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in childhood
for
the
development
William
ABSTRACT
H Dietz
Critical periods of development have been well not
been
carefully
the
identification may serve of In this will alterations use the the word critical onefor and for the adto the disbe
recognized However,
processes. of critical periods have not been focus preventive the sug- mechanisms decussion, gesdefined that increase that entrain that a critical the later
the
widely reported for nutritional diseases. gest that two and possibly three critical velopment tation occurs begins obesity and of between at these and its obesity infancy, 5 and 7 y of and its the age, complications. period and early
fat
and
adiposity
adolescence.
is initiated
risk of persistent period, that account for self remain process should The olescence velopment
the increased risk unclear. Nonetheless, serve stages. KEY ment, to focus
Am
developmental
periods considered
WORDS children
Obesity,
diabetes,
fat
distribution,
develop-
Prenatal
Obesity
period
Follow-up is now one the United behavioral of the most prevalent States (1, 2). Although factors (3, 4) appear early in life diseases in the popthat prenatal a variety of demodevelopment associated with obeIn October
of
infants
exposed
to
famine
prenatally
or
and
in later
German
the familial resemblances in fatness5, 6) indicate ( genetic effect on susceptibility to the disease. severity persistence obesity
severe
of
and
restricted food supthe a signifplies to the western Netherlands. At the beginning ofthe occupation In general, the average per capita daily ration approximated 7533 kJ (1800 affect the likelihood of kcalld) (15) and declined to 25 1 1 Id (600 kcal/d) in the 6 mo that Although childhoodfollowed. In May, 1945, after liberation, food supplies again promay be associated with vided 71 14 U (1700 kcal/d). The clear delineation of the onset and obesity accounts
adult
for well
present and
in adults
(8, have
9).
end
of
of the
the effects
famine
of
in the
maternal
Netherlands permitted
nutrition on
a careful
subsequent
assessment
growth. At the
development
been time behavioral (1 1) prowho to rubella in the first was of congenital abnorto the virus
(12) is
with
had
control
exposed
subjects
to the
drawn
famine (15).
whereas
the
does
the
not.
of
this
effect
of and
fetal 12th
on
the
external female
From
England
the Division
Medical
of Pediatric
Boston, HD25579 to WH
Gastroenterology
and from Tufts NICHD New University and
and Nutrition,
School grant of
New
Mcd-
to testosterone produces of
Center, by grant
from
3
NIDDK.
Address 213, 750 reprint requests Dietz, England
genitalia possibility
entrain
Box
alterations
states, such
of Received
has Accepted
as
adult
Washington Street, Boston, MA 02111. May 26, 1993. for publication November 10, 1993.
Nutrition
Am
Nutr
1994;59:955-9.
Printed
in
USA.
1994
American
Society
for
Clinical
955
956
was
120% among
The
preyin
.
alence utero
period.
of obesity
in the last trimester of pregnancy or in the immediate In contrast, the prevalence of obesitywas increased men who of infants that for period the were exposed (Fig of diabetic the third entrainment 1). mothers trimester offer additional may In a large to famine in utero of pregnancy
EJ
I
Non-Diabetics
1#{149}
suggestion
tolerance test. Prediabetic mothers were mal glucose tolerance who subsequently sity
50th 50th
20
in the
infants
and
children
was
defined
percentile desirable weight-for-gestational age or 140% of the percentile ofweight-for-height. Infantsborn to diabetic mothers were fatter at birth than were infants of prediabetic or nondiabetic mothers dren of
significantly
tJ
who Adapted were
:1
Pettit
AT EXAMINATION at subsequent
prediabetic, et al (16).
(years) ages
or
of obesity
diabetic, from
among
nondiabetic
children
during
born
their
of
the
same
age born
to pre-
or
mothers
(Fig
2).
The
of obesity among the to be independent of the childs other birth (16). studies have large
of diabetic mothers also obesity status at the time the the the persistent at ages In these observed
follow-up possibility
of infants intrauterine
and entrain
of birth weight for the subsequent 1 1, 15 (18), and 17 y (19), and the tracking of birth weight was infants of diabetic mothers. or maternal obesity, both sequent likely fatness. to parallel However, birth weight,
effect sequent fatness. Nonetheless, 6 (17),dude the possibility of genetic studies among Pathophysiology diabetes The and subtional are is withundersimplest exposure conceptualization is that appetite during this period. may
observations
determinants
prevalence
of diabetes
entrained
or overnutrition
differentiation
lamic centers responsible for the in utero exposure to undernutrition pocyte whereas pocyte pair the Likewise, nutrition
U. #{163}0 against or
in the last trimester to overnutrition early and undernutrition predispose undernutrition cellularity logical factors or of
of food
to later
later
Although firm adipose pocyte ticoids pogenic mone The fects effects evidence tissue
0
LU
C:,
site-dependent
sensitivity to or metabolism (21), alterations in lipoprotein enzymes receptor effects usually of (22, numbers of prenatal associated prenatal exposure 23), (24). nutritional with obesity on fatness, or changes
insulin (20) or glucocorlipase or mitochondrial liin insulin or lipolytic on suggest the morbid from that the horefthe en-
dissociated
may be indepencohorts, low birth pressure in children in or diabetes mortality (25, 28).
COHORT
FIG 1. Prevalence ofobesity in 19-y-old men exposed to famine either The effects of low birth weight on morbidity persisted after conin utero or during early postnatal life. Exposure to famine in the last trol for geographic region, socioeconomic status, mode of infant trimester of pregnancy or early infancy is associated with a reduced prevfeeding, and smoking. The same studies failed to demonstrate alence of obesity at age 19 y, whereas exposure early in pregnancy is any increase in morbidity or mortality for those individuals associated with an increased prevalence of obesity at age Adapted 19 y. from Ravelli et al(15). whose birth weight was greater than average.
CRITICAL These ses. risk dren nal For first-trimester apparent example, contradictions infants exposure whose offer birth several weight may
OBESITY whereas as teenagers of 20% of obese (36, risk persists Adolescence only
DEVELOPMENT 10% (9). of obese Approximately females returned adult males 70% to had of normal onset obese weight
to undernutrition
adiposity and hypertension or diabetes. weight is low because of third-trimester may diabetes, the Infants have that
37). These findings indicate that girls may be at parfor adult obesity if their disease is present or develops and adulthood also appears that adolescent-onset may herald to represent obesity a lifelong a critical in females problem. period for the into
an not are
adolescence,
(29). may
of obesity-associated individuals studied 1935), when 50th was mortality (BMI > 75th compared
Growth
subsequent suggest
morbidity.
was increased among men who percentile) during their high with men who were (38). both The mortality suggesting lean Morbidity men and persisted that the (BMI befrom women effect mordiadult of even
depends
percentile) adolescents also increased among during on high morbidity resulted effects more did school. and
of adiposity
sources may by begins represent adiposity. height2 decreases to increase. of
rebound
data another The increases (30, The 31). time (m)] suggest critical body in Beginning at which that the period mass the time for index first the of the year second rebound thickness cohort adiposity development [BMI; of wt life, BMI
significant
subsequent
controlled,
from adolescent obesity of adolescent obesity on consequences women. Data of obesity from (41), young and 1991)
5 at y of age,
presadult Norwesupport
observations.
to follow a similar pattern (5). Longitudinal observations 31) gest hood skinfold whose pared 6.5 and a somewhat that the time effect In both thicknesses adiposity with children late (31).
significant
Pathophysiology (30, by which adolescent-onset obesity lead to an larger cohort in southwestern Ohio (32) sug- The mechanisms increased likelihood of adverse sequelae or the persistence of at which adiposity rebound begins may have a obesity is not clear. One potential explanation for the apparent on fatness in adolescence (30, 32) and adultentrainment of morbidity during adolescence may be the pattern adolescents and adults, BMI and subscapularof fat deposition that occurs at this time. Boys, and to a lesser were significantly greater among children extent girls, appear to deposit fat centrally and lose fat periphrebound began early (before.5 y of age), 5 cornin France whose adiposity 31). clearly rebound a relationship was average between as they (6.0-. erally are apparently mature absent (43). and (42). from some Estrogen female gluteal and progesterone abdominal, femoral, androgen depots receptors (44). These receptors or omenexist in abfindings
y) or Although
and subsequent fatness, the prevalence examined. Therefore, the evidence that rebound represents obesity effect of children a critical is not adiposity who yet period for established. rebound on earlier
tissue adi-tal adipose dominal, omental, of obesity that the the period suggest adolescence the devel- during
However,
opment of subsequent explanation for the posity a longer parallel. only may be that of period Therefore, gains period
rebound
fat may An alternate are present, sence of androgens, eventual adiRegional differences grow fatter for
time. Rates of BMI increases differences in fatness at subsequent onset of the age-related increase No published to subsequent
reflect
an earlier
as differential effects of insulin on glucose uptake and limay remain well polysis may contribute to this process. ages may Intraabdominal fat in obese adults predicts diabetes (45), heart in fatness, (46), hypertension studies have disease fat distribution morbidity thermore, the sex-related differences tion inal (50). Increased fat may act on to reduce release the liver (47, 48), and hyperlipidemia (49). Furmay account for in the incidence a large proportion of of myocardial infarcfrom insulin of intraabdomresistance, glucose to glucose (52). may
Adolescence
Obesity
Adolescence velopment obesity of appear represents obesity. greater of Both for the the females final risk proposed of than onset for period and males. appears several for persistence the
and
hepatic
increased insulin
free clearance
fatty
acids and
circulation hyperinsulinemia
(53). Hyperinsulinemia and insulin resistance have been associto increase ated with hypertension (54,55). The high-risk plasma lipid prostudies obfile associated with increased intraabdominal fat appears indeserved an increased incidence of obesity in adolescent girls (34, pendent of hyperinsulinemia and abnormal carbohydrate metab35). Long-term follow-up studies of adolescents suggest that olism (56). An alternative perspective is that insulin resistance 30% of all obese adult women were obese early in adolescence, may represent a primary rather than a secondary event (57, 58). fatness (18, 33). with age Furthermore,
958
Whether to the tissue stimuli acting tributes remission to have have genie relapse and its yet appears any of the same of obesity more Fatty may sensitive potential remains than mechanisms unclear. does gluteal also Abdominal fat to
DIETZ predispose adipose lipolytic fat fat conobesity who no or studies lipoor fat the
Age (years)
7 8 9 10 11 12 13 14 15 16 17 18
9
8
1 I C
persistence (59, 60). on the liver to rates increased indicated stimuli play of obesity. distribution
7
6
acids released from intraabdominal help explain why intraabdominal and are higher may than also those fat. explain in women, However, to lipolytic why
tend C)
V
a a a
5
4
females males 3 2
\,\IIIIhhIItCC%C,,I
C) C
responses
persistence
of obesity
Summary These critical obesity observations periods and exist its attendant and effects suggest that at least for the two and possibly
in childhood complications
development
FIG 3. Incidence of obesity among 859 females and 1019 males measured annually between the ages of 7 and y in the Third 18 Harvard Growth Study, 1922-1935. The figure supports the assertion that the periods of adiposity rebound (ages 5-7 y) and adolescence represent times of increased risk for the development of obesity. Children were three not studied before age 7 y. of later
of diabetes,
hypertension.
at each of the critical periods outlined obesity that originate unclear. Likewise, age-specific therapeutic success have been confirmed in several studies, at least one of which has been established, and only limited data have followed subjects into adulthood, few longitudinal observations the potential hazards of weight-reduction have followed children with sufficient frequency through child- regarding Such data are essential to identify hood and adolescence to confirm that incident or persistent obe-children. effective time and target for efforts to prevent and sity increases at the periods outlined above. One exception is the Third ments several elude males with lescence Harvard Growth cohort Boston children appear adiposity marked
<
disease. on subsequent
The
relative
risks
of the
complications
cost-
Study,
which
included
annual
measure- obesity. in I gratefully acknowledge the inGrand, and Aviva Must for their and Aviva Must for her assistance
U
assistance of Jeffrey A Flier, Richard reviews of early drafts of the manuscript, with the data included in Figure 3. J
on a sizable towns near data from and females the peak of that
that coincides peak in adoReferences males (Fig periods these persistent 3). I. Gortmaker
obesity
is more
in females
These observations represent critical periods obesity The also is the focus mechanisms
support the likelihood that these two periods for the onset of obesity. Whether critical periods for the onset deposition of of our current research. that trigger adipose tissue
SL, Dietz
in the United Freedman GS. Secular
WH,
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