and model how internal
signals from changes of metabolism and body composition
combine with external factors to determine food intake. But
despite the cornucopia of possible model improvements, the
E456 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE
mathematical model presented here represents a significant
step forward in a systems physiology approach to whole
body human metabolism.
APPENDIX
Detailed Description of the Mathematical Model
The individual components of the mathematical model were based
on a variety of published in vivo human data, as described below.
Each model component was relatively simple, and only the most
important physiological effectors have been incorporated. Since con-
tinued development of the model is part of an ongoing research
program, additional relevant physiological data will be incorporated
within the existing computational framework to improve the realism
and predictive capabilities of the model. The model code can be
downloaded as a data supplement or at my website (http://www2.
niddk.nih.gov/NIDDKLabs/LBM/LBMHall.htm).
The concept of macronutrient balance is an expression of energy conser-
vation such that changes in the body’s energy stores were given by the sum
of fluxes entering the pools minus the fluxes exiting the pools. Thus, the
mathematical representation of macronutrient balance was given by the
following differential equations:
dG
␳C ⫽ CI ⫺ DNL ⫹ GNGP ⫹ GNGF ⫺ G3P ⫺ CarbOx
dt
dF
␳F ⫽ 3MFFAFI ⁄ MTG ⫹ ␧dDNL ⫺ KUexcr
dt
(1)
⫺ (1 ⫺ ␧k)KTG ⫺ FatOx
dP
␳P ⫽ PI ⫺ GNGP ⫺ ProtOx,
dt
where ␳C ⫽ 4.18 kcal/g, ␳F ⫽ 9.44 kcal/g, and ␳P ⫽ 4.7 kcal/g were
the energy densities of carbohydrate, fat, and protein, respectively
(67). MTG ⫽ 860 g/mol and MFFA ⫽ 273 g/mol were the molecular
masses of triacylglycerides and free fatty acids, respectively. The
efficiency of de novo lipogenesis, DNL, was represented as the
dimensionless parameter εd ⫽ 0.835, which is the enthalpy of com-
bustion of 0.37 g of fat divided by the enthalpy of combustion of the
1 g of glucose used to produce the fat (27). The efficiency of
ketogenesis, KTG, was represented by the parameter εk ⫽ 0.81,
calculated as the enthalpy of combustion of 4.5 mol of acetoacetate
divided by the enthalpy of combustion of 1 mol of stearic acid used to
produce the ketones (12). When the ketogenic rate increases, ketones
are excreted in the urine at the rate KUexcr. The macronutrient intake
rates CI and FI refer to the digestible energy intake of carbohydrate
and fat, respectively, whereas PI refers to the digestible energy intake
of protein corrected for the obligatory formation of ammonia with
protein metabolism. The energy cost of ureagenesis is accounted for
separately, as described below. The oxidation rates CarbOx, FatOx,
and ProtOx are summed to the TEE, less the small amount of heat
produced via flux through ketogenic and lipogenic pathways. Since
body composition changes take place on the time scale of weeks,
months, and years, the model was targeted to represent daily changes
of energy metabolism and not fluctuations of metabolism that occur
within 1 day. The nutrient balance equations were integrated using the
fourth-order Runge-Kutta algorithm with a time step size of 0.1 days (78).
Body Composition
The BW was the sum of the FFM and the FM. FFM was computed
using the following equation:
FFM ⫽ BM ⫹ ECF ⫹ ECP ⫹ LCM
⫽ BM ⫹ ECF ⫹ ECP ⫹ ICW ⫹ P ⫹ G ⫹ ICS
^ (2)
⫽ BM ⫹ ECF ⫹ ECP ⫹ ICW ⫹ P(1 ⫹ hP)
⫹ G(1 ⫹ hG) ⫹ ICS,
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where the FFM is composed of BM, ECF, ECP, and LCM. LCM is
composed of ICW, G, and P as well as a small contribution from
nucleic acids and other ICS. The protein fraction of the lean tissue cell
mass was P/LCM ⫽ 0.25, and the initial intracellular water fraction
was ICW/LCM ⫽ 0.7 (13, 109). ICW was then calculated dynami-
cally from P and G such that each gram of protein and glycogen was
associated with hP and hG grams of water, respectively. IĈW was a
constant amount of ICW computed to attain the appropriate initial
intracellular composition, assuming that G ⫽ 500 g, hG ⫽ 2.7, and
hP ⫽ 1.6 (13, 43, 71).
The initial ECF was calculated via the regression equations of Silva
et al. (94), and changes of ECF were calculated as follows:
dECF 1
⫽ 共⌬Nadiet ⫺ ␰Na共ECF ⫺ ECFinit兲
dt [Na]
⫺ ␰CI共1 ⫺ CI ⁄ CIb兲兲 ⫹ ⌬ECF (3)
d⌬ECF
␶BW ⫽ ␰BW共BW ⫺ BWinit兲 ⫺ ⌬ECF,
dt
where [Na] ⫽ 3.22 mg/ml is the extracellular sodium concentration,
⌬Nadiet is the change of dietary sodium in milligrams, and ⌬ECF is
the slow rate of increment in ECF that occurs with BW change on a
very long time scale of ␶BW, ⬃1,000 days. The value of ␰BW ⫽ 0.16
ml·kg⫺1·day⫺1 was chosen so that the steady-state increment of ECF
with weight change approximately matched the regression equations
of Silva et al. (94). The value of ␰Na was chosen according to the data
of Andersen et al. (6), who measured a change of sodium excretion of
5,000 mg/day following an infusion of 1.7 liters of isotonic saline.
Therefore, I assumed that a 5,000 mg/day change in sodium intake
would be balanced by a 1.7-liter change of ECF giving ␰Na ⫽ 3
mg·ml⫺1·day⫺1. Given that the normal sodium content of the diet
is ⬃4,000 mg/day and that a low-sodium diet must effectively shut
off sodium excretion, I assumed that ␰CI ⫽ 4,000 mg/day so that
removing dietary carbohydrate doubles the sodium excretion rate
compared with a very-low-sodium diet, as observed by Stinebaugh
and Schloeder (98).
I assumed that BM was 4% of the initial BW, and the ECP was
assumed to be a constant determined by the initial BM and ECF
values, as determined by the regression equations of Wang et al.
(108).
Whole Body Total Energy Expenditure
TEE was modeled by the following equation:
TEE ⫽ TEF ⫹ PAE ⫹ RMR, (4)
where TEF was the thermic effect of feeding, PAE was the energy
expended for physical activity and exercise, and RMR was the
remainder of the whole body energy expenditure, defined as the
resting metabolic rate. Explicit equations for each component of
energy expenditure follow.
Thermic Effect of Feeding
Feeding induces a rise of metabolic rate associated with the
digestion, absorption, and short-term storage of macronutrients and
was modeled by the following equation:
TEF ⫽ ␣FFI ⫹ ␣PPI ⫹ ␣CCI, (5)
where ␣F ⫽ 0.025, ␣P ⫽ 0.25, and ␣C ⫽ 0.075 defined the short-term
thermic effect of fat, protein, and carbohydrate feeding (12).
Adaptive Thermogenesis
Energy imbalance causes an adaptation of metabolic rate that
opposes weight change (22, 23, 62). Whether or not the adaptation of
energy expenditure is greater than expected based on body composi-
tion changes alone has been a matter of some debate (35, 70, 111).
 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE
The so-called adaptive thermogenesis is believed to affect both resting
and nonresting energy expenditure and has maximum amplitude
during the dynamic phase of weight change. Adaptive thermogenesis
also persists during weight maintenance at an altered body weight
(85). The non-RMR component of adaptive thermogenesis may reflect
either altered efficiency or amount of muscular work (63– 65, 87).
The onset of adaptive thermogenesis is rapid and may correspond
to altered levels of circulating thyroid hormones or catecholamines
(86, 111). I defined a dimensionless adaptive thermogenesis parame-
ter, T, which was generated by a first-order process in proportion to
the departure from the baseline energy intake EIb ⫽ CIb ⫹ FIb ⫹ PIb:
再 冎
␶T
dT
⫽
␭1共⌬EI ⁄ EIb兲 ⫺ T, if EI ⬍ EIb
dt ␭2共⌬EI ⁄ EIb兲 ⫺ T, else
where ⌬EI was the change from the baseline energy intake, ␶T ⫽ 7
days was the estimated time constant for the onset of adaptive
thermogenesis, and the parameters ␭1 and ␭2 quantified the effect of
underfeeding and overfeeding, respectively, and were determined
from the best fit to the Minnesota experiment data. The adaptive
thermogenesis parameter T acted on both the RMR and PAE compo-
nents of energy expenditure, as defined below. This simple model
assumed that adaptive thermogenesis reacted to perturbations of EI
and persisted as long as EI was different from baseline. Importantly,
the model allowed for the possibility that no adaptive thermogenic
mechanism was required to fit the data from the Minnesota experi-
ment. The amount that the best fit values for the ␭1 and ␭2 parameters
differ from zero provides an indication of the extent of adaptive thermo-
genesis that occurred during the underfeeding and overfeeding phases,
respectively, of the Minnesota experiment.
Physical Activity Energy Expenditure
The energy expended for typical physical activities is proportional
to the body weight of the individual (12, 105). Low-intensity physical
activities may be subject to the effects of adaptive thermogenesis,
whereas higher-intensity exercise appears to not be affected (87).
Therefore, the following equation was used for the physical activity
expenditure:
PAE ⫽ ␦(1 ⫹ ␴T)BW ⫹ ␷BW,
where ␦ was the nonexercise physical activity coefficient (in
kcal·kg⫺1·day⫺1), ␷ was the exercise coefficient (in kcal·kg⫺1·day⫺1),
and BW ⫽ FFM ⫹ FM was the body weight. The proportion of T that
was allocated to the modification of nonexercise PAE was determined
by the parameter ␴. The adaptation of PAE with T did not distinguish
between altered efficiency vs. amount of muscular work.
Resting Metabolic Rate
RMR includes the energy required to maintain irreversible meta-
bolic fluxes such as de novo lipogenesis, gluconeogenesis, and keto-
genesis as well as the turnover costs for protein, fat, and glycogen.
The following equation included these components:
RMR ⫽ Ec ⫹ ␥BMB ⫹ ␥FFM关FFM ⫺ MB ⫺ ⌬G(1 ⫹ hg)
⫺ (ECF ⫺ ECFinit)兴 ⫹ ␥FF ⫹ (1 ⫺ ␧d)DNL
⫹ (1 ⫺ ␧g)(GNGF ⫹ GNGP) ⫹ (1 ⫺ ␧K)KTG
dP
⫹ ␩NNexcr ⫹ (␩P ⫹ ␧P)DP ⫹ ␩P
dt
dF dG
⫹ ␩ FD F ⫹ ␩ F ⫹ ␩ GD G ⫹ ␩ G , normalized by the initial fat mass of the average Minnesota experi-
dt dt
where εg ⫽ 0.8 was the efficiency of gluconeogenesis (12) and the
constant, Ec, was a parameter chosen to ensure that the model
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E457
achieved energy balance during the balanced baseline diet (see Nu-
trient Balance Parameter Constraints below).
The specific metabolic rate of adipose tissue was ␥F ⫽ 4.5 kcal·
kg⫺1·day⫺1. The brain metabolic rate was ␥B ⫽ 240 kcal·kg⫺1·day⫺1,
and its mass was MB ⫽ 1.4 kg, which does not change with weight
gain or loss (26). The baseline specific metabolic rate of the fat-free
mass, ␥ˆ FFM ⫽ 19 kcal·kg⫺1·day⫺1, was determined by the specific
metabolic rates of the organs multiplied by the rate of change of the
organ mass with fat-free mass change according to the following
equation:
dMi
(6)
␥^ FFM ⫽ 兺i ␥i dFFM , (9)
where ␥i and Mi are the average specific metabolic rate and mass,
respectively, of the organ indexed by i. The organs included skeletal
muscle (␥SM ⫽ 13 kcal·kg⫺1·day⫺1, MSM ⫽ 28 kg, dMSM/dFFM ⫽
0.59), liver (␥L ⫽ 200 kcal·kg⫺1·day⫺1, ML ⫽ 1.8 kg, dML/dFFM ⫽
0.017), kidney (␥K ⫽ 440 kcal·kg⫺1·day⫺1, MK ⫽ 0.31 kg, dMk/
dFFM ⫽ 0.0038), heart (␥H ⫽ 440 kcal·kg⫺1·day⫺1, MH ⫽ 0.33 kg,
dMH/dFFM ⫽ 0.0029), and residual lean tissue mass (␥R ⫽ 12
kcal·kg⫺1·day⫺1, MR ⫽ 23.2 kg, dMR/dFFM ⫽ 0.37), as provided by
Elia (26), and the relationship between the organ masses and FFM was
determined from cross-sectional body composition data (Gallagher D,
personal communication). I assumed that there was no effect on RMR
arising solely from changes of glycogen content, ⌬G, and its associated
water or changes of ECF. Adaptive thermogenesis affected the baseline
specific metabolic rate for lean tissue cell mass according to the following
equation:
␥FFM ⫽ ␥^ FFM[1 ⫹ (1 ⫺ ␴)T] (10)
The last seven terms of Eq. 8 accounted for the energy cost for urea
synthesis and nitrogen excretion as well as the turnover of protein, fat,
and glycogen. Urea synthesis requires 4 mol ATP/mol nitrogen
excreted (76) and was represented by the parameter ␩N ⫽ 5.4 kcal/g
excreted nitrogen Nexcr. To calculate the energy cost for protein
turnover, consider that the whole body protein pool turns over with a
synthesis rate, SynthP, and a degradation rate, DP (in g/day). I
assumed that it cost ␩PSynthP to synthesize P and that the energy
(7) required for degradation was εPDP. Since dP/dt ⫽ SynthP ⫺ DP, the
energy cost for protein turnover was given by (␩P ⫹ εP)DP ⫹ ␩PdP/dt.
Similar arguments led to the other terms of Eq. 8 representing the
energy costs for fat and glycogen turnover, where the energy cost for
degradation was negligible. The values for the parameters were ␩F ⫽
0.18 kcal/g, ␩G ⫽ 0.21 kcal/g, εP ⫽ 0.17 kcal/g, and ␩P ⫽ 0.86 kcal/g.
These values were determined from the ATP costs for the respective
biochemical pathways (i.e., 8 ATP/TG synthesized, 2 ATP/glycosyl
unit of glycogen synthesized, 4 ATP/peptide bond synthesized plus 1
ATP for amino acid transport, and 1 ATP/peptide bond hydrolyzed)
(12, 28). I assumed that 19 kcal of macronutrient oxidation was
required to synthesize 1 mol of ATP (26).
Daily Average Lipolysis Rate
The daily average lipolysis rate, DF, was modeled as
冉 冊
2
^ F 3
DF ⫽ DF [Ldiet ⫹ LPA] (11)
FKeys
(8)
where D̂F ⫽ 140 g/day was the baseline daily average TG turnover
rate given by two-thirds of the fed lipolysis rate plus one-third of the
overnight-fasted lipolysis rate (53). The (F/FKeys)2/3 factor accounted
for the dependence of the basal lipolysis rate on the total fat mass
ment subject, FKeys. The two-thirds power reflects the hypothesis that
basal lipolysis scales with adipocyte surface area, which also matches
the FFA rate of appearance (Ra) as a function of body fat mass
E458 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE

observed by Bjorntorp et al. (10). The effect of diet on lipolysis, Ldiet,

is determined primarily by the carbohydrate content of the diet via
insulin. Furthermore, the lipolysis rate reaches half of its maximum
kL ⫽ ln 冉 AL ⫺ BL
1 ⫺ BL 冊 . (13)

value after ⬃2 days of fasting, and the magnitude of the increase is Although obesity increases basal lipolysis, the stimulatory effect of
attenuated with increasing body fat mass (58). To capture these effects, decreased carbohydrate intake is impaired (120). This effect was
I modeled the effect of dietary carbohydrate on the daily average lipolysis modeled in Eq. 12 by setting KL ⫽ 4 and SL ⫽ 2 such that the curve
rate as of lipolysis vs. CI becomes flattened as FM increases and matches the
dLdiet KLSL关1 ⫹ (AL ⫺ BL) ⫻ exp(⫺kLCI ⁄ CIb) ⫹ BL兴 data of Klein et al. (58), where long-term vs. short-term fasting
␶L ⫽ ⫺ Ldiet , stimulated lipolysis to a lesser degree in obese vs. lean subjects.
dt KLSL ⫹ MAX兵0, (F ⁄ FKeys ⫺ 1)SL其 Physical activity and exercise are known to stimulate lipolysis, and
(12) this was modeled in Eq. 11 by the factor LPA as follows:

冉 冊
where ␶L ⫽ 1/ln(2) ⫽ 1.44 days. The term in the square brackets
␦⫹␷
accounted for the modulation of lipolysis by the carbohydrate content LPA ⫽ ␺ ⫺1 , (14)
of the diet. For example, complete starvation (CI ⫽ 0) stimulated ␦init ⫹ ␷init
average daily lipolysis by a factor of AL ⫽ 3.1/[1 ⫺ exp(⫺2.5/␶L)] ⫽
3.8, as computed by the 3.1-fold increase of glycerol Ra following a where ␺ ⫽ 0.4 was the best fit value for the measured effect of graded
60-h fast (15) vs. the daily average glycerol Ra (53). Halving the exercise to increase lipolysis rates determined by FFA Ra measure-
carbohydrate content of the diet increased the average lipolysis rate by ments (39, 57, 84, 119).
factor of 1.4, as estimated by the increased area under the circulating
FFA curve following an isocaloric meal consisting of 33 vs. 66% Daily Average Ketogenesis Rate
carbohydrate (118). Given the above value for AL, the effect of
halving the carbohydrate content was modeled by choosing BL ⫽ 0.9. The daily rate of ketogenesis was modeled as a function of the daily
The following choice for kL ensured that the lipolysis rate was lipolysis rate, the protein content in the diet, and the glycogen level as
normalized for the baseline diet: follows:

KTG ⫽ ␳KDF AK冋冉 ^

DF ⁄ DF
KK ⫹ DF ⁄ DF
^ 冊 冉 冊 冉
exp ⫺kP
PI
PIb
exp ⫺kG
G
Ginit 冊册 , (15)

where ␳K ⫽ 4.45 kcal/g is the average energy density of ketones
calculated as average enthalpy of combustion of ␤-hydroxybuterate
and acetoacetate in a 2:1 ratio (12). AK ⫽ 0.8 is the maximum fraction
of FFA from lipolysis converted to ketones when PI ⫽ G ⫽ 0 (9).
When protein intake was at normal levels, I assumed that the maxi-
mum fraction of FFA converted to ketones was 0.4, since a protein
modified fast decreases circulating ketone levels by one-half com-
pared with fasting alone (106). Therefore, kp ⫽ ln(0.8/0.4) ⫽ 0.69.
When both glycogen and protein intake are at normal levels, I
assumed that the maximum fraction of FFA converted to ketones was
0.2; therefore kG ⫽ ln(0.4/0.2) ⫽ 0.69, and when the lipolysis rate was
normal I assumed that 10% of FFA from lipolysis was converted to
ketones such that KK ⫽1 (9).
Daily Average Ketone Excretion Rate
Ketones are excreted in the urine when circulating levels cross the
renal threshold for reuptake. I assumed that

冦 冧
0, if KTG ⁄ ␳K ⬍ KTGthresh
KUexcr ⫽ ␳KKUmax共KTG ⁄ ␳K ⫺ KTGthresh兲 , (16)
, else
共KTGmax ⫺ KTGthresh兲

where KTGthresh ⫽ 70 g/day, KUmax ⫽ 20 g/day, and KTGmax ⫽ 400
g/day such that the urinary excretion of ketones, KUexcr, matches the
excretion data during various ketone infusion rates, as measured by
Wildenhoff (114) and Sapir and Owen (89).
Ketone Oxidation Rate
Since ketones cannot be stored in the body in any significant
quantity, I assumed that once a ketone is produced it is either oxidized
or excreted. Therefore,
KetOx ⫽ KTG ⫺ KUexcr . (17)
Daily Average Proteolysis Rate
The daily average protein degradation rate, DP, was given by
tional to the normalized protein content of the body (112). Although
it is possible that the protein content of the diet may directly influence
protein turnover as represented by the parameter ␹ (83), the balance of
the current data suggests that ␹ ⫽ 0 (41, 75). Nevertheless, I included
this parameter in the model to allow for this possibility should new
data provide further evidence for such an effect.
Daily Average Glycogenolysis Rate
The daily average glycogen degradation rate, DG, was given by the
following equation:
DG ⫽ DG
^
冉 冊 G
Ginit
, (19)

^
DP ⫽ DP 冋冉 冊 冉 冊册
P
PKeys
⫹␹
⌬PI
PIb
, (18)
where the baseline glycogen turnover rate, D̂G ⫽ 180 g/day, was
determined by assuming that 70% was from hepatic glycogenolysis
and 30% from skeletal muscle with the hepatic contribution com-
where D̂P ⫽ 300 g/day was the baseline daily protein turnover rate puted as two-thirds of the fed plus one-third of the overnight-fasted
(107), and I assumed that the protein degradation rate was propor- hepatic glycogenolysis rate (69).

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 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE E459
Daily Average Fat, Protein, and Glycogen Synthesis Rates where the coefficients ⌫C ⫽ 0.39 and ⌫P ⫽ 0.32 were determined
by solving Eq. 23, using two sets of data. The first measured an
Mass conservation required that the daily average synthesis rates of initial nitrogen balance of ⫺4 g/day upon removal of baseline
fat, protein, and glycogen (SynthF, SynthP, and SynthG, respectively) dietary carbohydrate while keeping dietary protein at baseline
were given by values (47). I assumed that the negative nitrogen balance was
dF driven largely by increased gluconeogenesis and thereby deter-
SynthF ⫽ DF ⫹ mined the value of ⌫C. The second study found a 56% increase of
dt gluconeogenesis when protein intake was increased by a factor of
dP 2.5-fold, whereas carbohydrate intake was decreased by 20% (66).
SynthP ⫽ DP ⫹ (20) Given the value of ⌫C, these data determined the value of the sum
dt
dG of ⌫p ⫹ ␹ and therefore ⌫P.
SynthG ⫽ DG ⫹ .
dt De Novo Lipogenesis Rate
Glycerol 3-Phosphate Production Rate DNL occurs in both the liver and adipose tissue. Under free-
living conditions, adipose DNL has recently been measured to
Because adipose tissue lacks glycerol kinase, the glycerol 3-phos- contribute ⬃20% of new TG with a measured TG turnover rate of
phate backbone of adipose TG is derived primarily from glucose. ⬃50 g/day (99). Thus, adipose DNL is ⬃94 kcal/day. Measure-
Thus, the TG synthesis rate, SynthF, determined the rate of glycerol ments of daily hepatic DNL in circulating very low-density li-
3-phosphate production, G3P, according to poproteins (VLDL) have found that ⬃7% of VLDL TG occurs via

G3P ⫽ ␳CSynthF 冉 冊
MG
MTG
, (21)
DNL when a basal diet of 30% fat, 50% carbohydrate, and 15%
protein is consumed (49). Given that the daily VLDL TG secretion
rate is ⬃33 g/day (93), this corresponds to a hepatic DNL rate of
where MG ⫽ 92 g/mol and MTG ⫽ 860 g/mol are the molecular ⬃22 kcal/day. For an isocaloric diet of 10% fat, 75% carbohydrate, and
weights of glycerol and TG, respectively. 15% protein, hepatic DNL increases to 113 kcal/day (49).
When carbohydrate intake is excessively large and glycogen is
Glycerol Gluconeogenesis Rate saturated, DNL can be greatly amplified (2). Therefore, I modeled
DNL as a Hill function of the normalized glycogen content with a
Lipolysis of both endogenous and exogenous TG results in the maximum DNL rate given by the carbohydrate intake rate:
release of glycerol that can be converted to glucose via gluconeogen-
esis (8). Trimmer et al. (104) demonstrated that glycerol disappear- CI ⫻ (G ⁄ Ginit)d
DNL ⫽ . (24)
ance could be fully accounted for by glucose production. Therefore, I (G ⁄ Ginit)d ⫹ KDNL
d

assumed that all exogenous and endogenous glycerol entered the

GNG pathway according to the following equation: I chose KDNL ⫽ 2 and d ⫽ 4 such that the computed DNL rate

冉 冊 冉 冊
␳ CM G MG
GNGF ⫽ FI ⫹ D F␳ C . (22)
␳FMTG MTG
Since glycerol cannot be used by adipose tissue for TG synthesis
due to lack of glycerol kinase, all glycerol released by lipolysis is
eventually oxidized (apart from a negligibly small amount incorpo-
rated into altered pool sizes of nonadipose TG). By assuming that all
glycerol enters the GNG pathway, any model error was limited to an
overestimate of the energy expenditure associated with glycerol’s
initial conversion to glucose prior to oxidation. This error must be
very small, since the total energy cost for glycerol GNG in the basal
state was only 25 kcal/day.
Gluconeogenesis From Amino Acids
The GNGP rate in the model referred to the net rate of gluconeo-
genesis from amino acid-derived carbon. Whereas all amino acids
except leucine and lysine can be used as gluconeogenic substrates, the
primary gluconeogenic amino acids are alanine and glutamine. Much
of alanine gluconeogenesis does not contribute to the net amino acid
gluconeogenic rate since the carbon skeleton of alanine is derived
largely from carbohydrate precursors via skeletal muscle glycolysis
(77). In an extensive review of hepatic amino acid metabolism,
Jungas et al. (54) estimated that the net basal gluconeogenic rate
from amino acids, GN̂Gp, was 300 kcal/day.
Several factors may regulate GNGP, but for simplicity I have
assumed that GNGP was proportional to the normalized proteolysis
rate and was influenced by the diet as follows:
corresponded with measured in vivo DNL rates for experimentally
determined carbohydrate intakes and estimated glycogen levels (1, 2,
49, 99).
Macronutrient Oxidation Rates
The whole body energy expenditure rate, TEE, was accounted for
primarily by the sum of the heat produced from carbohydrate, fat, and
protein oxidation plus the heat produced via flux through the DNL
pathway (34) and ketogenesis. Furthermore, I assumed that the min-
imum carbohydrate oxidation rate was equal to the sum of the
gluconeogenic rates less the flux required to produce glycerol 3-phos-
phate and that ketone oxidation was treated as fat oxidation. Thus, the
remaining energy expenditure, TẼE, was apportioned between carbo-
hydrate, fat, and protein oxidation according to the fractions fC, fF,
and fP, respectively:
~
CarbOx ⫽ GNGf ⫹ GNGp ⫺ G3P ⫹ fC ⫻ TEE
~
FatOx ⫽ KetOx ⫹ fF ⫻ TEE (25)
~
ProtOx ⫽ fP ⫻ TEE,
where
~
TEE ⫽ TEE ⫺ (1 ⫺ ␧d)DNL ⫺ (1 ⫺ ␧k)KTG ⫺ KetOx
(26)
⫺ GNGf ⫺ GNGp ⫹ G3P.
The substrate oxidation fraction for each macronutrient depends on
a number of factors. First, increased lipolysis leads to concomitant

冋冉 冊 冉 冊
increased fatty acid oxidation (15). Second, carbohydrate oxidation
^ P ⌬CI depends on the carbohydrate intake as well as the glycogen content
GNGP ⫽ GNGP ⫺ ⌫C (32, 61). Third, dietary protein and carbohydrate intake directly
PKeys CIb

冉 冊册
(23) stimulate protein and carbohydrate oxidation, respectively, but dietary
⌬PI fat intake does not directly stimulate fat oxidation (36, 91). Fourth, I
⫹ (⌫P ⫹ ␹) ,
PIb assumed that lean tissue supplies amino acids for oxidation in pro-

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E460 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE

portion to the proetolysis rate. Finally, although inactivity causes modeled these effects by decreasing the fraction of energy expendi-
muscle wasting (11, 97), increased physical activity may promote ture derived from protein oxidation as physical activity increases.
nitrogen retention (14, 101, 112), and the PAE is accounted for On the basis of these physiological considerations, the substrate oxidation
primarily by increased oxidation of fat and carbohydrate (112). I fractions were computed according to the following expressions:

wG(DG ⁄ DG) ⫹ wCMAX兵0, (1 ⫹ SC⌬CI ⁄ CIb)其G ⁄ (Gmin ⫹ G)

^

fC ⫽ .
Z
^
wF(DF ⁄ DF)
fF ⫽
Z
wPMAX兵0, (1 ⫹ Psig)其 ⫹ (DP ⁄ DP)SAexp共⫺kA(␦ ⫹ ␷) ⁄ (␦b ⫹ ␷b)兲
^

fP ⫽ (27)
Z
dPsig
␶PI ⫽ SP⌬PI ⁄ PIb ⫺ Psig
dt

SP ⫽ 再 SP⫹ , if ⌬PI ⬎ 0
SP⫺ , else 冎 ,

where the w and S were dimensionless model parameters and ⌬CI · CarbOx FatOx ProtOx
and ⌬PI were changes from the basal carbohydrate intake, CIb, and VO2 ⫽ 0.831 ⫹ 2.03 ⫹ 0.966
␳C ␳F ␳P

冉 冊
protein intake, PIb, respectively. The small parameter, Gmin ⫽ 10
g, was chosen such that carbohydrate oxidation was restrained as GNGF G3P KUexcr
⫹ 0.133 ⫺ ⫹ 0.33
glycogen decreases and prevents glycogen from becoming nega- ␳C ␳C ␳K
tive. The signal for dietary protein intake perturbations, Psig, · CarbOx FatOx ProtOx (30)
changes with a time constant of ␶PI ⫽ 1.1 days, in accordance with VCO2 ⫽ 0.831 ⫹ 1.43 ⫹ 0.782
␳C ␳F ␳P
the data of Rand et al. (79), and the model allows for an asymmetry
GNGP DNL
between positive and negative perturbations of dietary protein. To ⫺ 0.126 ⫹ 0.238 .
normalize for the baseline physical activity, the constant kA was ␳P ␳C
chosen such that kA ⫽ ln(SA). Z was a normalization factor equal
The RQ was computed by dividing V̇CO2 by V̇O2. To compute the
to the sum of the numerators so that the sum of the fractions fC, fF, NPRQ, the total rate of nitrogen excretion was calculated:
and fP was equal to 1.
共ProtOx ⫹ GNGP兲
Nexcr ⫽ (31)
Respiratory Gas Exchange 6.25␳P
Oxidation of carbohydrate, fat, and protein was associated with con- where the factor 6.25 was the number of grams of protein per gram of
sumption of oxygen (O2) and production of carbon dioxide (CO2) nitrogen.
according to the stoichiometry of the net biochemical reactions (31, 37): When comparing model predictions for fuel selection with experi-
ments employing 24-h room indirect calorimetry, I used the simulated
1 g carbohydrate ⫹ 0.831 liters O2 ¡ 0.831 liters CO2 V̇CO2 and V̇O2 values from Eq. 30 and computed macronutrient oxidation
⫹ 0.6 g H2O1 g fat ⫹ 2.03 liters CO2 ¡ 1.43 liters CO2 (28) rates as if they were the actual indirect calorimetry measurements.
⫹ 1.09 g H2O1 g protein ⫹ 0.966 liters O2 ¡ 0.782 liters
Nutrient Balance Parameter Constraints
CO2 ⫹ 0.45 g H2O ⫹ 0.16 g N.
The baseline diet may not necessarily result in macronutrient or
Gluconeogenesis, lipogenesis, ketogenesis (with subsequent excre- energy balance. Therefore, I defined the following parameters to
tion), and glycerol 3-phosphate production also contribute to gas specify the initial degree of imbalance for fat, carbohydrate, and
exchange according to the following net reactions (27, 31, 37): protein: Fimbal, Gimbal, and Pimbal, respectively. Therefore, the baseline
diet satisfies the following relationship: TEE ⫹ Fimbal ⫹ Gimbal ⫹
1 g protein ⫹ 0.126 liters CO2 ¡ 1 g carbohydrate ⫹ 0.16 g N Pimbal ⫽ EIb, where the subscript b refers to the baseline state.
1 g glycerol ⫹ 0.133 liters O2 ¡ 1 g carbohydrate Therefore, by explicitly expressing the TEE in the baseline state I
1 g carbohydrate ¡ 0.37 g fat ⫹ 0.238 liters CO2 ⫹ 0.2 g H2O derived the following expression:
1 g fat ⫹ 0.52 liters O2 ¡ 1.57 g ketones (29) EIb ⫽ TEFb ⫹ PAEb ⫹ RMRb
1 g carbohydrate ¡ 1 g glycerol ⫹ 0.133 liters O2. ⫽ TEFb ⫹ (␦b ⫹ ␷b)BWb
⫹ EC ⫹ ␥BMB ⫹ ␥FFM(FFMb ⫺ MB) ⫹ ␥FFb
Oxidation of carbohydrate, fat, and protein can occur either directly ^ ^
⫹ (1 ⫺ ␧d)DNLb ⫹ (1 ⫺ ␧g)(GNGF ⫹ GNGP) (32)
or subsequent to intermediate exchange via lipogenesis or gluconeo- ^ ^ ^
genesis. In either case, the final ratio of CO2 produced to O2 con- ⫹ (1 ⫺ ␧k)KTGb ⫹ (␩P ⫹ ␧P)DP ⫹ ␩FDF ⫹ ␩GDG
sumed (i.e., the RQ) is independent of any intermediate exchanges in ⫹ (1 ⫹ ␩F ⁄ ␳F)Fimbal ⫹ (1 ⫹ ␩G ⁄ ␳C)Gimbal
accordance with the principles of indirect calorimetry (27, (PIb ⫺ Pimbal)
31, 37). ⫹ (1 ⫹ ␩P ⁄ ␳P)Pimbal ⫹ ␩N ,
6.25␳P
The simulated O2 consumption (V̇O2) and CO2 production (V̇CO2)
(in liters/day) were computed according to which was solved for the constant Ec.

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 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE E461
Assuming negligible baseline ketone excretion, rearrangement of (3MFFAFIb ⁄ MTG ⫹ ␧dDNLb ⫹ ␧kKTGb ⫺ Fimbal)
the nutrient balance equations gave ␨F ⬅
⍀
^ ^
CarbOxb ⫽ CIb ⫺ DNLb ⫹ GNGP ⫹ GNGF ⫺ G3Pb ⫺ Gimbal (CIb ⫺ DNLb ⫺ Gimbal)
␨C ⬅ (34)
FatOxb ⫽ 3MFFAFIb ⁄ MTG ⫹ ␧dDNLb ⫺ (1 ⫺ ␧k)KTGb ⫺ Fimbal ⍀
^
^
ProtOxb ⫽ PIb ⫺ GNGP ⫺ Pimbal . (33) (PIb ⫺ GNGP ⫺ Pimbal)
␨P ⬅ ,
Next, I defined the following parameters: ⍀
where ⍀ was given by
⍀ ⬅ EIb ⫺ (1 ⫺ ␧d)DNLb ⫺ (1 ⫺ ␧k)KTGb ⫺ KetOxb
^ ^
⫺ GNGF ⫺ GNGP ⫹ G3Pb ⫺ (1 ⫹ ␩G ⁄ ␳C)Gimbal (35)
⫺ (1 ⫹ ␩F ⁄ ␳F)Fimbal ⫺ (1 ⫹ ␩P ⁄ ␳P)Pimbal .
By substituting Eqs. 25 and 27 at the initial state, I obtained

wF(Finit ⁄ FKeys)2⁄3
⫽ ␨F
(Pinit ⁄ PKeys) ⫹ wP ⫹ wG(Ginit ⁄ GKeys) ⫹ wC共Ginit ⁄ (Ginit ⫹ Gmin)兲 ⫹ wF(Finit ⁄ FKeys)2⁄3
wG(Ginit ⁄ GKeys) ⫹ wC共Ginit ⁄ (Ginit ⫹ Gmin)兲
⫽ ␨C
(Pinit ⁄ PKeys) ⫹ wP ⫹ wG(Ginit ⁄ GKeys) ⫹ wC共Ginit ⁄ (Ginit ⫹ Gmin)兲 ⫹ wF(Finit ⁄ FKeys)2⁄3 (36)
(Pinit ⁄ PKeys) ⫹ wP
⫽ ␨P ,
(Pinit ⁄ PKeys) ⫹ wP ⫹ wG(Ginit ⁄ GKeys) ⫹ wC共Ginit ⁄ (Ginit ⫹ Gmin)兲 ⫹ wF(Finit ⁄ FKeys)2⁄3

where Finit, Ginit, and Pinit were the initial values for body fat, ⌬CI
glycogen, and protein, respectively. Elementary algebra led to the ⌬T ⫽ ␭2 共1 ⫺ ␶T ⫹ ␶Texp(⫺1 ⁄ ␶T)兲 (42)
following parameter constraints required to achieve the specified EIb
macronutrient imbalance:
was the average value of the thermogenesis parameter, T, over 1 day
␨C ⁄ ␨P(Pinit ⁄ PKeys ⫹ wP)(GKeys ⁄ Ginit) and ⌬DNL was computed at the midpoint of the glycogen increment
wG ⫽ according to the following equation:
1 ⫹ wC:G共GKeys ⁄ (Ginit ⫹ Gmin)兲

冉 冊冉 冊冉 冊冉 冊
(37)
␨F ␨C Pinit FKeys 2⁄3
(CIb ⫹ ⌬CI)(1 ⫹ ⌬G ⁄ 2Ginit)d
wF ⫽ 1⫹ ⫹ wP , ⌬DNL ⫽ ⫺ DNLb . (43)
1 ⫺ ␨F ␨P PKeys Finit d
KDNL ⫹ (1 ⫹ ⌬G ⁄ 2Ginit)d
where wC:G ⫽ wC/wG. The change of the gluconeogenic rate, ⌬GNG, was given by

Carbohydrate Perturbation Constraint

The parameters wC and SC determined how the model adapted to
⌬GNG ⫽ ⫺⌫C 冉 冊
⌬CI
CIb
^
GNGP ⫹ ␳C
MTG 冉 冊 MG ^
DF[(AL ⫺ BL)
(44)
⫻ exp共⫺kL(1 ⫹ ⌬CI ⁄ CIb)兲 ⫹ BL ⫺ 1].
changes of carbohydrate intake. I specified that an additional dietary
carbohydrate intake, ⌬CI, above baseline, CIb, resulted in an initial The carbohydrate balance Eq. 1 and the carbohydrate oxidation Eq.
positive carbohydrate imbalance of ␬C⌬CI, where 0 ⬍ ␬C ⬍ 1 25 gave
specified the proportion of ⌬CI directed toward glycogen storage.
Thus, the glycogen increment was ⌬G ⫽ ␬C⌬CI/␳C. The goal was to CIb ⫹ (1 ⫺ ␬C)⌬CI ⫺ (DNLb ⫹ ⌬DNL)
solve for the parameter SC such that the correct amount of carbohy- fC ⫽ ~ . (45)
TEE
drate was oxidized and deposited as glycogen during short-term
carbohydrate overfeeding. Based on the carbohydrate overfeeding Since I assume that the baseline diet results in a state of energy
study of Horton et al. (48), I chose ␬C ⫽ 0.5 when ⌬CI ⫽ 1,500 balance, I obtained the following equation for TẼE:
kcal/day.
~
The change of TEE was given by TEE ⫽ EIb ⫹ ⌬TEE ⫺ (1 ⫺ ␧d)DNL ⫺ (1 ⫺ ␧k)KTG
(46)
⌬TEE ⫽ ⌬TEF ⫹ ⌬PAE ⫹ ⌬RMR (38) ⫺ KetOx ⫺ GNGF ⫺ GNGP ⫹ G3P.

For a carbohydrate perturbation, the perturbed energy expenditure For simplicity, I assumed that
components were G3P ⫽ G3Pb
KTG ⫽ KetOx ⫽ KTGb . (47)
⌬TEF ⫽ ␣C⌬CI (39)
⌬PAE ⫽ ␦bBWb␴⌬T (40) I define the parameter ⌰ as
␬ C␩ G CIb ⫹ (1 ⫺ ␬C)⌬CI ⫺ (DNLb ⫹ ⌬DNL)
⌬RMR ⫽ ⌬CI ⫹ ␥^ FFMFFMb(1 ⫺ ␴)⌬T ⌰⬅ . (48)
␳C ~
TEE
(41)
⫹ (1 ⫺ ␧d)⌬DNL ⫹ (1 ⫺ ␧g)⌬GNG,
Therefore, using Eq. 27, I solved Eq. 45 for SC, which gave the
where carbohydrate feeding constraint:

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E462 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE

SC ⫽
⌬CI
冋 ~
CIb ⌰(1 ⫹ wp ⫹ w ~
F ⫹ w G)
(1 ⫺ ⌰)wC
⫺
~
w G
(1 ⫺ ⌰)wC
册
⫺ 1 , (49)
Table 2. Parameter values fit to the Minnesota experiment
data
Parameter Value Description
where
␭1 0.74 Underfeeding adaptive thermogenesis
F ⫽ wF关 (AL ⫺ BL) ⫻ exp共 ⫺kL(1 ⫹ ⌬CI ⁄ CIb)兲 ⫹ BL兴
~
w ␭2

冉 冊
0.02 Overfeeding adaptive thermogenesis
~ ⌬G (50) ␴ 0.52 Thermogenesis effect on PAE vs. RMR
w G ⫽ wG 1 ⫹ . wP 1.1 Weighting of ProtOx for basal PI
2Ginit wC:G 0.93 Ratio of CarbOx weighting parameters
SP⫺ 1.7 Sensitivity of ProtOx to reduced PI
Protein Perturbation Constraint
See Glossary of Model Variables for definitions of the abbreviations.
The parameters wP and SP⫹ determined how the model adapted
short-term substrate oxidation rates to changes of protein intake. In a
meticulous study of whole body protein balance, Oddoye and Margen excreted such that ␬P ⫽ 0.1 when ⌬PI ⫽ 640 kcal/day, ⌬CI ⫽ ⫺310
(74) measured nitrogen balance in subjects consuming isocaloric diets kcal/day, and ⌬FI ⫽ ⫺330 kcal/day.
with moderate or high protein content. These studies found that ⬃90% To compute the value for SP⫹ to match the data of Oddoye and
of the additional dietary nitrogen on the high-protein diet was rapidly Margen (74), I began with the protein balance Eqs. 1 and 25 to derive
^
PIb ⫹ (1 ⫺ ␬P)⌬PI ⫺ GNGP ⫺ ⌬GNGP
fP ⫽ ~ , (51)
Table 1. Model parameters determined from published data TEE
where the changes of gluconeogenic rates were given by

冋 册
Parameter Value Description

␳F 9.44 kcal/g Energy density of F ^ ⌬PI ⌬CI

⌬GNGP ⫽ GNGP (⌫P ⫹ ␹) ⫺ ⌫C
␳P 4.7 kcal/g Energy density of P PIb CIb
␳G
␳K
hP
4.18 kcal/g
4.45 kcal/g
1.6 g H2O/g
Energy density of G
Energy density of ketones
P hydration coefficient
⌬GNGF ⫽ ⌬FI 冉 冊 冉 冊冋
␳ CM G
␳FMTG
⫹ ␳C
MG ^
MTG
DF (AL ⫺ BL) (52)
hG
␩F
␩P
2.7 g H2O/g
0.18 kcal/g
0.86 kcal/g
G hydration coefficient
F synthesis cost
P synthesis cost
⫻ exp ⫺kL 冉 冉 冊冊 册 1⫹
⌬CI
CIb
⫹ BL ⫺ 1 .
εP 0.17 kcal/g P degradation cost
␩G 0.21 kcal/g G synthesis cost The change of TEE was given by
␩N 5.4 kcal/g Urea synthesis cost/g nitrogen ⌬TEE ⫽ ⌬TEF ⫹ ⌬PAE ⫹ ⌬RMR, (53)
εd 0.835 DNL efficiency
εg 0.8 GNG efficiency where
εk 0.81 KTG efficiency
␣F 0.025 TEF factor for FI ⌬TEF ⫽ ␣C⌬CI ⫹ ␣F⌬FI ⫹ ␣P⌬PI, (54)
␣C 0.075 TEF factor for CI
␣P and

冉 冊
0.25 TEF factor for PI
␥F 4.5 kcal 䡠 kg⫺1 䡠 day⫺1 Specific RMR for adipose ␩P
^
␳P␹DP
␥ˆ FFM 19 kcal 䡠 kg⫺1 䡠 day⫺1 Basal specific RMR for FFM ⌬RMR ⫽ ⌬PI ␬P ⫹ ⫹ (1 ⫺ ␧g)(⌬GNGF
␰BW 0.16 ECF response to BW changes ␳P PIb (55)
␰CI 4000 mg/day ECF response to CI changes ⫹ ⌬GNGP) ⫹ (1 ⫺ ␧d)⌬DNL.
␰Na 3 mg 䡠 ml⫺1 䡠 day⫺1 ECF response to sodium changes
␶BW 1,000 days ECF response time for BW changes Since the perturbed diet was isocaloric and there were no changes
␶T 7 days Response time for T changes of physical activity,
D̂g 180 g/day Baseline glycogenolysis rate
KDNL 2 Glycogen constant for DNL ⌬PAE ⫽ ⌬T ⫽ 0. (56)
d 4 Hill coefficient for DNL
D̂F 140 g/day Baseline lipolysis rate I also assumed that
AL 3.8 Maximum lipolysis change G3P ⫽ G3Pb
BL 0.9 Minimum lipolysis change
␶L 1.44 days Response time for lipolysis KTG ⫽ KetOx ⫽ KTGb (57)
KL 4 Body fat constant for lipolysis
SL 2 Hill coefficient for lipolysis
␺ 0.4 PA effect on lipolysis Table 3. Parameter values determined from constraints on
AK 0.8 Maximum KTG fraction energy balance, nutrient balance, and physical inactivity as
kP 0.69 Effect of PI on KTG well as perturbations of dietary protein and carbohydrate
kG 0.69 Effect of G on KTG
KK 1 Sets basal KTG rate Parameter Value Description
KTGthresh 70 g/day Renal threshold KTG rate
KUmax 20 g/day Maximum ketone excretion SP⫹ 3.8 Sensitivity of ProtOx to increased PI
KTGmax 400 g/day Maximum KTG SC 0.85 Sensitivity of CarbOx to CI changes
D̂P 300 g/day Baseline proteolysis rate wG 9.4 Weighting of CarbOx for glycogenolysis
␹ 0 Effect of PI on protein turnover wF 14.8 Weighting of FatOx for lipolysis
GN̂GP 300 kcal/day Basal GNGP rate Ec ⫺435 kcal/day Constant energy expenditure offset
⌫C 0.39 Effect of CI on GNGP
⌫P 0.32 Effect of PI on GNGP See Glossary of Model Variables for definitions of the abbreviations. Other
␶PI 1.1 days Response time of ProtOx to PI changes than the constant values for SC and SP⫹, these parameters are calculated
according to the initial conditions corresponding to different subject groups.
See Glossary of Model Variables for definitions of the abbreviations. The values listed are for the average Minnesota experiment subject.

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 MODEL OF HUMAN METABOLISM AND BODY WEIGHT CHANGE E463
and that glycogen would change by approximately ⌬G ⬇ ␬C ⌬CI/␳C, the sum of squares of weighted residuals between the simulation
thereby altering DNL as follows: outputs and the data from the Minnesota human starvation experiment
(55). I used the following measurement error estimates to define the
(CIb ⫹ ⌬CI)(1 ⫹ ⌬G ⁄ Ginit)d CIb
⌬DNL ⫽ ⫺ . (58) weights for the parameter optimization algorithm: ⌬BW ⫽ 0.2 kg,
d
KDNL ⫹ (1 ⫹ ⌬G ⁄ Ginit)d d
KDNL ⫹1 ⌬FM ⫽ 0.5 kg, and ⌬RMR ⫽ 50 kcal/day. The best fit parameter
values are listed in Table 2, and the constrained parameters are listed
Using Eq. 27, I solved Eq. 51 for SP, which gave the following in Table 3.
constraint:

SP⫹ ⫽
⌬PI
冋
~
PIb ⌽(w ~ ~
F ⫹ w G ⫹ w C)
(1 ⫺ ⌽)wP
⫺
(1 ⫹ ␹⌬PI ⁄ PIb)
wP
册
⫺ 1 , (59)
ACKNOWLEDGMENTS
I thank Dympna Gallagher, Susan Jebb, Peter Murgatroyd, Eric Ravussin, Bill
Rumpler, and Steve Smith for insightful discussions and access to their data.
where ⌽ was defined as
^ GRANTS
PIb ⫹ (1 ⫺ ␬P)⌬PI ⫺ GNGP ⫺ ⌬GNGP
⌽⬅ ~ (60) This research was supported by the Intramural Research Program of the
TEE National Institutes of Health/National Institute of Diabetes and Digestive and
Kidney Diseases.
and
DISCLOSURES
F ⫽ wF关 (AL ⫺ BL) ⫻ exp共 ⫺kL(1 ⫹ ⌬CI ⁄ CIb)兲 ⫹ BL兴
~
w
~ No conflicts of interest are declared by the author.
w C ⫽ wC(1 ⫹ SC⌬CI ⁄ CIb) (61)
~
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