Am J Clin Nutr 1994 Dietz 955 9

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Am J Cl in N utr 1 99 4;5 9:9 55 -9 . P rin ted in USA . © 1994 Am er ican So cie ty for C lin ic al N u trit ion 95 5

C ritica l pe r iods in ch ild hood fo r the deve lopm en t

o f obes ity1 -

W illiam H D ie tz

Spec ia l A rtic le

ABSTRACT C ritical p erio ds of dev elo pm ent have b een w e ll

recog n ized fo r m any behav io ra l and deve lopm enta l p rocesses.

H ow ev er , as o thers have p o in ted ou t, such periods hav e n o t been

w ide ly repor ted fo r nu tritiona l d iseases . M any ob serva tions su g-

ges t th at tw o and possib ly th ree c ritica l p e rio ds ex is t fo r th e de-

ve lopm ent o f obes ity an d its com plica tio ns. T hese inc lude ges-

tation and early in fancy , the period of ad ipos ity rebound tha t

occurs be tw een 5 and 7 y of age , and ado lescence . O b es ity th at

beg ins a t th ese periods app ears to inc rease the risk of p ersis ten t

o besity and its com plica tions . T he m echan ism s th at accoun t fo r

the in c reased risk assoc ia ted w ith ob es ity a t th ese ages rem ain

u nc lea r. N one the less , th e ex is ten ce of c ritica l pe riod s shou ld

se rv e to focus preven tive effo rts o n th ese deve lo pm enta l

s tages . A m J C lin N u tr 1 99 4;5 9:9 55-9 .

K EY W O RD S O besity , d iabe tes , fa t d is tribu tion , deve lop -

m en t, ch ild ren

In troduc t ion

O besity is n ow on e of the m ost p rev alen t d iseases in th e pop-

u la tion of the U nited S ta tes (1 , 2 ). A lthou gh a varie ty of dem o -

graph ic and behav io ral facto rs (3 , 4 ) app ear asso c ia ted w ith obe-

s ity , the fam ilial resem blan ces in fa tn ess5 , 6 ) in d ica te a sign if-

ican t gene tic e ffec t on suscep tib ility to the d isease . In gen eral,

the severity o f ob es ity and age a t onse t a ffec t the like lihood o f

the pers is tence of obesity in to adu lthood . A lth ough ch ildhood-

onse t obes ity tha t pe rs is ts in to adu lthoo d m ay be assoc iated w ith

m ore sev ere adu lt d isease (7) , ch ild hood-onset ob esity accounts

fo r a m in ority o f th e cases o f ob esity p resen t in adu lts (8 , 9 ).

C ritica l o r sen sitiv e (10) period s in d eve lo pm ent h ave been

w ell desc ribed fo r m any phys io log ic and behav io ral (1 1) p ro -

cesses . For exam ple , exposure o f the fe tus to rube lla in th e firs t

trim este r o f p regn an cy produ ces a varie ty o f co ngen ital abno r-

m alitie s , w hereas la te r in trau te rine exposure to the v iru s does no t.

O ne of the bes t exam p les o f th is p hen om enon (12) is th e e ffec t

of fe ta l d ihydro tes toste ron e ex posu re o n the ex te rna l g en ita lia.

In trau te rine exp osu re o f fem ales to tes toste ron e be tw een the 8 th

and 12 th w k of feta l deve lopm ent p rod uces fem ale pseudoher-

m aphrod ites . L ikew ise , the absence of d ihydro tes toste ron e in

m ales during the sam e period pro duces am bigu ous or fem in ized

ex te rn al gen ita lia (1 3).

T he po ss ib ility tha t n u trition al a lte ra tions a t c ritica l p er io ds of

d eve lopm ent entrain nutr itiona l state s, such a s adult ob esity , ha s

no t been care fu lly ex p lo red (12 ). N one the less , th e iden tifica tion

of cr itica l p er io ds fo r the deve lo pm ent o f ob es ity m ay serve t

focus p reven tive effo r ts and prom ote charac te rization of the

m echan ism s tha t en tra in body fa t and its d istribu tion . In th is d is -

cuss ion , a cr itica l pe riod fo r th e deve lopm en t o f ob es ity w ill b

defined as a deve lopm enta l stage in w h ich phys io log ic a lte ra tions

inc rease th e late r p rev alence of ob es ity . W e w ill use the w orden train to descr ib e the pro cess tha t is in itia ted during the critica l

pe riod , because its de fin ition ‘ ‘to d raw alon g w ith or a fte r o ne-

se lf” (14) does no t im ply a m echan ism tha t acco un ts fo r th

p rocess tha t fo llow s .

T he prena ta l pe riod , the period of ad ip osity rebound , an d ad-

o lescen ce appear to rep resen t th ree c ritical pe riods fo r th e de

v elopm en t o f o besity . E ach of these w ill be cons idered in tu rn .

Pren ata l p eriod

Obes i ty

Follow -u p s tud ies o f in fan ts exposed to fam in e pren ata lly o

early in life and o f in fan ts o f d iabe tic m o thers stro ng ly sug gest

th at p rena ta l and perina ta l o ver- o r und ernu tritio n in fluences the

d eve lo pm ent o f fa tness in la te r life .

In O ctober 1944 th e G erm an occupat ion res tricted theood su p-

p lies to th e w estern N e ther lan ds. A t the b eg inn ing o fth e oc cup atio n

the av erag e pe r cap ita da ily ra tion app rox im ated 7533 kJ (180 0

kca l ld ) (15 ) and dec lined to 25 1 1 Id (600 kca l/d ) in th e 6 m o tha t

fo llow ed . In M ay , 194 5 , a fte r libe ra tion , foo d sup p lies aga in pro -

v ided 71 14 U (1700 k cal/d ). T he c lea r de lin ea tion of th e on se t an d

end of the fam in e in the N etherlands permit ted a care fu l assessm en t

of the effects o f m aterna l n utr ition on sub sequen t grow th . A t t

tim e of the ir m ilita ry induc tion , therowth of 19 -y -o ld D utch m en

w ho h ad been ex posed to fam in e in u te ro or in the p erin a ta l pe riod

w as com pared w ith age-m atch ed con tro l su b jec ts d raw n from areas

o f H olland th at had no t b een exp osed to the fam in e15) . Obes i ty

F rom the D iv ision o f Ped ia tric G astroen te ro lo gy an d N utritio n , N ew

England M edical C en ter, B o sto n , a nd T ufts U n ive rsi ty Schoo l of M cd

icine, B o sto n .

2 Supported b y g rant H D 25579 from N IC H D and gran t P 30 -DK 46200

from N ID D K .

3 A dd res s rep rin t req ue sts to W H D ietz , N ew England M edic al C en ter ,

B ox 213, 75 0 W ashing ton S tree t, B oston , M A 02111 .

R eceived M ay 26 , 1993 .

A ccep ted fo r pub lica tio n N ovem ber 10 , 19 93 .



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95 6 DIETZ

w as defined as a w eigh t- fo r-he igh t > 120% of s tandard . T he prey -

a lence o f obes ity appeared low est am ong m en exposed to fam ine in

u te ro in the las t trim este r o f p regnancy o r in the imm ediate po stna ta l

per iod . In con tras t, the p reva lence of ob es ityw as inc reased am ong

young m en w ho w ere exposed to fam ine in u tero in the firs tw o

tnm es ters o f p reg nancy (F ig 1 ).

S tud ies o f in fan ts o f d iabe tic m others o ffe r add itiona l suppo rt fo r

the sugg estion tha t the th ird tr im es ter o f p regn an cy m ay rep resen t a

c ritica l pe riod fo r the en tra inm en t o f fa tness. In a la rge po pu la tio n

o f P im a m others and the ir in fan ts (16 ), m others w ere defined as

d iabe tic based on the presence of d iabe tes o r an abnorm al g lucose

to le rance tes t. P red iabe tic m o thers w ere d efin ed as those w ith nor-

m al g lu co se to le rance w ho sub sequen tly deve lop ed d iabe tes . O be-

s ity in the in fan ts and ch ild ren w as defined as a w eigh t 140% o f the

50th p ercen tile des irab le w eig h t-fo r-gesta tio na l age or 140% o f the

50th percen tile o fw eigh t-fo r-he igh t. In fan tsborn to d iabe tic m others

w ere fatte r at b irth than w ere in fan ts o f p red iab e tic o r n ond iabe tic

m others (16). F urthe rm ore , the preva lence of o besity am ong ch il-

d ren of d iabe tic m others a t ag es -9 , 10- 14 , and 15 -19 y w as

sign ifican tly h igh er than the p rev alence o f obe sity am ong child ren

of th e sam e age born to p re - o r nond iabe tic m others (F ig 2). T h e

preva lence of obes ity am ong the ch ild ren of d iabe tic m others a lso

appeared to be independ en t o f th e m other’s obes ity sta tu s at the tim e

of the ch ild ’s b irth (16).

S evera l o th er la rge stud ies have confirm ed the persis ten t ef fect

o f b irth w eigh t fo r the su bsequ en t r isk of obes ity a t ages 6 (17),

1 1 , 15 (18 ), and 17 y (19) , and in adu lthoo d (9 ). In these s tu d ies

th e track in g of b ir th w eigh t w as low er th an tha t o bse rv ed am ong

in fan ts o f d iabe tic m others. N one d ete rm ined g esta tio na l d iabe tes

o r m ate rna l obes ity , bo th of w hich af fec t b irth w eigh t and sub-

sequen t fatness. H ow ever, because the p reva len ce of d iab etes is

like ly to para llel b irth w eigh t, these find in gs a re cons isten t w ith

F IG 1 . P rev alence ofo besity in 1 9-y -o ld m en exposed to fam ine e ith er

in u te ro or du rin g early po stna ta l life . E xposure to fam ine in the las t

trim este r o f p regnancy or ea rly in fancy is asso cia ted w ith a reduced p rev-

a len ce of obesity at age 1 9 y , w hereas ex posure early in pregn an cy is

as soc iate d w ith an inc rea sed p rev alence of o bes ity at a ge 1 9 y .dap ted

from Rave lli e t a l(15 ) .

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FI G 2. Prev alence o f obesity a t subsequen t ages am ong ch ild ren bo rn

to m others w ho w e re d iabet ic , p red iabet ic , o r no nd iabe tic d uring the ir

p reg nancy . A d apted from P ett it e t a l (16 ).

th e fo llow -u p stu d ies o f in fan ts o f d iabe tic m others, and su pport

the possib ility tha t the in trau te rine env ironm ent m ay en tra in sub-

sequen t fa tn ess. N one the less , none of the la tte r o bse rva tions cx-

dude the possib ility o f g ene tic de te rm inan ts th at o pera te in u te ro .

Pathophysiology

The s im p les t concep tua liza tion of the effec ts o f in u te ro nu tri-

tiona l ex posure is tha t ap pe tite reg u lation and ad ipocy te num bers

a re en tra in ed dur in g th is period . E ar ly in u te ro ex posu re to e ithe r

und er- o r overnu tr ition m ay affec t the d iffe ren tia tio n o f h ypo tha-

lam ic cen te rs respo nsib le fo r th e con tro l o f food in take15) . Late

in u tero exp osure to undern u trition m ay reduce the ex tens iv e ad i-

pocy te rep lica tion tha t o ccurs in th e las t trim es te r o f p regnancy ,

w hereas late in u tero expo sure to overn u trition m ay cause ad i-

pocy te hy perp lasia (15 ) . There fo re , ea rly u ndernu trition m ay im -

pa ir the regu la tio n of foo d in take , and p red ispo se to la te r o besity .

L ikew ise , th ird tr im es ter and postna ta l u ndernu trition or over-

nu tritio n m ay in f lu en ce ad ipose tis su e ce llu la rity and p ro tect

aga inst o r prom ote late r o be sity .

A ltho ugh these m echan ism s represen t log ica l hyp o theses, no

f irm ev idence ex is ts fo r eithe r. A dd itiona l fac to rs tha t m ay affect

ad ip ose tissue m ass inc lude d iffe ren tia l o r s ite -depen den t ad i-

po cy te sens itiv ity to o r m etabo lism of insu lin (20 ) o r g lu co co r-

tico ids (21), a lte ra tions in lipopro te in lipase or m itoch ondria l li

po gen ic enzym es (22 , 23), o r ch an ges in insu lin o r lipo ly tic hor-

m on e recep to r num bers (24 ).

T he effec ts o f p rena ta l nu tritiona l exposure on the m orb id ef-

fec ts u sua lly assoc ia ted w ith ob es ity appear d issoc ia ted from the

effec ts o f p rena ta l ex posure on fa tness , and sug gest th a t the en

tra inm en t o f obes ity and its assoc ia ted d iseases m ay be ind epen-

den t p rocesses . F or exam ple , in severa l E ng lish coh orts, low birth

w eigh t in c reased the risk of e lev ated b lood pressu re in ch ild ren

and adu lts (25 , 26), ab norm al g lucose to le rance or d iabe tes in

adu ltho od (2 7), and increased card iovascu lar m o rtality25 , 28) .

The effec ts o f low birth w eigh t on m orb id ity p ersisted afte r con-

tro l fo r geograp h ic reg ion , so cioecon om ic s ta tu s, m ode of in fan t

feed ing , and sm ok in g . T he sam e s tud ies failed to d em onstra te

any increase in m orb id ity o r m o rta lity fo r tho se ind iv idua ls

w hose b irth w eigh t w as g rea te r th an average .



CR IT ICA L PER IO D S FOR O B ES IT Y DEV EL O PM EN T 957

T hese apparen t con trad ic tions o f f e r sev eral te s tab le hy po th e-

se s . Fo r ex am p le , in f an ts w ho se b irth w e ig h t is low because o f

f irst-trim es te r ex posure to u ndernu trition m ay incur an increased

risk o f su bsequ en t ad ipos ity and hy p erten sion or d iab e te s . C h il-

d ren w ho se b irth w e ig h t is low b ecause o f th ird -trim este r m ater-

nal undernu trition m ay in cur an in creased risk o f subseq uen t hy -

pertensio n and d iabe tes , bu t no t o besity . Perhaps the latte r m d i-

v iduals represen t th e ‘ ‘ m etab o lically obese, norm al-w e ig h t

ind iv idua l ’ ‘ (29 ). In f an ts w ho are ex po sed in u te ro to m aternal

ov ernu trition m ay hav e an increased risk o f obesity , bu t a low er

risk o f sub sequen t m orb id ity . C o n f irm atio n o f th e latter hy po th -

e s is w ou ld sug gest th at th e dev e lopm en t o f subsequen t obesity -

re lated d isease in in f an ts o f d iabe tic m o thers depends on pro -

cesse s th at d if f e r o r o ccur late r in dev e lopm en t.

Period of ad iposi t y r ebound

S ev eral sources o f data sug gest that the tim e o f ad ipo sity re -

bou nd m ay represen t ano ther critical period f o r the dev e lopm en t

o f subsequen t ad ipos ity . T he bod y m ass index [B M I; w t (k g )

d iv ided by he ig h t2 (m )] in creases in the f irst y ear o f lif e , and

sub sequen tly decreases (30 , 31 ). B eg inn ing at5 y o f age , B M I

ag ain beg in s to in crease . T he tim e at w h ich the secon d increase

occurs has been called the p erio d o f ad ipos ity reboun d (30 , 31 ).

C hanges in f atness m easured by triceps-sk in f o ld th ick ness appear

to f o llow a s im ilar patte rn (5).

L on g itu d inal observ atio ns f rom a sm all co hort in France (30 ,

31 ) and a som ew hat larg er coh ort in so u thw es te rn O h io (3 2 ) sug -

ges t that the tim e at w h ich ad ip osity rebo und b eg in s m ay hav e a

s ig n if ican t e f f ec t on f atness in ad o le scence (3 0 , 32 ) and adu lt-

hood (31 ) . In bo th ado le scen ts an d adu lts, B M I an d subscapu lar-

sk in f o ld th ick nesses w ere s ign if ican tly g reate r am ong ch ild ren

w h ose ad iposity reboun d beg an early (be f o re.5 y o f age ), co rn -

p ared w ith ch ild ren w hose ad ipo sity reb ound w as av erage (6 .0 - .

6 .5 y ) o r late (af te r 7 y ) (30 , 31 ).

A lthou gh these d ata show c learly a relationsh ip be tw een ad i-po sity rebo und and sub sequen t f atn ess , the prev alence o f obesity

has no t been ex am in ed . T here f o re , the ev idence th at th e p erio d

o f ad ip osity rebound rep resen ts a critical period f o r the dev e l-

opm en t o f subsequen t ob es ity is n o t y et e stab lish ed . A n alte rnate

ex p lanatio n f o r th e e f f ec t o f ad ipo sity rebound on ev en tual ad i-

pos ity m ay be that ch ild ren w h o reb ound earlie r g row f atte r f o r

a long er p erio d o f tim e . R ate s o f B M I increases m ay rem ain

paralle l. T here f o re , d if f e rences in f atness at subseq uen t ages m ay

on ly re f lect an earlie r onse t o f the ag e -re lated increase in f atness ,

and paralle l gain s in f atness thereaf te r. N o pu b lished s tu d ie s hav e

link ed the p erio d o f ad ipos ity reboun d to su bsequ en t m orb id ity

o r m o rtality .

Adolescence

Obesity

A do le scence represen ts the f in al p roposed period f o r th e d e-

v e lo pm en t o f obes ity . B o th the risk o f onset and pers istence o f

obesity appear greater f o r f em ale s than f o r m ales.

T he canaliz ation o f f atness w ith age app ears to in crease

th ro ugho u t ch ildho od (18 , 3 3 ). Furth erm ore , sev eral s tu d ie s ob -

serv ed an increased inc idence o f obes ity in ad o lescen t g irls (3 4 ,

35 ) . L o ng -te rm f o llow -u p s tud ie s o f ado le scen ts sugg es t that

30% of all o bese adu lt w om en w ere ob ese early in ado le scen ce ,

w h ereas on ly 10% of o bese adu lt m ale s had onse t o f th e ir obesity

as teenagers (9 ). A pp rox im ate ly 70% of obese m ales , bu t on ly

20% of o bese f em ales retu rned to norm al w e igh t ov er a 10 -

period (3 6 , 37 ). T hese f in d ings in d icate th at g irls m ay b e at par-

ticu lar risk f o r adu lt obes ity if the ir d isease is p resen t o r dev e lops

during ado lescence, and that ado le scen t-onset obes ity in f em ales

that persis ts in to adu lthoo d m ay herald a lif e lo ng pro b lem .

A d o lescence also ap pears to represen t a critical p erio d f o r the

en trainm en t o f ob es ity -assoc iated m orb id ity . In aS-y f o l l ow - u p

stud y o f ind iv idu als s tud ied during the T h ird H arv ard G row th

S tu dy (19 22 - 19 35 ), m ortality w as in creased am on g m en w ho

w ere ov erw e igh t (B M I > 7 5 th percen tile ) during the ir h ig h

sch oo l y ears w hen com pared w ith m en w ho w ere lean (B M I be

tw een 25 th and 50 th p ercen tile ) ad o lescen ts (38 ). M orb id ity f rom

sev eral d iseases w as also increased am ong b o th m en and w om en

c lassif ied as ob ese d uring h igh scho o l. T he s ign if ican t e f f ec t

h igh schoo l w eigh t o n m orb id ity and m ortality pers isted ev en

w hen w e igh t at ag e 5 3 y w as con tro lled , sugg esting that the m or-

b id ity and m o rtality e f f ec ts re su lted f rom ad o le scen t obesity d i

rec tly , rather than f rom the e f f ec ts o f ad o lescen t obes ity on adu lt

w e igh t. M en tend ed to su f f er m ore consequences o f o besity p res -

en t during ado le scence than d id w om en . D ata f rom y oun g adu lt

o v erw eigh t D u tch (39 ), D an ish (4 0 ), S w ed ish (41 ), and N orw e-

g ian m en (H T W aaler, p erson al com m un ication , 1 991 ) su pport

th es e o bse rv atio ns .

Pathophysiology

T h e m ech an ism s by w h ich ado le scen t-on se t ob es ity lead to a

in creased lik e lih ood o f adv erse seque lae or the pers is tence

obes ity is no t c lear. O n e po ten tial ex p lanatio n f o r the apparen t

en trainm en t o f m orb id ity durin g ad o le scence m ay be the p atte rn

o f f at depo sitio n that occurs at th is tim e . B oy s , an d to a le sse

ex ten t g irls , appear to depo sit f at cen trally and lo se f at periph -

e rally as they m ature (42 ) . E strog en and p roges te ro ne recep to rs

are apparen tly absen t f rom f em ale abdom inal, f em oral, o r om en -

tal ad ip ose tissue (43 ). H ow ev er, androg en recep to rs ex is t in ab

d om inal, om en tal, an d som e g lu teal depo ts (44 ). T hese f ind ing s

sugg es t that th e sex ual d im o rph ism o f ad ipo se tissue depos itio n

du rin g ado le scence m ay be de term in ed by de f au lt. I f and rogens

are p resen t, f at m ay be depos ited in traab dom inally . In the a

sen ce o f androg ens, f at m ay be depos ited in the g lu teal reg ion .

R eg ional d if f e rences in ad ipocy te recep to rs o r m e tabo lism ,

w e ll as d if f e ren tial e f f ec ts o f in su lin on g lucose up tak e and

po ly s is m ay con tribu te to th is p rocess .

In traabdom in al f at in obese adu lts p red ic ts d iabe te s (4 5 ), heart

d isease (46 ), hy pertens io n (47 , 48 ) , and hy p erlip idem ia (49 ). Fur-

th erm ore , f at d istribu tion m ay accou n t f o r a larg e p roportion

th e sex -related d if f e rences in the inc idence o f m y o card ial in f arc -

tion (50 ). Increased re lease o f f ree f atty acid s f rom in traabdom -

inal f at m ay ac t on the liv e r to p roduce hepatic in su lin re s is tance ,

and to redu ce in su lin -m ed iated suppression o f h ep atic g luco se

pro duc tio n and release (51 ). T h ese e f f ec ts con tribu te to g lu co se

in to le rance an d no n -in su lin -dependen t d iabe te s m e llitu s (52 ).

L ik ew ise , increased f ree f atty acid s in the po rtal c ircu latio n m a

decrease in su lin c learance an d con trib u te to hy perin su linem ia

(53). H yper i nsu l i n em ia and insu l i n r esi st ance have been associ -

ated w ith hy perten sion (54 ,55). T he h igh -risk p lasm a lip id pro -

f ile assoc iated w ith in creased in traabdom inal f at appears inde

p enden t o f hy perin su linem ia and abno rm al carboh y drate m etab -

o lism (56 ) . A n alte rn ativ e p erspec tiv e is th at in su lin re s istance

m ay represen t a prim ary rather than a secon dary ev en t (57 , 58



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95 8 DIETZ

Whether any o f the same potential mechanism s also predispose

to the pers istence o f obesity remains unc lear. A bdom inal adipose

tis sue appears mo re sensitiv e than does g luteal fat to lipo ly tic

stimuli (5 9 , 60 ) . Fatty ac ids released from intraabdom inal fat

ac ting on the liver may he lp ex plain w hy intraabdom inal fat co n-

tribute s to hyperinsulinem ia, and may also explain w hy obesity

rem iss ion rate s in men are higher than tho se in w omen, w ho tend

to have increased depo sition o f g luteal fat. How ever, no s tudie s

have ye t indicated that adipocy te respo nses to lipo ly tic o r lipo -

genie s timuli play a central ro le in the likelihoo d o f rem ission or

re lapse o f obes ity . Care ful s tudie s o f the ontogeny o f body fat

and its distribution and o f the sy nerg istic fac to rs that affect the

pers istence o f obes ity are essential.

Summary

These observations sugg es t that at leas t tw o and possibly three

critical periods ex is t in childho od for the deve lopment o f later

obes ity and its attendant complications o f diabe te s, hypertension.

hypercho le s tero lem ia. and cardiov ascular disease .

A ltho ugh the ef fects o f birth w e ight on subsequent obesity

have been confirmed in several s tudies , at leas t one o f w hich has

fo llow ed subjec ts into adulthood, few long itudinal o bserv ations

have fo llow ed children w ith suffic ient frequency through child-

hood and ado lescence to confirm that inc ident or pers istent obe -

sity increases at the periods o utlined above . One exceptio n is the

Third Harv ard Grow th S tudy , w hich inc luded annual measure -

ments on a sizable cohort o f children from 1 st to 12 th grades in

several tow ns near B os ton (38 ) . A ltho ugh this study did no t in-

e lude data from children < 7 y o f ag e , inc idence data in bo th

males and females appear to show an early peak that co inc ides

w ith the peak o f adipos ity rebo und, and a second peak in ado -

le scence that is more marked in fem ale s than in male s (Fig 3 ) .

These observatio ns support the likelihoo d that these tw o periods

represent critical perio ds for the onse t o f o besity . W hether these

perio ds also represent critical periods for the onse t o f persis tent

obesity is the focus o f our current research.

The mechanism s that trigg er adipose tis sue depo sition in spe -

cific locations at some periods o f fetal deve lopment and child-

hood remain unc lear. N one thele s s, these perio ds represent ma-

turational stages ideally suited for the study o f the interac tion o f

env ironmental fac to rs w ith the genes that co ntro l dev elo pment.

The mechanism s that entrain the long -term deve lopment o f the

body fat mass , the po ss ibility that the morbidity o f o besity may

depend on the critical period in w hich obes ity deve lops , and iden-

tificatio n o f the hormones and the means by w hich they induce

sex -spec ific reg ional adipo cy te replication are log ically the sub-

jec ts o f further inv es tigations.

The ex is tence o f critical periods for the deve lo pment o f adi-

pos ity and its seque lae may also serve to focus prev entive and

therapeutic e fforts on deve lopmental s tag es w hen these e fforts

are like ly to be most co st e ffec tive . For example , im proved dia-

be tic contro l may reduce the e ffects o f gestational diabe te s on

birth w e ight and subsequent fatness. How ev er, e fforts to contro l

w e ig ht during the third trimes ter because o f the putative e ffec ts

o f w e ig ht gain on subsequent fatness canno t be supported based

on the data rev iew ed. U ntil further data are forthcom ing , the po -

tential grow th re tardatio n induced by third-trimes ter w e ig ht co n-

tro l may be more hazardous than w hatever e ffec ts third-trimes ter

w e ight gain may have on neonatal adipos ity .

A ge (y ea rs )

FIG 3 . Inc idence o f o besity among 8 59 female s and 1019 males mea-

sured annually be tw een the ages o f 7 and8 y in the Third Harvard

Grow th S tudy , 1922 -193 5 . The figure suppo rts the assertion that the

periods o f adiposity rebo und (ages 5 -7 y ) and ado le scence represent

tim es o f increased risk for the deve lo pment o f obesity . Children w ere

no t s tudied be fo re age 7 y .

The re lative risks o f the complications o r pers is tence o f obesity

that orig inate at each o f the critical periods outlined abo ve remain

unclear. Likew ise , age -spec ific therapeutic success rates have no t

been established, and only lim ited data hav e been published

reg arding the po tential hazards o f w e ight-reduction therapy

children. S uch data are essential to identify the most co st

e ffec tive tim e and targe t for e ffo rts to prev ent and treat childhood

obesity. U

I gratefully acknow ledge the assistance o f Je ffrey A Flier, Richard J

Grand, and A v iva M ust for their rev iew s o f early drafts o f the manuscript,

and A v iv a M ust fo r her ass istance w ith the data inc luded in Figure 3 .

References

I. Gortmaker SL, D ietz WH, S obo l AM , W ehler CA . Increas ing pediatric

obesity in the U nited S tate s. Am J D is Child l9 87 ;141:535-40 .

2. Shear CL, Freedman D S, B urke GL, Harsha DW , W ebber LSBerenson GS . S ecular trends o f obesity in early life: the B ogalusa

Heart S tudy . Am J Public Health 1988:78:75-7 .

3 . D ie tz WH, Gortmaker SL. Fac to rs w ithin the phys ical env iro nment as -

sociated w ith childho od obesity . Am J Clin N utr 19 84 ;39 :6 l9 -2 4 .

4. D ie tz WH, Gortmaker SL. D o w e fatten o ur children at the TV se t?

Te lev ision v iew ing and obesity in children and ado le scents. Pedi-

a tri cs 1 98 5:7 5 :8 0 7- 12 .

5. Garn SM . Continuities and changes in fatness from infancy through

adulthoo d. Curr Prob Pediatr 19 85 :15 :1 -4 7 .

6 . Bouchard C, S avard R, D upres i-P. Tremblay A , Leblanc C. B ody

composition in adopted and bio log ical s iblings. Hum B io l

1985 :57 :61 -75 .

7 . Rimm Ii, Rimm AA . A ssoc iatio n be tw een juvenile onset obes ity and

severe adult obes ity in 73 ,53 2 w omen. Am J Public Health

1976 :66 :479 -81 .

8 . A braham 5 , N o rdsieck M . Relationship o fxcess w eight in children

and adults. Public Health Rep 1 960 :75 :26 3 -73 .

9 . B raddon FEM , Rodgers B , W adsw orth MEJ, D av ie s JMC. Onse t o f

obesity in a 36 year birth cohort. B r M ed J 1986 ;2 93 :299 -303 .

1 0 . Tanner JM . Fo e tus into man. Cambridg e , MA : Harv ard U niversity

Press , 199 0 .

1 1 . Illingw orth RS , Lis ter J. The critical o r sens itiv e period w ith spec ial

re ference to certain feeding problem s in infants and children. J Pc -

d iatr l 96 4;6 5:8 39 -4 8.

12 . Lucas A . Prog ramm ing by early nutrition in man. In: B o ck OR,

Whelan J, eds. T he childho od environment and adult disease . N ew

York: John W iley and Sons, 19 91 :38 -5 5 .



CR IT ICA L PER IO DS FO R OB ES IT Y D EV EL O PM EN T 95 9

13. G rum baeh M M , C onte FA . D isord ers of sex dif f erentiatio n . In :

W ilson JD , Fos ter DW , cds. W illiam s tex tbook o f endocrino log y .

8 th ed . Ph iladelphia: W B S aunders C o , 19 92 :853 -95 1 .

14. W eb ste r’s N ew Co llegiate D ictio nary . S p ring f ie ld , M A : GC

M erriam C o. 1980 .

15. R av ell i G -P, S tein Z A , S usser M W . O bes ity in y oung m en af ter

f am ine ex posure in ute ro and early in fancy . N Engl J M ed

1976:295:349-53.

16. Pett it D i, B aird HR . A leek K A , B ennett PA , K now le r W C . E x ces-

s iv e obe sity in of f spring of Pim a Ind ian w om en w ith diabetes durin g

p regnancy . N Engl J M ed 1983 :308:242 -5 .

1 7. B in k in N J, Y ip R , Fleshood L , T row b ridg e FL . B irth w eigh t and

childhood grow th . Pediatrics 1988 :82:828-34.

1 8. C risp A H , Doug las JW B , R oss JM , S tonehil l E . S om e dev elo pm ental

aspects o f d isord ers o r w eight. J Psy chosom R es 1970 :14 :313-20.

1 9. S eidm an DS , L aor A , G ale R , S tev enson DK , D anon Y L . A long i-

tudinal s tud y of birth w eight and being o v erw e igh t in late adole s-

e ence. A m J D is Ch ild 1991 :145:782 -5 .

20 . S w inburn B A , N y om ba B L , S aad M F, e t al. In su lin re sis tan ce as-

sociated w ith low er rate s of w eight gain in Pim a Ind ian s. J C lin

In v e st 1991;88: 168 -73 .

21 . B ray GA . Obesity , a d iso rde r o f nutrient partitio nin g: T he M ON A

L IS A hy po thesis . J N utr 1 991 :12 1 :1146 -62 .

22 . L eib el R L , E den N K , Fried S K . Phy s io log ic b as is f o r the con tro l o f

body fat d istribution in hum ans. A nnu R ev N utr 1989:9 :417-43.

23 . E ck e l R H . L ipop rotein lipase: a m u ltif un etio nal en z ym e relev ant to

com m on m e tabolic d iseases . N E ng l J M ed 1989:320:1060-8 .

24 . M artin M L , Jensen M D . E f f ec ts o f bo dy f at d istribu tion on reg ional

lipoly sis in obes ity . J C lin In ve st 1 99 1:8 8:6 09 -1 3.

25 . B ark er D JP, O sm ond C , G o ld ing J, K uh D , W adsw o rth M E J.

G row th in u tero , b lo od p ressure in childhood and adult li f e , and

m ortali ty f rom cardio v ascular disease . B r M ed1987 :298:564 -7 .

26 . B ark e r D JP, B ull A R , O sm ond C , S im m ond s S J. Fe tal and placen tal

s iz e and risk of hy perten sio n in adult lif e . B r M ed J 1990;301 :259-62.

27 . H ales CN , B ark er D JP, C lark PM S , e t al. Fe tal and in fan t g row th and

im paired g lucose to lerance at ag e 64 . B r M ed J 1991:303 :1019 -22 .

28 . B ark er D JP, O sm ond C , W inte r PD , M arjetts B , S im m ond s S J.

W eight in in fancy and death f rom ischaem ic heart d isease. L an cet

1989;2:577-80.

29 . R uderm an N B , S chneid er SH , B erchto ld P. T he “m etabo lically -ob ese ,”

norm al w e igh t ind iv idual. A m J C lin N utr 1981:34:1617-21.

3 0. R olland -Cache ra M -F, D eheeg er M , B ellisle F, S em pe M , G uilloud-

B atouille M , Patois E . A d ipo sity rebound in children: a sim ple in -

d icator f o r p red icting obes ity . A m J C lin N u tr 1984 :39 :129-35.

3 1. R o lland-Cache ra M -F, D eheege r M , Gu illo ud -B atail le M , A v ons P,

Pato is E , S em pe M . T rack in g th e dev e lopm ent o f adipos ity f rom one

m on th of ag e to adulthood. A nn H um B io l 1987:14:219 -29 .

3 2. S ie rv ogel R M , R oche A F, G uo 5 , M uk herje ED , C hum lea W C . Pat-

tern s o f change in w e igh t/s tatu re2 f rom 2 to 18 y ears : f indings f rom

long -term serial data for children in the Fels L ongitudinal G row th

S tud y . m t J O bes 1991;15:479 -85 .

3 3. Z ack PM , H arlan W R , L eav erton PE , Co rnoni-Hun tle y J. A long i-

tudinal s tud y of body fatness in childhood and ado lescence. J Pediatr

1979;95: 126-30.

3 4. D ietz W H . O besity in in fan ts, children, and ado lescen ts in the U nited

S tates I. Id entif icatio n , n atu ral h istory , and af te r ef f ects . N u tr R ev

1 9 8 1: 1 : 1 1 7 - 3 7 .

35 . Johnson M L , B urk e B S , M ay er J. T he prev alence and in cid en ce of

obes ity in a cro ss-section of e lem en tary and secondary school chil-

d ren . A m J C lin N utr 1956 ;4:231-8 .

3 6 . G arn S M , C o le PE . D o the ob ese rem ain ob ese and the lean rem ain

lean? A m J Pub lic H ealth 198 0 ;70 :351 -3 .

3 7 . G arn S M , B ailey SM , C o le PE . C on tinu itie s and changes in f atn ess

and o besity . In : S chem m el R , ed . N u trition phy sio logy and ob es ity .

W es t Palm B each , FL : CR C Press, Inc . 197 9 .

38 . M ust A , Jacqu es PF, D allal G E , B ajem a CJ, D ic tz W H . L ong-term

m orb idity and m ortality o f o v e rw e igh t ado lescents: a fo llow -up o

th e Harv ard G row th S tud y o f 1922 to 1935. N E ng I J M e

1992:327:1350-5 .

39 . H oofm ans M DA F, K rom hou t D , Couland er C dc L . B ody m ass i

d cx at the age o f 18 and its ef f e cts on 32-y ear-m ortality f rom cor-

onary heart d isease and cancer. J C lin Ep idem iol 1989:42:513 -20 .

40 . S o ren sen T IA , S onne -ho lm S . M ortali ty in ex trem e ly o v e rw e igh t

y oung m en. J Ch ron D is 1977 :30 :359-67.

4 1. M ossb erg H -O . 40 -Y ear- f o llow -up o f o v e rw e igh t children. L an ce t

1 9 89 : 2 : 4 9 1- 3 .

42 . M ueller W H . T he changes w ith ag e of the anatom ical distribution

o f f at. S oc S c i M ed 1982 ;1 6 :19 l-6 .

43 . R ebu f f e ’-S c riv e M , B ronnegard M , N ilsson A , E lda J, Gu staf sson

J-A , B jo rn to rp P. S te ro id h orm one recep to rs in hum an ad iposeis-

sues . J C lin Endocrin ol M etab 1990:71:1215-9 .

4 4. M iller L K , K ral JO , S train OW , Z um o f f B . A ndrogen b ind ing

am m on ium sulf ate p rec ip itate s o f hum an adipose tis sue cy toso ls.

S tero ids 199 0:5 5:4 10 -5 .

45 . L und gren H , B eng ts so n C , B lo hm e 0 , L ap idus L , S jo s trom L . A d-

ip osity and ad ipo se tis sue distrib utio n in relation to inc idence o

d iab etes in w om en: results f rom a p rospec tiv e popu lation s tud y i

G oth enburg, S w eden . In t J O bes 1989 :13 :413-23.

4 6. L arsson B , S v ardsudd K , W elin L , W ilh clm sen L , B jornto rp P. T ibblin

G . A bdom inal ad ipo se tissue dis trib ution , obe sity and risk of card io-

v ascular disease and death: a 13 -y ear f o llow -up o f participan ts in th e

s t ud y o f me n b o r n i n 1 9 1 3 . Br Me d J 1 9 8 4 : 28 8 : 14 0 1 - 4.

47. W e ins ier R L , N orris D J, B irch R S ,t al. T he relativ e contribu tio n

o f bod y fat and fat pattern to b lood pressure lev el. H y pe rten sio n

1985:7:578-85.

4 8. K aplan N . T he deadly quartet: upp er body obes ity , g lu cose in to ler-

ance , h y pe rtrig ly ceridem ia, and hy pe rtension. A rch Inte rn M ed

1 9 8 9: 1 4 9: 1 5 14 - 2 0 .

49. Freedm an D S , Jacob sen S J, B arboriak JJ, e t al . B ody fat d is trib ution

and m ale/f em ale d if f erence s in lip ids and lip oprote ins. C irculation

1 9 9 0: 8 1 : 1 4 9 8- 5 0 6 .

50. L arsson B , B engtsson C , B jo rnto rp P. et al . Is abdom inal bod y f

d istribu tion a m ajo r ex planation fo r th e sex d if f erence in the m c i-

d ence of m y ocardial in f arction? A m J E pidem io l 1992:135 :266-73.

5 1. B jo rntorp P. A bdom inal obes ity and the dev elo pm en t of n on insu lin

d ependent diabe tes m elli tus . D iab ete s M e tab R ev 1988 :4:615 -22 .

5 2. B jornto rp P. Portal ad ipo se tissue as gen erator of risk f actors f or car-

d iov ascular disease and d iabe tes . A rte rio scle ros is I99 (): 10 :493-6 .

53 . H ennes M M I, S h rago E , K issebah A H . R ecepto r and postrecepto r

e f f ec ts o f f ree f atty acid s on hepatic in sulin d y nam ics. In t J O bes

1 99 1 ; 14 :83 1 -4 1 .

54 . L and sbe rg L . In sulin and hy p ertension: le ssons learned f rom obes ity .

N Eng l J M ed 19 87 :317 :3 78 -9 .

55 . D eFron z o R A . T he e f f ec t o f insulin on renal sod ium m etabolism :

rev iew w ith c lin ical im plications . D iabe tolo gia 1981:21: 165-7 1.

56 . Ferland M , D esp res J-P, N adeau A , e t al. C on tribu tion s o f g lucose

to lerance and plasm a in sulin le v els to the re lationship s b etw een body

fat d istribution and plasm a lipopro tein le v els in w om en . In t J O bes

1 9 9 1: 1 5 : 6 7 7 - 8 8 .

57 . R eav en GM . B an ting lec tu re , 1 988 : ro le o f in su lin re sis tan ce in hu -m an d isease . D iab etes 1988:37:1595 -607.

58 . DeFronz o R A , Ferran n in i E . In su lin re sis tance : a m ultif ace ted sy ndrom e

re spons ib le f o r N IDDM , obesity , h y pe rtension, dy slip id em ia and ath-

e roselerotic cardio v ascular disease. D iabetes C are 1991:14:173 -94.

5 9. R ebuf f e’-S criv e M , Enk L , C rona N , et al. Fat c ell m etabo lism

d if f e ren t regions in w om en . J C lin Inv est 1 985;75:1973 -6 .

6 0. W ahrenbe rg H , L onnqv ist F, A m er P. M echan ism s underly in g re

gional d if f erence s in lipo ly sis in hum an ad ipo se tis sue . J C lin Inv est

1989;84:458-67.

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