Modeling of lipid and protein depletion

during total starvation

Michel Caloin
Centre dEcologie et Physiologie Energetiques, Centre National de la
Recherche Scientique/Unite Propre de Recherche 9010, 67087 Strasbourg, France
Submitted 11 September 2003; accepted in nal form 21 May 2004
Caloin, Michel. Modeling of lipid and protein depletion during
total starvation. Am J Physiol Endocrinol Metab 287: E790E798,
2004. First published May 27, 2004; 10.1152/ajpendo.00414.2003.
This study presents a model describing lipid and protein depletion of
an individual facing total starvation. The model distinguishes two
compartments of body mass: a metabolic compartment and a struc-
tural compartment. It is considered that the lipids and the proteins of
the metabolic compartment ensure the totality of physiological func-
tions. The main assumptions of the model lie in the denitions of lipid
mass and protein mass of the metabolic compartment, which are
related to total lipid mass and total body mass, respectively. Under
these assumptions, for a given individual, the ratio of lipid and protein
utilization rates is proportional to the adiposity. The model accounts
for the protein sparing observed at high adiposity levels and enables
us to discuss the individuals survival in relation to the levels of lipid
and protein depletion. The time course of changes in lipid and protein
depletion rates can be calculated by introducing the energy expendi-
ture of the individual. In simulations, it was assumed that specic
energy expenditure was constant during starvation and that mortality
occurred at a critical level of protein depletion. The most character-
istic results derived from these simulations concern the kinetics of
protein depletion, which depend markedly on initial adiposity. Ac-
cordingly, in obese subjects, the rate of protein losses remains fairly
constant during fasting, whereas it increases from the onset of the fast
in lean subjects, in agreement with experimental observations. In the
model, protein and lipid depletion rates are both proportional to
energy expenditure, which needs to be conrmed from complemen-
tary data.
body composition; protein sparing; energy expenditure
DURING TOTAL STARVATION, the energy required to maintain
physiological functions is derived from the oxidation of body
lipids and proteins, because glycogen stores are exhausted at
the onset of fasting (3). Lipids, however, represent the main
energy source. They have a high energy density and can be
almost entirely depleted to cover maintenance requirements
(45, 49). By contrast, proteins, which have a much lower
energy density, can be only partly depleted due to their vital
enzymatic, mechanical, and structural roles. Accordingly, their
contribution to energy demand is rather modest (17, 28, 33,
37). The result is that, conversely to lipid catabolism, protein
catabolism is not clearly related to energy production and
remains essentially unexplained (27). It could be attributed to
gluconeogenesis, which converts proteins into glucose to meet
the glucose requirements of the brain after the exhaustion of
glycogen stores (2, 4). However, this hypothesis is unlikely,
given the large variability in the rate of protein depletion
among individuals (14, 16, 36). To better understand the
physiological basis for protein catabolism and its consequences
for the survival of individuals, many studies have intended to
quantify protein losses during starvation. They have succeeded
in pointing out characteristic trends that were observed in
humans as well as in animals, fasting spontaneously or sub-
mitted experimentally to food deprivation.
From changes in protein metabolism, three phases can be
distinguished during a fast (see Ref. 41 for review; also Refs.
20, 32, 34, 43). The rst phase (phase I) corresponds to a phase
of transition between the fed state and starvation, during which
the individual nishes utilizing diet-derived energy. This tran-
sient phase is relatively short, between several hours and
several days, depending on the individual. It is characterized by
a rapid decrease in daily protein losses, usually measured from
nitrogen excretion. Throughout the following phase (phase II),
daily protein losses remain approximately constant. The dura-
tion of this phase depends on the initial lipid mass and was
shown to last for several months in obese individuals (8, 43).
At the end of phase II, protein utilization increases, which is
reected by a rise in nitrogen excretion (20, 34). This feature,
characterizing the entrance to the terminal phase of the fast
(phase III) is always very brief, since the important daily
protein losses lead shortly to the death of the individual. It must
be noted that this last phase is not systematically observed (22,
41). It seems to have never been observed in obese subjects (33).
One of the most fundamental results, pointed out by Voit
(48) at the beginning of the last century and later conrmed in
many studies, is that, for the same body mass, the level of
nitrogen excretion during phase II depends on the initial
adiposity of the individual. The higher the initial adiposity is,
the lower the nitrogen excretion will be (9, 15, 18, 20, 25, 35).
This relationship between protein losses and adiposity could be
a determining factor for survival, because it enables the indi-
vidual to spare its proteins in the case of a prolonged fast. The
mechanism of this protein sparing, however, has not yet been
entirely elucidated.
The rst modeling approach describing the response of an
individual to changes in energy balance was proposed by
Payne and Dugdale (39, 40). The model postulates the exis-
tence of an internal control of lipid and protein utilization
processes. The basic assumption is that the ratio of the rates of
lipid and protein mobilization during starvation, which is
supposed to be equal to the ratio of the rates of lipid and protein
deposition during refeeding, is an individual characteristic. Its
value is constant within the same individual but varies between
Address for reprint requests and other correspondence: M. Caloin, Centre
dEcologie et Physiologie Energetiques, 23 rue Becquerel, 67087 Strasbourg
Cedex 2, France (E-mail: michel.caloin@c-strasbourg.fr).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked advertisement
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Am J Physiol Endocrinol Metab 287: E790E798, 2004.
First published May 27, 2004; 10.1152/ajpendo.00414.2003.
0193-1849/04 $5.00 Copyright 2004 the American Physiological Society http://www.ajpendo.org E790
individuals. In a recent study, Dulloo and Jacquet (14) ana-
lyzed the interindividual variability of this ratio, which could
be explained from the sizes of both lipid and protein reserves.
However, the basic assumption of the model implies that the
lipid and protein depletion rates vary similarly during starva-
tion, which is not compatible with the marked rise in protein
catabolism measured at the end of fasting in lean subjects
(9, 20).
The present study suggests an alternative approach, which
does not assume a constant ratio in the rates of lipid and protein
utilization. The proposed model distinguishes two compart-
ments of the body mass, a metabolic compartment and a
structural compartment. It is considered that the lipids and the
proteins of the metabolic compartment ensure the totality of
physiological functions of the individual. The particularity of
the model lies on an attempt of quantication of lipid and
protein masses of the metabolic compartment, which are re-
lated to total lipid mass and total body mass, respectively.
Under the assumptions of the model, for a given individual, the
ratio of the lipid and protein utilization rates is proportional to
the adiposity of the individual. Therefore, this ratio depends on
body composition and varies during fasting. The model has
been developed with the main objective of describing quanti-
tatively the effect of initial adiposity and energy expenditure on
lipid and protein depletion. In the course of the study, the
predictions of the model are discussed in relation to some of
the most characteristic data previously reported.
DESCRIPTION OF THE MODEL
The model is developed at the whole body level, and no
distinction is made between the various lipid and protein
sources. Phase I of fasting is excluded from this study, since
during this initial period the individual nishes utilizing its
food stores. During total starvation, the body mass is consid-
ered as having two compartments, a metabolic compartment
and a structural compartment. The metabolic compartment
represents the proteins and the lipids, which, at a given time of
fasting, are involved in the biochemical processes ensuring the
whole physiological homeostasis. The structural compartment
is constituted by the other components of the body mass. It
includes in particular the proteins and the lipids that, in the
course of the fast, will be transferred into the metabolic
compartment to supply the substrates required for the mainte-
nance of the physiological functions.
The model is based on the following three assumptions.
1) The lipid mass of the metabolic compartment, L
m
, is
proportional to the total lipid mass, L, so that
L
m
L (1)
where is a constant for a given individual.
2) The proteins of the metabolic compartment govern the
totality of physiological functions of the individual. It is
considered that their mass, P
m
, is proportional to the total body
mass, M, so that
P
m
M (2)
The coefcient is also assumed to be constant for a given
individual.
3) The energy required to maintain physiological functions
is provided by the oxidation of the lipids and proteins of the
metabolic compartment. The proportion of substrates oxidized
is considered to reect the composition of the metabolic
compartment. This can be expressed by the relationship
dL
m
/dP
m
L
m
/P
m
(3)
where dL
m
and dP
m
represent the lipid and protein losses of
the metabolic compartment. Excluding any nitrogen recy-
cling during fasting, which up to now has been observed
only in bears during hibernation (38), the oxidized sub-
strates are eliminated from the organism. Therefore, the
lipid and protein losses of the total body mass, dL and dP
respectively, are equal to the lipid and protein losses of the
metabolic compartment, so that
dL dL
m
and dP dP
m
(4)
Combining relationships Eqs. 1-4, one obtains the basic
equation of the model
dL/dP l/ (5)
where l L/M is the adiposity, and / is a constant
characteristic of the individual. According to this relationship,
the relative parts of lipids and proteins used during fasting vary
with the adiposity of the individual.
In the following sections, it is rst demonstrated that Eq.
5 may account for characteristic data collected in fasting
birds or mammals, indicating that the proportion of energy
derived from protein at the beginning of starvation is mainly
dependent on initial adiposity. This analysis leads to an
estimate of the coefcient, which is the only characteristic
parameter of the model. On the basis of Eq. 5, it is then
shown that, for a given individual, the changes in lipid and
protein masses during starvation can be related to the
change in adiposity. A relationship between the initial and
nal adiposity and the level of protein depletion is deduced,
which could explain the differences in body composition
observed between individuals at the end of starvation. In the
last section, a kinetic extension of the model is derived by
introducing the energy expenditure of the individual. In this
extension, it will be assumed that specic energy expendi-
ture is constant during fasting. This assumption enables one
to calculate the time course of change in adiposity and,
subsequently, to express the changes in lipid and protein
masses as a function of time.
APPLICATIONS
Protein Sparing in Relation to Initial Adiposity
One of the most characteristic results emphasized in pioneer
studies is the relationship between the rate of protein depletion
and the adiposity of the individual. For a given body mass, the
daily protein loss during phase II is inversely related to the
initial adiposity. Therefore, a high level of lipid stores enables
the individual to spare its protein during starvation.
To compare the effect of initial adiposity on protein losses
between individuals or species, the effectiveness of protein
sparing is generally expressed in terms of the P
R
ratio dened
as the contribution of protein to energy production (13), so that
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P
R
c
P
dP/c
L
dL c
P
dP (6)
where c
L
and c
P
are the energy equivalents of lipids and
proteins, 39.3 and 17.8 kJ/g, respectively (45). It was found
that the experimental values of this ratio varied only slightly
during phase II (26, 33). The data in Fig. 1, collected by Jenni
and Jenni-Eiermann (27), present the P
R
values determined at the
beginning of phase II or during phase II as a function of the initial
adiposity of individuals. Cherel and Groscolas (7) proposed a
similar compilation, which exhibits the same experimental trends.
Although these data are related to various animal species and
concern active as well as inactive fasting individuals, it appears
that the P
R
values in phase II depend markedly on the initial
adiposity: they decrease when the initial adiposity increases. This
result can be discussed using the model.
Taking into account Eq. 5, the P
R
ratio (Eq. 6) can be written
as
P
R
c
P
/c
L
l c
P
(7)
This equation relates P
R
to the adiposity for a given value.
Due to the short duration of phase I, the adiposity at the
beginning of phase II does not differ signicantly from the
initial adiposity l
i
. Therefore, the contribution of protein to
energy production during phase II, P
R2
, which is expected to be
similar the P
R
value at the beginning of phase II, can be
estimated using the relationship
P
R2
c
P
/c
L
l
i
c
P
(8)
According to Eq 8, P
R2
is mainly dependent on the initial
adiposity of the individual and on the value of the coefcient.
The curves in Fig. 1 illustrate Eq. 8 for three values of : 2.5,
4.5, and 6.5 10
2
. It can be observed that the upper and
lower curves envelop most of the data and that the middle
curve describes the general trend of experimental variation. It
should be pointed out that the large dispersion of data could
reect the inaccuracy in the determinations of protein and lipid
losses and/or initial adiposity. It could also be attributed to
interindividual or interspecies variability in the coefcient,
which cannot be assessed from this small number of data. On
the basis of this analysis, the value used in the rest of this
study will be set at the intermediate value of 4.5 10
2
. In the
model, the reduction in the P
R
values at high levels of initial
adiposity is due to the higher dilution of proteins by lipids in
the metabolic compartment.
Lipid and Protein Masses as a Function of Adiposity
Neglecting glycogen stores, which represent usually 1% of
fuel stores and are depleted at the onset of fasting, (3, 23, 30,
45), the total body mass during starvation can be described by
M WP L R (9)
where W, P, L, and R are the masses of water, proteins, lipids,
and minerals, respectively.
The mass of minerals, generally measured by the mass of
ashes after complete combustion, represents 4% of body
mass in fed individuals. Previous studies have shown that the
mass of minerals varies only slightly during fasting (6, 9, 47).
On the basis of these results, it will be assumed that the mass
of minerals is constant during a fast and that it can be estimated
by R r
i
M
i
, where M
i
is the initial body mass and r
i
is the
proportion of minerals in initial body mass. Because phase I is
excluded from this study, in the following developments the
initial values of the variables will correspond to the values of
these variables at the beginning of phase II.
Because water is relatively insoluble in lipids, body water is
essentially associated with proteins. The hydration coefcient
of proteins, dened by w W/P, ranges generally between 2.5
and 3.5. It varies between individuals and species (19). For a
given individual, it also varies between organs. Thus muscle
proteins, preferentially mobilized during fasting (21, 23, 46),
have higher water content than proteins constitutive of the
skeleton. Therefore, it can be expected that the hydration
coefcient will decrease in the course of fasting. Such a
decrease, however, is low in king penguins (6) and is not
signicant in rats or petrels (9, 24). Accordingly, in this
approach the hydration coefcient will be considered constant
during starvation.
Under these two assumptions, R and w constant during
fasting, Eq. 9 can be written as
M hP L r
i
M
i
(10)
with h 1 w. At the onset of the fast, the protein mass,P
i
,
calculated from Eq. 10, is given by
P
i
M
i
1 l
i
r
i
/h (11)
During fasting, the changes in the masses of the different
components can be related by differentiating Eq. 10, which
gives
dM h dP dL (12)
For a given change in total body mass, dM, the changes in
lipid and protein mass, dL and dP, cannot be calculated from
Eq. 12 alone; it is necessary to introduce a complementary
relationship between these components. In the model, such a
relationship is given by Eq. 5. Taking this equation into
Fig. 1. Contribution of protein to energy production in phase II as a function
of initial adiposity of individuals. Data are from Jenni and Jenni-Eiermann
(27). Continuous lines were calculated by Eq. 8 for 3 values: 0.025 (curve 1),
0.045 (curve 2), and 0.065 (curve 3). Parameter values: cL 39.3 kJ/g, cP
17.8 kJ/g.
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account, the change in lipid mass during fasting can be related
to the change in adiposity by the relationship (see APPENDIX A)
L L
i
Cl
i
Fl M
i
l
i
Cl
i
Fl (13a)
where C(l
i
) [(a l
i
)/l
i
]

and F(l) [l/(a l)]

. The
coefcients a 1 h and 1/a are constants for a given
individual. Total body mass and protein mass are then simply
calculated as
M L/l (13b)
and
P ML r
i
M
i
/h (13c)
Throughout this study, the parameter values will be taken as
r
i
0.04, h 4, and 0.045. One deduces that a 0.82 and
1.22.
According to Eq. 13, ac, the masses of the different
components are proportional to the initial body mass. The
result is that, for a given individual, the change in the M/M
i
,
L/M
i
, and P/M
i
ratios during fasting are only dependent on the
change in adiposity. Figure 2, A and B presents the variations
of these ratios for two values of initial adiposity, 10 and 45%.
They are independent of the energy expenditure of the indi-
vidual.
The validity of the preceding relationships was examined
using data obtained by Robin et al. (44) and presented in
Fig. 3, A and C. They illustrate the changes in protein and
lipid mass as a function of total body mass in emperor
penguins during a 4-mo fast. The mean body mass of
individuals was 38 kg at the beginning of the fast and 18
kg at the end of the fast. Their initial adiposity was close to
30%. Experimental data clearly show two phases. In the rst
phase, for body mass values between 38 and 25 kg, lipid and
protein masses decreased linearly with total body mass. In
the second phase, mass loss increased for proteins, and it
decreased for lipids. Figure 3, B and D present the theoret-
ical variations calculated from Eq. 13, ac. There is good
agreement with the experimental trends. It can be noted that
the phase of linear decrease was also observed in other
species, in particular in the great-winged petrel (24) and in
the European hedgehog (5). However, the second phase did
not appear in these studies, for the fast was stopped before
the entrance in the terminal phase.
Survival of Individuals in Relation to Levels of Lipid and
Protein Depletion
When mortality occurs at the end of a fast, lipid depletion
generally exceeds 80%, whereas protein losses represent
50% of initial protein mass. Because lipids constitute the
main energy store, a good estimate of the duration of survival
can be obtained from initial lipid mass, converted into energy
units, and daily energy expenditure measured at the onset of
starvation (45).
However, fundamentally, the relationship between the dura-
tion of survival and lipid exhaustion is not clearly established.
Indeed, in some experiments death occurred before all of the
lipid stores had been fully used. Thus, in obese rats having an
initial adiposity of 45%, adiposity was still 25% when death
occurred, whereas lean rats with an initial adiposity of 10%
could deplete their lipid stores almost entirely and survive a
2-wk fast (9). These results support the assumption that mor-
tality is not necessarily associated with lipid exhaustion but
results from a critical level of protein depletion leading to an
irreversible alteration of physiological functions (17, 33, 37).
This assumption can be discussed in the framework of the
model.
Let P
i
and P
f
designate the initial and nal protein masses.
The corresponding level of protein depletion, d, is dened by
d P
i
P
f
/P
i
(14)
For a given individual, the change in protein mass during
fasting is related to the change in adiposity (Fig. 2, A and B).
The result is that the adiposity at the end of the fast can be
calculated from the initial adiposity of the individual and the
level of protein depletion. This calculation is addressed in
APPENDIX B. It is illustrated in Fig. 4, which presents the nal
adiposity as a function of the initial adiposity for three levels of
protein depletion. It can be observed that a level of protein
depletion ranging between 30 and 35% accounts for the results
reported in both lean and obese rats, since the nal adiposity
calculated using Eq. B3 is 2% in lean rats and 2226% in
Fig. 2. M/Mi, L/Mi and P/Mi ratios with adiposity
during fasting, calculated from Eq. 13, ac, for 2
levels of initial adiposity: A, 10%; B, 45%. Param-
eter values: ri 0.04, h 4, 0.045.
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obese rats. Therefore, the difference in the residual adiposity
measured between lean and obese rats at the end of the fast
could be explained by the existence of a critical level of protein
depletion. This assumption will be retained in the rest of this
study. However, it needs to be discussed more accurately from
complementary data.
Kinetics of Lipid and Protein Depletion
A kinetic extension of the model can be achieved by intro-
ducing the energy expenditure of the individual. Because
during starvation the energy needs are met by the oxidation of
lipids and proteins, the energy expenditure E is related to the
lipid and protein depletion rates by the relationship
E c
L
dL/dt c
P
dP/dt (15)
Therefore, by combining Eqs. 5 and 15 the lipid and protein
depletion rates can be expressed as
dL/dt lE/c
L
l c
P
(16a)
and
dP/dt E/c
L
l c
P
(16b)
They vary during starvation with the adiposity and the energy
expenditure of the individual.
Energy expenditure is not constant during fasting. In
particular, it varies with the change in the body mass of the
individual. For this reason, it is usually expressed in terms
of specic energy expenditure , dened as E/M. Some
studies have characterized the change in the value during
fasting. However, the results are not all concordant; they
may differ according to the experimental situations (10).
Thus, in king penguins, specic energy expenditure was
found to remain approximately unchanged in the course of
the fast (10, 31), whereas it increased slightly in emperor
penguins (12) or decreased slightly in domestic geese (34).
In this study, it will be considered that specic energy
expenditure is constant during fasting, so that
E/ME
i
/M
i

i
(17)
where E
i
is the initial energy expenditure and
i
is the initial
specic energy expenditure. Under this assumption, Eq. 16, a
and b can be written as
Fig. 3. Changes in lipid and protein masses with total
body mass during prolonged fasting in emperor pen-
guins. A and C: experimental data [from Robin et al.
(44)]. B and D: curves calculated by Eq. 13, ac, with the
initial values Mi 38 kg and li 0.3. Parameters are the
same as for Fig. 2.
Fig. 4. Final adiposity as a function of initial adiposity for 3 levels of protein
depletion (30, 35, and 40%). Theoretical curves were calculated using Eq. B3.
Parameters are the same as for Fig. 2.
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dL/dt
i
L/c
L
l c
P
(18a)
and
dP/dt
i
M/c
L
l c
P
(18b)
It follows from Eqs. 13 and 18 that lipid and protein
depletion rates are proportional to
i
and M
i
and depend on the
initial adiposity of the individual and on its adiposity during
fasting. Therefore, their time dependence is only governed by
the time dependence of adiposity, which can be derived from
Eqs. A3 and 18a (see APPENDIX C) and is given by the relation-
ship
t 1/
i
C
1
log
e
a l/a l
i
C
2
log
e
l
i
/l (19)
where a 1 h, C
1
c
L
c
P
/a and C
2
c
P
/a. It is
illustrated in Fig. 5 for two values of initial adiposity and specic
energy expenditure. In these simulations, the nal level of protein
depletion is 40%. According to Eq. 19, the effect of a change in
the
i
value on the time dependence of adiposity can be taken into
account by a change in the time scale, the ratio of the time scales
being inversely proportional to the ratio of the specic energy
expenditures.
Calculation of kinetics of lipid and protein depletion. For a
set of initial values M
i
, l
i
, and
i
, lipid and protein depletion rates
are rst calculated as a function of adiposity using Eqs. 13 and 18.
They are then expressed as a function of time using Eq. 19.
In most fasting experiments, rough experimental data con-
cern daily body mass loss and daily nitrogen loss, which can be
measured continuously during starvation with noninvasive
methods. These data can be simply derived from the preceding
calculations, as total body mass loss is related to lipid and
protein mass losses by Eq. 12, and nitrogen mass loss can be
deduced from protein mass loss by considering that 6.25 g of
protein contain 1 g of nitrogen (45).
Effect of initial adiposity on kinetics of lipid and nitrogen
depletion. Kinetics of daily nitrogen excretion and daily body
mass loss measured in fasting lean and obese rats (9) were
compared with the simulations of the model. This comparison
is presented in Fig. 6. The theoretical curves were calculated
using the initial values M
i
250 g and l
i
0.1 for lean rats,
and M
i
500 g and l
i
0.45 for obese rats. The specic
energy expenditure,
i
, which was not measured experimen-
tally, was set in the simulations to account approximately for
the level of nitrogen excretion in phase II (0.30 and 0.27
kJ g
1
day
1
for lean and obese rats, respectively). In Fig. 6,
B and D, the nal level of protein depletion was 30% for the
continuous lines and 40% for the dashed lines.
At the beginning of the fast, experimental curves (Fig. 6, A
and C) show a phase of rapid decrease in daily nitrogen
excretion and daily body mass loss. As mentioned in the
presentation of the model, this phase, which corresponds to the
transition between fed state and starvation (phase I) is not taken
into account in this analysis. If one excludes this initial phase,
it can be observed that the curves calculated using the same
parameter values (Fig. 6, B and D) describe satisfactorily the
experimental data for both lean and obese rats. In particular,
the level of nitrogen excretion (Fig. 6B) remains approximately
constant in obese rats, whereas it increases from the onset of
fasting in lean rats.
The effect of initial adiposity on the kinetics of lipid and
nitrogen depletion is presented more specically in Fig. 7. The
different curves correspond to four levels of initial adiposity,
10, 20, 30, and 45%. They were calculated for the same initial
values of body mass and specic energy expenditure (M
i
1
kg and
i
0.3 kJ g
1
day
1
). In this analysis, the initial M
i
and
i
values may be chosen arbitrarily, since a modication in
the M
i
value can be accounted for by a change in the scale of
the y-axis (Eqs. 13 and 18) and a modication in the
i
value
by a change in the scale of both axes (Eqs. 18 and 19). As
expected, for the same protein depletion, the duration of fasting
increases with the initial adiposity of individuals. In Fig. 7A, it
can be noted that, at the beginning of starvation, daily lipid
losses depend only slightly on initial adiposity. For the four
levels of initial adiposity, the rate of lipid depletion decreases
almost linearly with time, but the decrease is much more
pronounced at the low l
i
values. However, the most character-
istic results are related to daily nitrogen losses (Fig. 7B). In
accord with the protein-sparing process discussed in the rst
section, daily nitrogen losses at the beginning of fasting de-
crease when initial adiposity increases. For levels of initial
adiposity 30%, the rate of nitrogen depletion remains ap-
proximately unchanged during fasting, but it increases progres-
sively with time at the lower levels of initial adiposity. There-
fore, conversely to what was suggested by Goodman et al. (20),
the nal rise in nitrogen excretion observed in lean subjects
does not necessarily reect a change in the regulatory controls
of protein metabolism. In the model, it could result from the
increase in the protein to lipid ratio of the metabolic compo-
nent, due to the exhaustion of lipid stores.
Effect of energy expenditure on kinetics of lipid and protein
depletion. According to Eq. 16, a and b, lipid and protein
depletion rates are proportional to energy expenditure. The
proportionality between lipid depletion rate and energy expen-
diture is expected, at least qualitatively, since lipids are the
main energy source during the major part of the fast. In
contrast, due to the low contribution of proteins to energy
production, the rate of protein depletion is not necessarily
Fig. 5. Time course of change in adiposity during fasting, calculated by Eq. 19
for 2 values of initial adiposity (10 and 45%) and 2 values of specic energy
expenditure: 0.3 kJ g
1
day
1
(curves 1); 0.6 kJ g
1
day
1
(curves 2). In
these simulations, the nal level of protein depletion is 40%. Parameter values:
ri 0.04, h 4, 0.045, cL 39.3 kJ/g, cP 17.8 kJ/g.
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related to energy expenditure, and the validity of Eq. 16b needs
to be assessed.
To date, only one study (5) analyzed the effect of a reduction
in energy expenditure on lipid and protein depletion rates. In
that study, lipid and protein losses were measured in two
groups of hedgehogs, one group being maintained at the
constant temperature of 20C (shallow hypothermal fast) and
the second one being transferred at 5C (deep hypothermal
fast). The energy expenditure was 2.4 times lower in shal-
low- than in deep-hypothermal fasting hedgehogs. This study
concluded that there was a similar dependence of lipid and
protein losses with energy expenditure, which agrees with
Eqs. 16.
In the case of an increase in energy demand, the data from
the literature are less accurate due to the complexity of exper-
imental approaches. Studies have been carried out in birds
fasting in the cold or during migration, which are generally
considered sustained periods of starvation. Their metabolic
requirements were two or more times those of inactive birds
fasting at thermoneutrality (1, 29, 42). The few data reported
on migrating birds suggested proportionality between lipid and
protein losses and energy expenditure (see Ref. 27), which also
agrees with Eqs. 16. However, in the case of cold-stressed
birds, the results are contradictory, as Klaassen and Biebach
(29) reported a similar increase in lipid and protein catabolism,
whereas Thouzeau et al. (47) concluded that there was an
increase in lipid catabolism without signicant change in
protein catabolism. Complementary data are therefore required
to specify this effect.
CONCLUSION
The model presented here attempts to describe the changes
in the rates of lipid and protein depletion during starvation. The
basic equation of the model stipulates that during fasting, the
ratio of lipid and protein depletion rates is proportional to the
adiposity of the individual. The coefcient of proportionality,
, is the only characteristic parameter of the model. The model
accounts for the change in the contribution of proteins to
energy production with the initial adiposity of the individual. It
enables discussing the survival of individuals in relation to the
level of lipid and protein depletion. Thus it was shown that in
lean and in obese subjects, mortality could be associated to a
Fig. 6. Time course of changes in daily nitrogen
loss and daily body mass loss in lean and obese
fasting rats. A and C: experimental data [redrawn
with permission from Cherel et al. (9), Springer-
Verlag, 1992]. B and D: curves calculated using
Eqs. 13, 18, and 19 (see text) with initial values
Mi 250 g, li 0.1, i 0.30 kJ g
1
day
1
for
lean rats, and Mi 500 g, li 0.45, i 0.27
kJ g
1
day
1
for obese rats. Final level of protein
depletion is 30% for continuous lines and 40% for
dashed lines. Parameters are the same as for Fig. 5.
Fig. 7. Time course of changes in daily lipid loss and daily nitrogen loss
during fasting for 4 levels of initial adiposity (10, 20, 30, and 45%). Ccurves
were calculated using Eqs. 13, 18, and 19 (see text) with initial values Mi
1 kg and i 0.3 kJ g
1
day
1
. Final level of protein depletion is 30% for
continuous lines and 40% for dashed lines. Parameters are the same as for
Fig. 5.
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critical level of protein depletion. These above results are
independent of the energy expenditure of the individual.
The kinetics of lipid and protein losses can also be calculated
from the model by introducing energy expenditure. They are
found to be mainly dependent on initial adiposity and energy
expenditure. In the simulations, it was considered that specic
energy expenditure was constant during fasting, and that mor-
tality occurred for a critical level of protein depletion. From the
results relative to daily protein losses, it was shown that the
observation of phases II and III of fasting described in previous
studies depends essentially on the initial adiposity of the
individual. For levels of adiposity higher than 30%, the rate of
protein depletion remains approximately constant over all the
duration of the fast. Only phase II is observed. By contrast, for
levels of adiposity less than 20% the rate of protein depletion
increases from the onset of fasting, reecting a rapid entrance
in phase III. In the model, the rates of lipid and protein
depletion are both proportional to energy expenditure, which
cannot be conrmed from the data presently available. Com-
plementary experiments associating measurements of body
composition, nitrogen excretion and energy expenditure will be
required to specify the validity of the model, which could
constitute a simple framework to compare quantitatively the
response to fasting between individuals and species.
APPENDIX A
Change in lipid mass as a function of the change in adiposity.
Using the basic equation of the model (Eq. 5), the change in total body
mass during fasting (Eq. 12) can be written as
dM h l/ldL (A1)
On the other hand, differentiation of the l L/M ratio leads to the
relationship
dM dL/l L dl/l
2
(A2)
Combining Eqs. A1 and A2, one obtains the differential equation
dL/L 1/1 h ldl/l (A3)
which relates the change in lipid mass to the change in adiposity.
Integration of this equation gives (see Ref. 11)
L Cl/a l

(A4)
where a 1 h and 1/a are constants for a given individual.
C is the constant of integration, which can be determined by intro-
ducing the initial condition L L
i
for l l
i
APPENDIX B
Relationship between change in adiposity and level of protein
depletion. The protein mass at the end of the fast, P
f
, can be calculated
from the initial protein mass and the level of protein depletion.
Combining Eqs. 11 and 14 yields
P
f
M
i
1 l
i
r
i
1 d/h (B1)
Using Eq. 13, a-c, P
f
can also be expressed as
P
f
M
i
Cl
i
Fl
f
1 l
f
l
i
/l
f
r
i
/h (B2)
where l
f
is the nal adiposity. Identication of Eqs. B1 and B2 leads
to the equation
Cl
i
Fl
f
1 l
f
l
i
/l
f
1 l
i
1 d r
i
d 0 (B3)
which relates initial adiposity, nal adiposity, and the level of protein
depletion.
APPENDIX C
Time course of change in adiposity during fasting. On the assump-
tion that specic energy expenditure is constant during fasting, the
change with time in adiposity can be calculated by combining Eqs. A3
and 18a, which leads to the differential equation
c
L
l c
P
dl/l1 h l
i
dt (C1)
On the right side of this equation, the minus sign corresponds to the
fact that Eq. 18a describes the kinetics of lipid losses. This preceding
equation can be integrated analytically (see Ref. 11). Introducing the
initial condition l l
i
for t 0, one obtains the time dependence of
adiposity given in Eq. 19.
ACKNOWLEDGMENTS
I thank Dr. Yvon Le Maho for helpful comments. My thanks are also due
to Alexandre Zahariev for technical assistance in the manuscript preparation.
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