obesity reviews
doi: 10.1111/j.1467-789X.2010.00767.x
Obesity Management
obr_767
348..361
Voluntary weight loss: systematic review of early
phase body composition changes
S. B. Heymsfield1, D. Thomas2, A. M. Nguyen3, J. Z. Peng1, C. Martin4, W. Shen5, B. Strauss6,
A. Bosy-Westphal7 and M. J. Muller7
1
Summary
Inc., Rahway, 2Department of Mathematical
Weight loss follows when adult humans enter a phase of negative energy balance
brought about by reducing energy intake and/or increasing energy expenditure.
The weight loss period is usually viewed as a continuous process, ending when
energy equilibrium is achieved at a lower weight or with death following depletion
of fuel stores. However, growing evidence supports the expanded view that
induction of negative energy balance leads to well-defined physiological effects
characterized by three discrete phases (I-III). At present there are no comprehensive reviews of the ‘early’ phase of weight loss, a gap highlighted by recent interest
in rapidly testing new treatments with short-term protocols. Herein we show from
earlier reports and with new data that weight loss during phase I is: mathematically quantifiable with a t1/2 < 1-week and 4- to 6-week duration; includes
well-defined rapidly evolving body composition and energy expenditure changes;
and is moderated by multiple factors including subject sex and activity level,
nutrients ingested at baseline and during the negative energy balance period, and
hormone and pharmacologic treatments. Our in depth review collectively
characterizes phase I as a distinct weight loss period while revealing important
knowledge gaps that can be filled with appropriately designed future studies.
Merck Research Laboratories, Merck & Co.,
Sciences, Montclair State University, Montclair,
NJ, 3Merck Research Laboratories, North
Wales, PA, 4Ingestive Behavior Laboratory,
Pennington Biomedical Research Center,
Baton Rouge, LA; 5Columbia University,
College of Physicians and Surgeons, New
York, NY, USA; 6Monash University
Department of Medicine, Monash Medical
Centre, Clayton, Victoria, Australia; 7Institute
of Human Nutrition and Food Science,
Christian-Albrechts University, Kiel, Germany
Received 7 April 2010; accepted 16 April
2010
Address for correspondence: SB Heymsfield,
Global Center for Scientific Affairs, Merck
Research Laboratories, 126 E. Lincoln
Keywords: Body composition, energy balance, mathematical modelling, obesity.
Avenue, PO Box 2000, RY34A-A238, Rahway,
NJ 07065-0900, USA. E-mail:
obesity reviews (2011) 12, e348–e361
Steven.heymsfield@pbrc.edu
Introduction
Weight loss is a phenomenon universally recognized and
even experienced by most adults. Whether voluntary, as
with dieting for excess adiposity, or involuntary with
famine or disease, weight loss has captured the attention of
scientists, clinicians and public health workers for more
than a century.
Voluntary weight loss and associated changes in body
composition take on new importance in light of the current
obesity epidemic. Can observed weight changes with
lifestyle interventions, including diet and exercise, be
ascribed to loss of body fat or some other less desirable
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compartments? Is the composition of weight loss with lifestyle interventions ‘constant’ or are there time-dependent
changes corresponding to well-orchestrated physiological
and metabolic processes? Does subject baseline adiposity,
age or sex influence the composition of weight loss? These
are only a few of the many questions posed by investigators
studying this topic for the past century and who continue to
explore this increasingly important research area.
Studies aimed at evaluating dietary, pharmacologic and
surgical treatments for obesity typically set body-weight
change, a global measure of energy balance, as a primary
efficacy measure. Optimally treatment measures should
promote mainly loss of energy-dense body fat and limit the
© 2010 The Authors
obesity reviews © 2010 International Association for the Study of Obesity 12, e348–e361
obesity reviews
losses of functional compartments such as body protein
and bone minerals. Accordingly, well-designed weight loss
studies are increasingly including measures of body composition with the dual purpose of establishing efficacy
based on changes in total and regional fat mass and safety
based on changes in the mass of key lean tissue compartments. Several studies over the past two decades report
original research or have assembled the published literature
on this topic and developed working estimates reporting
the expected composition of weight loss as fat and lean
mass with fasting (1–3), very-low-calorie diets (VLCDs,
(4,5)), low-calorie diets (5–9), pharmacologic interventions
(5), exercise programmes (6,7) and bariatric surgical treatments (10). Several generalizations emerge from these
previous reports, although important gaps remain. In particular, most of these earlier studies focus on long term
treatment effects, usually 12 weeks or more, and very little
collective information is available on temporal changes
in body composition immediately following induction of
negative energy balance. These short-term weight loss
effects are relevant as a strong desire exists to rapidly screen
and evaluate new therapies.
The aim of the current report is to fill the knowledge gap
regarding early changes in body weight and composition
following induction of negative energy balance through
voluntary measures such as with lifestyle or pharmacologic
treatments. Our reference to ‘early’ changes empirically
focuses on time spans of up to 12 weeks after initiation of
weight loss treatments. Technical features related to body
composition evaluation are described throughout our
review and we provide an overview of this topic in Supplementary Material, I.
Overview of weight loss phases
Weight loss ensues in three potential phases (I–III) when
subjects are placed in a state of negative energy balance.
The first phase, lasting several days or weeks, is associated
with rapid or ‘fast’ weight loss (2,3). This is the weight loss
phase on which we focus the present review.
The second phase that follows is associated with slower
weight loss as shown in the upper panel of Fig. 1 by data
collected from Subject L (Levanzin, (11)), the voluntary
‘professional’ male faster. The second phase of weight loss
experienced by Subject L follows phase I, represented in the
figure by a several-day period of what appears to be a rapid
curvilinear loss in weight.
A third phase, brief in duration and not well characterized in humans for ethical reasons, occurs once fat stores
are depleted and available fuels during periods of negative
energy balance are drawn almost entirely from body
protein (12). Dulloo and Jacquet (13), however, debate the
existence of an acute ‘pre-mortal rise in N excretion’ (i.e.
phase III) and instead posit that fat and protein reserves are
Early phase weight loss
S. B. Heymsfield et al.
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Figure 1 (Upper panel) Daily weight of Subject L (11) over the course
of his voluntary total fast with the exception of non-caloric fluids. (Lower
panel) Semi-log plot of body weight vs. day of fast. The data are
described by a two-compartment model developed using WinNonlin
software (Pharsight, St. Louis, MO, USA) with an early rapid phase
(open circles) and later slow phase (triangles). The slow-phase line
along with half-life and l2 of the equation 1 are shown in the figure.
exhausted simultaneously at which point the subject succumbs from starvation. For practical and ethical reasons
most of the available experimental research on humans
focuses on phases I and II of weight loss.
Kinetic models
Weight loss follows a classic dose-response model so that
when subjects are placed into negative energy balance the
weight loss that ensues can be modelled by a linear combination of exponential decay functions. Phases I and II of
weight loss can be formulated by the sum of two exponential decay terms:
W (t ) = W0 ( f1e − λ1t + f2e − λ2t )
(1)
where W(t) represents weight on day t and the coefficients
satisfy the property that f1 + f2 = 1 and l1 >> l2 (2,3). The
kinetics of weight loss observed during Subject L’s 31 d fast
in 1912 are shown in Fig. 1 as a semi log plot, with a short
phase I half-life of 1.9 d and phase II following with a
© 2010 The Authors
obesity reviews © 2010 International Association for the Study of Obesity 12, e348–e361
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Early phase weight loss
Phase
Sex/weight (n)
M/60.6 kg (1)
M/63.6 kg (6)
M/128 kg (3)
M/142.6 kg (9)
F/56.3 kg (1)
F/99.3 kg (11)
F/131 kg (3)
F/131.3 kg (3)
Nitrogen
Non-obese (4)
Obese (9)
obesity reviews
S. B. Heymsfield et al.
I
II
f1
l1 (per day)
f2
l2 (per day)
t1/2
0.049
0.057
0.364
0.368
1.9
1.9
5.2
0.951
0.943
0.961
0.962
0.949
0.988
0.969
0.957
0.00634
0.00544
0.00261
0.00364
0.00644
0.0022
0.00289
0.00296
109.3
127.4
265.6
190.4
107.6
315
239.8
234.2
0.038
0.051
0.012
0.244
0.586
0.377
2.8
1.2
1.8
0.043
0.134
0.01
0.06
0.284
0.0655
2.4
10.6
0.99
0.94
0.00599
0.0016
115.7
433.2
t1/2
Table 1 Kinetics of body weight and nitrogen
loss during periods of negative energy
balance
Sources: Modified from references 2 and 3.
The table presents parameters of the exponential function: (equation 1).
F, female; f, fraction of body weight; l, decay constant; M, male; t1/2, half-life.
longer half-life of 109.3 d. Nearly all carefully conducted
weight loss studies that include a baseline stabilization
period show this characteristic two phase weight loss
pattern. The weight loss curve during phases I and II
appears as one continuous smooth curve even though
phases I and II are governed by different rates of decay.
Forbes first formalized these mathematical associations
and derived model parameters for equation 1 based on
available literature at the time (2,3). We have rearranged
and added to Forbes’ estimates as shown in Table 1. The
half-life of phase I based on the limited available weight
data is generally short, typically less than 1 week, and is
longer in obese than in lean subjects. If we assume 4–5
half-lives reaches 94–97% completion of phase I, the upper
limit based on phase I estimates from weight data in
Table 1 is about 1-month with a range of 5–26 d.
The half-life for phase II is considerably longer than that
for phase I, ranging in the limited available data from about
100 d in lean subjects to 300 d (i.e. 14–43 weeks) in subjects with very high body weights. The two-phase weight
loss model is convenient as it allows us to further explore
the underlying components of weight loss and related metabolic effects. We now focus on the biology of phase I, the
early weight loss period, in the sections that follow.
Early weight loss phase
Body composition changes
The loss in body weight during phase I reflects losses of
both fat and fat-free mass, the latter representing the sum
of all major molecular components including protein, glycogen, water, minerals and electrolytes (Supplementary
Material, I). We begin our review with an analysis of each
fat-free mass component change in response to negative
energy balance. We then review the kinetics of fat mass
change with voluntary weight loss.
Fat-free mass
Protein
The main nutritional concern with voluntary weight loss is
depletion of body protein. Excessive loss of body protein is
associated with adverse functional effects, for example
depletion of cardiac structural and functional proteins with
a reduction in myocardial mass, ventricular rupture and
cardiac arrhythmias (14). Total body protein is not easily
measured in living humans, the established reference
method neutron activation analysis (15) of limited availability, high cost, and a need of technical expertise for
construction, operation and maintenance. Moreover, in
vivo neutron activation analysis (IVNA) is typically associated with radiation exposure, largely limiting evaluated
subjects to men and non-reproductive age women (15).
Frequently spaced measurements over time with interventions are not possible with IVNA as the cumulative radiation exposure is unacceptable. The alternative approach,
applied in most studies, is to evaluate nitrogen (N) balance
as a proxy for protein balance; as protein is 16% N, then
Dprotein (g) = 6.25 ¥ DN (g) (15). These studies are ideally
carried out in patients living on a metabolic ward and
include N balance estimates as the difference between N
intake and the sum of measured fecal and urinary N losses;
miscellaneous N losses from skin are estimated.
A typical N balance study for 11 obese women placed
on a 5-week 900 kcal d-1 liquid diet following a 1-week
maintenance period is shown in Fig. 2 (16). At baseline,
with the subjects in N equilibrium, the daily urinary N loss
© 2010 The Authors
obesity reviews © 2010 International Association for the Study of Obesity 12, e348–e361
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18
100
Skeletal
Muscle
80
Body
W i ht
Weig
Liver
Adipose
Tissue
60
40
20
0
0
10
30
40
50
60
Day
Non-collagen protein
Urine N
14
150
12
% of baseline
grrams/day
20
Low-Calorie Diet
10
8
6
100
4
g
grams/day
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120
Intake N
Stool N
16
Skeletal
Muscle
50
Liver
0
0
10
20
30
40
50
60
Day
2
-3 0
S. B. Heymsfield et al.
Body & organ-tissue weight
18
16
14
12
10
8
6
4
2
0
% of baseline
grams/day
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10
20
30
40
50
60
N Balance
-8
Baseline
Days
Figure 2 Components of and total N balance (⫾SEM) observed in 11
obese women switched from a maintenance intake (1-week) to a
900 kcal d-1 formula diet for 5 weeks. Modified from reference 16.
is about 14 g reflecting a protein intake in the range of
80–90 g d-1. Urinary total N and urea losses rapidly
decline with the reduction in energy and protein intake;
there is a corresponding return in N balance towards baseline equilibrium levels with the metabolic adaptations that
follow. Nitrogen balance is maximally negative immediately following the reduction in dietary protein intake,
reflecting a daily loss of ~5–6 g N or 35–40 g protein.
Protein in this study represented 5% to 6% of weight loss
during phase I and the relative contribution of protein to
weight loss then decreased by about one-half during phase
II. The half-life of the early weight loss phase is less than
2 d, followed by phase II with ~135 d required for N
balance to reach zero.
The early N loss with fasting is represented mainly by
gastrointestinal tract and liver proteins involved with nutrient processing, while later losses are from skeletal muscle
Figure 3 Upper panel: Changes in body weight and composition,
expressed as a percent of baseline, following a reduction in food intake
of 60% in mature male Long Evans rats. Lower panel: Corresponding
percent changes in skeletal muscle (quadriceps) and liver non-collagen
protein. Results are X ⫾ SE. Modified from 17.
and to a less extent from visceral organs (12). An example
is shown in Fig. 3 of a rodent semi-starvation model in
which rapid loss of liver mass and non-collagen protein
occur early during underfeeding in contrast to slower rates
of body weight and skeletal muscle non-collagen protein
losses (17). Colles et al. (18) also observed a rapid loss of
total liver volume by a combination of magnetic resonance
imaging (MRI) and computed tomography (CT) in severely
obese subjects over the course of a 12-week VLCD study.
At 12 weeks there was a 10.6% loss in weight while the
corresponding loss of liver volume was 18.7%, the majority of which (~80%; P < 0.001) was observed after 2 weeks
of diet treatment; no measurements were made of liver lipid
or glycogen. The brain is typically spared until the later
stages of famine and severe starvation in which atrophy has
been reported (19). The rates of organ and tissue depletion
with negative energy balance are thus highly variable and
information on relevant human effects, particular at the
molecular level, remains limited.
Forbes combined estimates of baseline total body protein
with balance data to arrive at the N-balance half-lives for
non-obese and obese subjects as shown in Table 1 (2,3).
The half-lives for N depletion of non-obese subjects are 2.4
© 2010 The Authors
obesity reviews © 2010 International Association for the Study of Obesity 12, e348–e361
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S. B. Heymsfield et al.
and 115.7 d for phases I and II, respectively. Appreciably
longer half-lives are observed for obese subjects, 10.6 and
433.2 d, respectively.
Phase I during a typical diet or fast is thus characterized
by relatively large losses of body protein that diminish in
magnitude during phase II. Assuming an upper limit halflife of ~10 d, phase I based on N balance would maximally
extend about 6 weeks, somewhat longer than the 4-week
estimate from weight loss kinetics. Given the very limited
data used to derive these estimates, it appears as if phase I
would be complete in most subjects within the first 6 weeks
of voluntary weight loss. We continue to explore this question with data presented in later sections.
Proteins exist within the intracellular and extracellular
environments in association with water and electrolytes.
A water network links secondary structures within the
protein molecule and determines the fine detail of the protein’s structure. Fenn and Haege carried out a classic study
reported in 1940 that defined the water associated with cat
liver proteins (20). The authors observed that each gram of
deposited protein is accompanied by (X ⫾ SD) 3.35 ⫾
0.11 g of water. MacKay and Bergman in their earlier study
(1934, (21)) of young albino rats fed casein arrived at a
lower value for water association with protein, 2 g g-1.
McBride et al. (1941, (22)) raised concerns related to the
earlier experimental studies of both Fenn and Haege (20)
and MacKay and Bergman (21) as the studies relate to
water association with glycogen. Hall recently (2008, (23))
examined this question in relation to the energy deficit per
unit weight loss in humans and suggested an empirical
hydration of 1.6 g H2O per g protein. Proteins, particularly
intracellular proteins, thus strongly associate with water
and this effect accounts for a larger change in body mass
than can be accounted for solely by protein catabolism.
Water associated with protein catabolism thus is an important contributor to the rapid weight loss observed in
phase I.
Starvation response. Bloom first reported in 1959 the use
of total starvation for treating severe obesity (24). Subsequent balance studies revealed that starvation leads to
disproportionate protein loss compared with a low-calorie
diet and this weight control option was eventually abandoned. As an example, Ball et al. (25) placed five obese
subjects on an 800 kcal d-1 liquid formula for 14 d with
evaluation of fat and ‘lean mass’ (sum of water and protein)
changes using a combination of tritiated water dilution and
N balance. Subjects were then switched to a starvation
protocol for the next 16 d following which there was a 7 d
refeeding period. The rate of weight loss with low-calorie
dieting was similar to that observed with total starvation,
769 g d-1 compared with 651 g d-1. The rate of fat-free
mass loss during low-calorie dieting was 224 g d-1, much
less than the 576 g d-1 observed during total starvation.
The rate of fat loss during the low-calorie diet period was
553 g d-1, substantially greater than with starvation
(75 g d-1). Other small scale studies using balance methods
similarly conclude that massive protein loss accompanies
the early phase of total starvation (26).
Glycogen
While not a major functional concern as with protein,
glycogen provides a short-term energy supply and negative
glycogen balance is an important contributor to phase I
weight loss. Glycogen is present within skeletal muscle and
liver cell granules that also include tightly bound glycogen
phosphorylase and synthase (12,27). The glycogen molecule is highly branched and the observed rapid glucose
residue turnover in vivo occurs mainly at the outer
branches with a stable inner core (12). Glycogen within
hepatocytes can contribute up to 8% of postprandial liver
mass, which amounts to ~100–120 g in the average adult
(12). Glycogen within skeletal muscle cells accounts for
~1% of wet mass or ~200–300 g, depending on subject
conditioning and diet (12). Acheson et al. (28) evaluated
adult volunteers using a dietary restriction-refeeding
protocol and found that glycogen stores maximally
approached or even exceeded 1 kg; once beyond saturation
levels, carbohydrates are disposed of by high oxidation
rates and de novo lipid synthesis.
As with protein, glycogen is hydrated in vivo and to some
extent the amount of bound water depends on the molecular weights and associated structure of various analysed
glycogen fractions. Fenn and Haege in their study (20)
estimated that each 1 g of glycogen deposited in liver will
be accompanied by (X ⫾ SD) 1.46 ⫾ 0.21 g of water. This
level of hydration (59%) is very similar to that observed
by Mas et al. (55%; (29)) in E. coli K12 during periods
of glycogen accumulation. Nilsson (30) evaluated postabsorptive human liver tissue and estimated water binding
as 2.4 g per g liver glycogen. McBride et al. (22) in their
study of male rats arrived at a higher value, 2.7 g H2O per
g liver glycogen.
With starvation or semi-starvation, as is typical with the
use of a low-calorie diet, there is rapid depletion of the
glycogen pool over several days. Although the baseline
amount present and the rate of glycogen loss is highly
variable between subjects, we can assume that with about
250–300 g catabolized on a traditional composition lowcalorie diet that the overweight or obese subject will lose
another 350 to 450 g of water and associated electrolytes
from the intracellular compartment. This prediction is supported by Benedict’s observations on Subject L (11) whose
rapid weight loss (Fig. 1) is paralleled by rapid depletion of
body ‘carbohydrate’ over about a 10 d period (Supplemental Material, III).
© 2010 The Authors
obesity reviews © 2010 International Association for the Study of Obesity 12, e348–e361
obesity reviews
Fluid-electrolytes
The regulation of electrolyte and water excretion is highly
complex with many interactions among neurological and
hormonal stimuli. Most of the currently available information on this topic relates to fluid-electrolyte effects of
fasting or total starvation. A partial reduction in food
intake is more complex with respect to fluid balance than
total starvation as the amounts and proportions of dietderived macronutrients, minerals and electrolytes are
highly variable.
The typical early changes in fluid balance associated
with low-calorie diet treatment are demonstrated by the
study of Wynn et al. (31). The authors examined Na, K
and N balances during 68 d while subjects ingested a
655–789 kcal d-1 liquid formula diet. Subjects were variable numbers of obese men (n = 6–9) and women (n =
7–16), depending on phase of study. Sodium balance was
markedly negative during week 1, particularly on d 1
(~-30 to 60 mmol d-1; men > women), and was closely
associated with fluid balance (-100 to -500 g d-1). Potassium balance paralleled N balance, reflecting intracellular
protein and fluid losses; both K and N balance
approached stable negative levels after the first 28 d of
treatment towards the end of phase I. The main source of
fluid loss after the first week of treatment derived mainly
from the intracellular compartment.
Starvation response. During the early phase of a total fast
in obese subjects, notably within the first 7–10 d, there is a
kaliuresis with a total potassium loss of about 300 mmol
(32). As noted earlier, intracellular glycogenolysis and proteolysis release bound water and electrolytes that likely
account for most of the urinary potassium losses. In addition to potassium and nitrogen, ‘protoplasmic loss’ during
a fast also releases phosphate, calcium, magnesium and
small amounts of sodium that are then excreted through
renal mechanisms (32).
Benedict in 1915 first reported that the early phase of
fasting is also associated with an increase in urinary
sodium excretion, the so-called ‘natriuresis of fasting’ (11).
The level of observed sodium loss is greater than can be
accounted for by the lowering of or absence of dietary
sodium intake. Extensive subsequent studies following
Benedict ascribe this period of negative sodium and extracellular fluid (ECF) balance to four main factors related to
the cessation of food intake and the metabolic events
accompanying starvation that follow: a decrease in dietary
sodium with a rapid period of related negative sodium
balance (decline of ~50% d-1) that is independent of
weight loss (33); generation of ketone bodies (e.g.
b-hydroxybutyrate) secondary to free-fatty acid catabolism
with metabolic acidosis, ketosis and ketonuria (34,35)
with cationic sodium matching the organic acids to main-
Early phase weight loss
S. B. Heymsfield et al.
e353
tain electrical neutrality; and hypoinsulinemia leading to
natriuresis through insulin’s direct effects on renal tubular
sodium transport (35,36) and to a less extent effects on the
sympathetic nervous system with activation of the reninangiotensin system (37).
The combined effects of glycogen, protein and fluid loss
largely account for the rapidity of phase I weight loss
compared with the slower rates observed in phase II. The
rapid phase I weight loss phenomenon is the basis for
countless ‘quick fix’ diets promoted over the last century
and that are still pervasive in our diet-conscious culture.
Bone
The remaining fat-free mass component is bone or fat-free
skeleton which for the 70 kg Reference Man weighs
about 8.1 kg and includes 1.9 kg protein, mainly in the
form of collagen, with a total mineral content of ~2.8 kg
(38). Skeletal weight is increased in obese subjects and
bone remodelling and formation is strongly influenced by
mechanical loading effects (39). The larger bone mass
observed in obese post-menopausal women may also
relate to aromatization of androstenedione to the bonepreserving hormone estrone that takes place in adipose
tissue (40). The topic of bone loss during weight reduction treatment with low-calorie diets has been of great
interest, particularly as the majority of treated patients
are women in whom osteoporosis is a concern.
The main technique for monitoring changes in bone
mass with dieting is dual-energy X-ray absorptiometry
(DXA) that provides a measure of bone mineral content,
primarily in the form of calcium hydroxyappetite (15,41).
Bone mineral density, of the whole body or regions, can
also be evaluated by DXA but is not relevant to the
current discussion. CT, MRI and ultrasound methods are
also available for the study bone changes with voluntary
weight loss (42). Other biomarkers include those found in
blood and urine that estimate the rate of bone turnover
(43).
When considering the bone loss accompanying voluntary
weight loss, moderating factors include diet (i.e. magnitude
of energy deficit, macronutrient profile and calcium/
vitamin D intake), duration (e.g. bone remodelling cycle ~6
months in older individuals), subject characteristics (e.g.
pre- vs. post-menopausal women), magnitude of adiposity
and bone evaluation method (e.g. regional vs. whole-body
DXA for bone mineral density or bone mineral content).
Carefully controlled studies lasting up to several months
show that with voluntary weight loss no or very small
changes in total body bone mineral content as measured by
DXA are observed when overweight or obese subjects are
provided adequate amounts of calcium and vitamin D
(Supplementary Material, II). A reasonable assumption
based on this available information is that skeletal mass
remains minimally changed during the early phase of
© 2010 The Authors
obesity reviews © 2010 International Association for the Study of Obesity 12, e348–e361
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voluntary weight loss. Confirmation of this observation,
with appropriate measurement methods, would be useful
when planning future weight loss studies.
Fat mass
Very few studies have closely examined the kinetics of
changes in fat mass during the early period of weight loss,
except for the limited publications using energy-nitrogen
and metabolic balance methods (11,44). The other available techniques for assessing body composition are not very
precise, have associated radiation exposure, apply assumptions that are not valid or validated in the short term, or are
impractical to carry out at closely spaced time intervals
(Supplementary Material, I). Nevertheless, we can construct a general model of how total body fat mass changes
during the early period of underfeeding.
Sources of metabolic fuel during periods of negative
energy balance include glycogen, protein and fat. Glycogen stores, as noted earlier, are largely consumed within
the first week when subjects substantially reduce their
energy intake. A two phase loss of protein is observed
with half-life examples presented in Table 1. The ‘early
phase’ protein loss is thus also relatively short, extending
maximally several weeks depending on the magnitude of
energy restriction and baseline subject characteristics. The
remaining energy balance deficit must therefore come
from fat. We can then surmise that the fraction of weight
loss as fat is minimal during the first days or weeks of
energy restriction and then increases as early losses of glycogen and protein slow or cease as the subject reaches the
end of phase I. On the other hand, the magnitude of
energy imbalance is also slowing as subjects lose body
mass with lowering of energy expenditure and adaptive
mechanisms additionally decrease the resting heat production rate (45). This model predicts that the fraction of
weight loss as fat increases during phase I and that over
time relative loss of body fat can be fit by curvilinear
models as described for weight and nitrogen, as shown in
Table 1.
While ‘fat’, defined mainly by triglyceride, is the appropriate molecular entity related to energy stores, we now
recognize that fat is distributed in ‘adipose tissue’ with
specific regional properties (46). With induction of negative
energy balance and weight loss, corresponding relative
rates of adipose tissue loss are highly variable and range
from rapidly mobilized visceral adipose tissue (47) to minimally influenced bone marrow adipose tissue (48). Thus,
loss of total body fat with voluntary dieting reflects the
integrated changes within several regional adipose tissue
compartments. How these differences in adipose tissue fat
loss rates distribute across the three weight loss phases has
not been firmly established.
Influencing factors
Temporal and sex effects
Phase I up to this point in our review includes variable
maximal rates of protein, glycogen and fluid loss that
greatly diminish with entry into phase II. We can then
surmise that the corresponding rate of collective fat-free
mass loss is also relatively large during phase I, particularly
during the initial period following induction of negative
energy balance.
The temporal changes in relative weight loss composition
during the first month of treatment is provided by the
VLCD study of Krotkiewski (49) that evaluated diet
supplementation with medium chain triglycerides (MCT)
in obese women. In addition to subjects placed on the MCT
formula, Krotkiewski also included groups treated with
VLCDs containing either long chain triglycerides or that
were low in fat. The DXA-derived body composition
results are shown in Fig. 4. As predicted, the fraction of
weight loss as fat-free mass was high at 1 week of VLCD
treatment, about 0.4–0.6 across all three diet groups. The
fraction of weight loss as fat-free mass subsequently
decreased at weeks 2 and 4 in the three groups to 0.3–0.4.
The relative contributions of fat and fat-free mass to
early weight loss beyond 4 weeks are provided by results of
the Calerie (50–52) and Kiel studies. The primary data
were available to us from both of these studies that we use
in the analyses that follow. Additional details of these
studies are provided in Supplemental Material, IV and V
and in the original respective publications (50–52).
The main evaluated database for which serial DXA measurements were available was from the 24-week Calerie
study (50–52) that had four overweight subject groups
including a non-diet control, calorie restriction (CR) at
25% diet-imposed energy deficit, CR plus structured exercise (Ex) as walking, running and cycling (25% energy
deficit, 12.5% diet and 12.5% exercise), and a VLCD
(890 kcal d-1) until 15% weight loss followed by a weight
maintenance diet (Supplemental Material, IV). The VLCD
maintenance diet phase was reached at approximately 8
weeks in women and 11 weeks in men and we therefore
focus the main analyses that follow on this 3-month period
of collective negative energy balance. Subjects were ethnically mixed men (age < 50 years) and women (age < 45
years) randomly assigned to the four groups.
The pooled weight loss and body composition results for
Calerie study participants in the CR and VLCD groups up
to week 12 are shown in the upper panel of Fig. 5. Fat-free
mass loss was rapid during the early weeks of the protocol
and then stabilized around weeks 10–12. Fat mass and
body-weight loss continued up to week 12.
On a relative basis, only about 5% of fat-free mass
was lost by week 12, in sharp contrast to a much larger
© 2010 The Authors
obesity reviews © 2010 International Association for the Study of Obesity 12, e348–e361
obesity reviews
Early phase weight loss
S. B. Heymsfield et al.
e355
Krotkiewski VLCD study
0
DWeight (kg)
-1
Wk 1
Wk 2
Wk 3
Wk 4
-2
-3
Grp 1
-4
Grp 2
-5
Grp 3
-6
-7
-8
-9
0.80
0.70
Figure 4 Upper panel: Changes in body
weight in three groups of obese women
receiving a 579 kcal d-1 VLCDs differing in
lipid source as reported by Krotkiewski (49).
Lower panel: The corresponding changes in
the ratio DFFM/Dweight. FFM, fat-free mass;
VLCD, very-low-calorie diet.
DFFM/Dweight
0.60
0.50
Wk 1
0.40
Wk 2
0.30
Wk 4
0.20
0.10
0.00
Grp 1
percentage of fat mass for which depletion of total body fat
approached 25% of the baseline amount (Fig. 5, lower
panel). The combined losses of fat-free mass and fat mass
led to a body-weight loss of ~10% by week 12 of the
protocol.
The differing rates of fat-free mass and fat mass loss
led to changes in the fractional contributions of each
compartment to body-weight loss over time (Fig. 6). As in
Krotkiewski’s 4-week study (49), the fraction of weight loss
as fat-free mass was high early during the Calerie protocol
(mean ⫾ SD, week 4; 0.54 ⫾ 0.23) with a curvilinear
decrease up to week 12 (0.35 ⫾ 0.17). The fraction of
weight loss as fat, the reciprocal of the fraction of weight
loss as fat-free mass, began low at week 4 and gradually
increased up to week 12. At week 24 (data not shown) the
fraction of weight loss as fat-free mass decreased further
from week 12 to 0.29 ⫾ 0.14 in the combined CR and
VLCD groups.
These observations are thus consistent with the previously reported kinetics of individual component losses as
protein, glycogen, fluid and fat during the early phase of
voluntary weight loss and the phase I half-lives of weight
and protein loss as summarized in Table 1. The relative
contributions of fat and fat-free mass with voluntary
Grp 2
Grp 3
weight loss are thus not ‘constant’, but change rapidly
during phase I and appear to change at a much slower
rate in phase II. Again, we can reaffirm that the energy
density of weight change is not constant during phase I,
but increases rapidly and then slows with entry into
phase II.
More experimental data at closely spaced time points in
various populations would ideally provide higher resolution phase I estimates for component half-lives. From Krotkiewski’s study (Fig. 4; (49)) and the Calerie results (Fig. 6)
we can again estimate that the early rapid phase of weight
loss with associated body composition effects extends from
diet inception up to about 4 to 6 weeks with sustained
negative energy balance.
The larger Kiel VLCD study (Supplemental Material, V)
provided DXA body composition estimates at baseline and
at approximately 10 weeks of weight loss. The fractions of
weight loss as fat and fat-free mass are shown separately
for men and women participating in the Kiel study along
with the corresponding representative 10-week Calerie
data in Fig. 7. Men had a larger fraction of weight loss as
fat-free mass than women (Calerie, P = 0.078; Kiel, P =
0.059; and pooled men vs. women from the two studies, P
= 0.010). Similarly, the fraction of weight loss as fat at the
© 2010 The Authors
obesity reviews © 2010 International Association for the Study of Obesity 12, e348–e361
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Early phase weight loss
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S. B. Heymsfield et al.
Fraction of weight loss as fat-free mass
Calerie study
0.70
2
Change in mass (kg)
0.60
0
-2 0
5
10
15
-4
-6
-8
P = 0.078
P = 0.010
0.40
Men
0.30
Women
BW
0.20
Fat
0.10
FFM
0.00
Calerie
-10
Calerie study
5
0
-5 0
5
Kiel
Total
Figure 7 Fraction of weight loss as fat-free mass observed in men and
women participating in the Calerie study caloric restriction group
(50–52) and Kiel-VLCD studies. Results are X ⫾ SE. P-values are for
men vs. women in each respective study group and for all subjects
combined. VLCD, very-low-calorie diet.
Week
% change from BL
P = 0.059
0.50
10
15
sex differences in the kinetic parameters of phase I with
appropriately powered samples.
-10
-15
BW
-20
Fat
Magnitude of energy deficit
FFM
-25
Week
Figure 5 Loss in weight, fat and fat-free mass (FFM) in the Calerie
Study (50–52) participants assigned to the caloric restriction and VLCD
groups, expressed as absolute mass (upper panel) and as a percent
of baseline mass (lower panel). Results are presented as X ⫾ SE.
BL, baseline; BW, body weight; VLCD, very-low-calorie diet.
Figure 6 Fraction of weight change (D) as fat and fat-free mass (FFM)
vs. study week for Calerie Study (50–52) participants assigned to the
caloric restriction and VLCD groups. Results are presented as X ⫾ SE.
VLCD, very-low-calorie diet.
10-week time point was less in the men than in the women.
Chaston et al. in their systematic review (5) found that for
dietary and behavioural weight loss interventions the fraction of weight loss as fat-free mass was also larger in men
(X ⫾ SD, 27 ⫾ 7%) than in women (20 ⫾ 8%). These
observations strongly support the need to further evaluate
Some early VLCDs in the range of 300–400 kcal d-1 that
facilitated rapid and large amounts of weight loss were
associated with depletion of body cell mass leading to
serious adverse events (53), although modern formula diets
tend to be higher in energy content, have high-quality
protein sources, and include adequate amounts of electrolytes, minerals, vitamins and trace elements. Chaston et al.
(5) in their systematic review reported a greater percentage
of weight loss as fat-free mass with VLCDs compared with
low-calorie diets. Their sample of appropriate studies was,
however, relatively small (n = 4) and body composition
methods were varied across studies, including underwater
weighing (n = 3) and DXA (n = 1). The Calerie sample CR
and VLCD groups are also small (n = 12 and 11 subjects)
and include both men (n = 10) and women (n = 13) so that
the subject number within each cell has limited power to
test the hypothesis that FFM is preferentially lost with
VLCD treatment. For the combined men and women in CR
and VLCD groups at 10 weeks, the DFFM was (X ⫾ SD)
-1.47 ⫾ 0.90 kg and -4.10 ⫾ 2.0 kg, respectively; the
corresponding DFFM/DW were 0.32 ⫾ 0.20 and 0.36 ⫾
0.11 (P = NS). The DFFM/DW over the full 24-week course
of the Calerie study for CR and VLCD groups is shown in
Fig. S4. Despite large weight loss differences between the
groups, there were no discernable between-group relative
differences in FFM loss.
A key question emerging from the previous reports and
the current data review is if and how the magnitude of
relative FFM loss is influenced by the degree of negative
energy balance during the early phase of weight loss. As for
other areas discussed in our review, more information is
needed on early body composition effects in appropriately
powered samples based on subjects selected to create sex,
© 2010 The Authors
obesity reviews © 2010 International Association for the Study of Obesity 12, e348–e361
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S. B. Heymsfield et al.
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Figure 8 Composition of weight loss observed
with total fasting and two 800 kcal d-1 VLCDs,
one with a balanced (B) nutrient composition
and the other a high-fat low-carbohydrate
ketogenic (K) diet. Based on 54. VLCD,
very-low-calorie diet.
Change in mass (g d−1)
0
-100
Fat
-200
Protein
-300
-400
-500
Water
-600
-700
-800
B-VLCD
age, body mass index (BMI) and physical activity balance
across groups.
Diet composition
Diet mineral, electrolyte, protein, fat and carbohydrate
content all influence components of phase I weight loss.
Earlier sections reviewed contributions of diet sodium and
calcium content to phase I changes in respective fluid and
bone mineral balances. In addition to total energy content,
the proportions of protein, fat and carbohydrate have an
important influence of the composition of early voluntary
weight loss.
The main features of these macronutrient effects are well
characterized by the 50 d energy-nitrogen balance study of
Yang and Van Itallie (54). Men with severe obesity (n = 6)
were treated with three randomly sequenced 10-d diet
protocols, including a total fast, a balanced nutrient
800 kcal d-1 VLCD and a low-carbohydrate-high-fat
ketogenic 800 kcal d-1 diet. Subjects ingested a balanced
1200 kcal d-1 formula diet for 5 d before and following
each of the three experimental periods.
As expected, with the total fast there were large losses of
the three evaluated components, protein, fat and water;
weight loss was correspondingly large (X ⫾ SD, 750.7 ⫾
50.9 g d-1; Fig. 8). Weight loss on the ketogenic diet (466.6
⫾ 51.3 g d-1) was much larger than on the isocaloric balanced nutrient VLCD (277.9 ⫾ 32.1 g d-1), although this
difference was primarily accounted for by differences in
water balance; fat and protein losses were similar during
treatment with the two VLCDs. Ketosis with ketonuria was
present during the ketogenic VLCD period.
Although this is an extreme example of phase I diet
composition effects, diets varying widely in composition
are currently used in both clinical research and practice
settings. These metabolic and body composition effects
should be considered when planning studies that examine
diets within the phase I time frame.
Exercise
Physical activity contributes to total energy expenditure
and is thus an important component of energy balance.
K-VLCD
Total Fast
Physical activities are characterized by type, duration,
intensity and other important features that differ between
studies. An exercise programme is often prescribed in association with other lifestyle measures as part of a comprehensive overweight and obesity treatment programme.
In addition to contributing to the magnitude of imposed
negative energy balance, added exercise purportedly prevents or reduces loss of fat-free mass through trophic and
hormonal effects on skeletal muscle and other organs and
tissues (55–58). Forbes critically reviewed this hypothesis
(56,57) and there are also several meta analyses that
explore this topic (6,7). Most authors agree that exercise,
depending on type, intensity and duration, has some fatfree mass sparing effects (6,7,55–58), although the composition of this ‘spared weight’ is not well defined. Exercise
can influence fluid balance (59), glycogen formation (60)
and protein turnover (61).
The important question from the perspective of our
review is how exercise influences the early phase of weight
loss. Most of the earlier studies did not specifically address
this question and we thus provide an initial overview from
Calerie study results. Calerie included two groups with a
similar prescribed energy deficit of 25% below baseline
(Fig. S3). The energy deficit was created by food restriction
in the CR group and by food restriction and added exercise
in the CR+Ex group (12.5% CR and 12.5% Ex). The loss
of fat-free mass in the CR+Ex group up to the 12-week
evaluation time point was about one-half that of the CR
group (Fig. 9) with variable statistical significance for
between-group differences. Three of the 12 subjects in the
CR+Ex group had no loss or gain in fat-free mass up to
week 12 compared with none in the CR group. These
observations are highly suggestive that added exercise
influences the kinetics of fat-free mass loss during the early
phase of weight loss treatment.
Baseline adiposity
Does baseline subject adiposity moderate the magnitude of
phase I fat-free mass loss? Assume that an extreme athlete
has a body mass consisting of solely fat-free mass without
any body fat. When placed into negative energy balance
© 2010 The Authors
obesity reviews © 2010 International Association for the Study of Obesity 12, e348–e361
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Early phase weight loss
obesity reviews
S. B. Heymsfield et al.
Fat-free mass (kg)
Change in mass (kg)
0.0
p = 0.05
0.03
0.03
0.01
-0.5
-1.0
CR
EX
-1.5
-2.0
-2.5
-3.0
4
6
Week
10
12
this subject’s metabolic processes would by necessity
consume the only two available fuel sources, glycogen and
protein.
The data needed to answer this question is extremely
limited and the main insight available is from the Minnesota Semistarvation Experiment (8), although the first
study time point after baseline is at 12 weeks. This classic
study included young men who were placed on a
~1800 kcal d-1 balanced caloric restriction diet with body
composition measured by underwater weighing. Body
weight was adjusted through variation in food intake prior
to the restriction period in order to ‘normalize’ the men’s
weights, so as a group they were not in a long-term energy
equilibrium state a baseline.
We explored the relation between baseline adiposity and
composition of weight change by stratifying the men into
quintiles based on baseline %fat. We then plotted the group
mean fraction of weight loss as fat-free mass against baseline quintile for the 12-week time point. The men in the
lowest quintile of baseline %fat had a substantially larger
fractional loss of fat-free mass than did the men in the
middle (2–4) or highest baseline %fat quintiles (Fig. S5).
Note that baseline %fat in the lowest quintile was
extremely low (~7%); all three groups had a similar BMI of
about 22 kg m-2 ((8); Supplemental Material, VI). This
observation supports a related earlier analysis reported by
Dulloo et al. (13,62).
We also examined Calerie and Kiel study data to test the
hypothesis that baseline adiposity influences the fraction of
weight loss as fat-free mass. No significant associations
between baseline %fat and the fraction of weight loss as
fat-free mass were observed at any time point in these
exploratory analyses. As with other topics noted in our
review, this important question needs resolution in future
carefully controlled trials.
Hormones and drugs
Pharmacologic and hormonal treatments are reported to
alter early phase protein, fat-free mass and fat mass losses.
Figure 9 Loss of fat and fat-free mass in the
calorie restricted (CR) and CR+exercise (EX)
Calerie study (50–52) groups. Results are
X ⫾ SE.
For example, classical energy-nitrogen and metabolic
balance studies have been used to characterize hormone
and drug effects (63–65). A key feature of some of these
studies is the use of experimental designs that recognize the
distinguishing features of phase I and II weight loss. For
example, pharmacologic doses of T3 were frequently used
in the past in association with caloric restriction as a means
of treating obese subjects. T3 as used in this context was
hypothesized to have catabolic effects mainly on skeletal
muscle. As the protein losses during phase I are likely from
mixed sources, including liver, gastrointestinal tract and
skeletal muscle, Abraham et al. (63) conducted their T3
study in obese subjects following 30 d of caloric restriction
when phase I was largely completed and nitrogen losses
reflected primarily skeletal muscle catabolism. In support
of the hypothesis, high doses of T3 during this presumed
initial phase II period caused striking increases in N loss
compared with placebo treatment.
Observations such as those of Abraham et al. (63)
emphasize the importance of designing hormonal and pharmacologic weight loss studies with careful consideration of
phase I effects.
Early weight loss as a distinct phase
Forbes was the first to fully articulate the idea that weight
loss vs. time functions have mathematically quantifiable
features allowing separation of these curves into at least
two different kinetic components (i.e. phases I and II;
(2,3)). Our review extends Forbes’ concept by providing a
synthesis of the vast amounts of human data in support of
the view that voluntary weight loss proceeds in three potentially discrete phases.
We have expanded on Forbes’ innovative concept by
showing that phase I is characterized by distinct body composition and metabolic effects that differentiate it from the
later phases of weight loss. First, as subjects switch from
their ‘usual diet’ to a new lower food intake, there are
multiple variable changes in macronutrient, mineral and
electrolyte balances that stabilize over time on the new diet.
© 2010 The Authors
obesity reviews © 2010 International Association for the Study of Obesity 12, e348–e361
obesity reviews
Phase I thus reflects these ‘washout’ effects and that are in
most cases not present in phase II.
Second, switching from one plane of nutrition to a new
lower level of food intake triggers hierarchal changes in fuel
stores and related body composition effects with depletion
of glycogen stores and early phase protein losses that come
into equilibrium with the onset of phase II.
Third, well-established neuro-hormonal mechanisms are
invoked early in the course of weight loss such as in the
leptin and thyroid hormone axes (66), only briefly touched
upon in our review, that slow energy expenditure and
protein turnover with activation of a host of other metabolic and neurobiological processes that help to sustain life
in the face of negative energy balance. The ‘adaptive’ phase
I period can thus for heuristic purposes be considered a
distinct period of rapid weight loss appearing when subjects change from a maintenance plane of nutrition to a
new lower level of nutrient intake.
From available literature and our own pooled data it
tentatively appears as if at least five factors moderate the
kinetic features of phase I, including (i) the magnitudes of
energy, nitrogen and sodium balances as derived from the
differences between subject baseline intakes and losses; (ii)
sex, with more relative fat-free mass loss in men; (iii) diet
macronutrient composition, (iv) physical activity level,
with greater activity reducing relative fat-free mass losses
and (v) selected hormonal and pharmacologic treatments.
Our evaluation samples, Calerie and Kiel, tended to be
small and we likely did not have adequate power to detect
age effects; our subjects were mainly Caucasians so that
race effects could not be adequately explored. The extent to
which these and other factors (e.g. baseline adiposity)
impact specifically on the composition of phase II weight
loss remains unclear as previous critical reviews often combined short and long term weight loss studies in their
pooled analyses.
An important observation emerging from our findings is
that the phase I – phase II composition of weight loss
difference impacts on classically assumed stable ratios such
as the energy density of body-weight change (23) and the
Pratio, defined as the fraction of energy mobilized as protein
with food restriction (13,62). Further exploration of these
time-related effects on classic ratios is justified based on
observations reported in the current review.
Our comprehensive evaluation of phase I weight loss also
provides critical new ideas for developing human energy
balance models, a burgeoning area of biological research
(Supplementary Material, VII).
Conclusions
Our findings support the view that early weight loss following reduction in or cessation of food intake reflects the
combined kinetics of multiple compartmental changes with
Early phase weight loss
S. B. Heymsfield et al.
e359
varying half-lives. Many of these processes are not well
characterized in humans as some of the required in vivo
studies are difficult or impractical to carry out and the
available methods are not sufficiently accurate to make
quantitative assessments. With these limitations, our findings suggest that the early phase of weight loss reflects the
combined losses of water/electrolytes, glycogen, protein
and fat and to a less extent bone minerals. Although we
empirically set 12 weeks as the upper boundary for investigating the early period of weight loss, an exact length of
phase I cannot be assigned and likely varies in duration
depending on the nature of dietary intervention and
baseline subject characteristics. A reasonable assumption
emerging from our findings is that for most subjects phase
I likely lasts 4 weeks or less, perhaps in some cases up to 6
weeks, based on the limited published half-life data for
body weight and protein balance along with the supportive
new experimental data provided in our review.
An important conclusion emerging from our analyses is
that planned weight loss studies exploring various interventions should be designed to accommodate the differing
early and late phase body composition effects. For
example, an intervention focusing on body fat loss would
not ideally be designed with body weight as the primary
outcome measure unless the duration extended beyond
several weeks or months as the fraction of weight loss as fat
increases rapidly and is highly variable during phase I. The
use of fat-free mass as a safety measure with pharmacologic
treatments would need to consider the differing early and
later phase effects on fluid, glycogen and protein losses.
Many other relevant examples abound and the present
study highlights the important need to further elaborate on
the underlying biology of early weight loss and to similarly
explore the main features of phase II weight loss as
approached in the current report.
Conflict of Interest Statement
No conflict of interest was declared.
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Supporting information
Additional Supporting Information may be found in the
online version of this article:
Supplementary
Supplementary
Bone Effects.
Supplementary
Supplementary
Supplementary
Supplementary
Supplementary
Supplementary
Material I: Body Composition Analysis.
Material II: Voluntary Weight Loss and
Material
Material
Material
Material
Material
Material
III: Subject L.
IV: Calerie Study.
V: Kiel Study.
VI: Minnesota Experiment.
VII: Energy Balance Models.
VIII: References.
Please note: Wiley-Blackwell is not responsible for the
content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the
article.
© 2010 The Authors
obesity reviews © 2010 International Association for the Study of Obesity 12, e348–e361