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Pediatr (Rio J). 2018;94(6):582---595

www.jped.com.br

EVIEW ARTICLE

s willingness to exercise programmed in utero?eviewing sedentary behavior and the benefits ofhysical activity in intrauterine growth restricted

ndividuals�

drianne Rahde Bischoffa,b,∗, Fábio da Silva Cunhac, Roberta Dalle Mollec,aulo José Cauduro Marósticac, Patrícia Pelufo Silveirac,d

University of Toronto, Department of Pediatrics, Division of Neonatology, Toronto, CanadaHospital for Sick Children, Toronto, CanadaUniversidade Federal do Rio Grande do Sul, Faculdade de Medicina, Departamento de Pediatria, Programa de Pós-Graduacão emaúde da Crianca e do Adolescente, Porto Alegre, RS, BrazilMcGill University, Douglas Mental Health University Institute, Ludmer Centre for Neuroinformatics and Mental Health,ontreal, Canada

eceived 7 September 2017; accepted 15 December 2017vailable online 22 February 2018

KEYWORDSDOHaD;IUGR;Physical activity;Sedentary behavior

AbstractObjective: The literature suggests that a fetus will adapt to surrounding adversities by opti-mizing its use of energy to improve survival, ultimately leading to the programming of theindividual’s energy intake and expenditure. While recent reviews focused on the fetal pro-gramming of energy intake and food preferences, there is also some evidence that fetaladversity is associated with diminished physical activity levels. Therefore, we aimed to review(a) the evidence for an association between being born with intrauterine growth restrictionand sedentarism over the life-course and (b) the potential benefits of physical activity overcardiometabolic risk factors for this population.Sources: PubMed, Scielo, Scopus and Embase.Summary of findings: Most clinical studies that used objective measures found no association

between intrauterine growth restriction and physical activity levels, while most studies thatused self-reported questionnaires revealed such relationships, particularly leisure time physicalactivity. Experimental studies support the existence of fetal programming of physical activity,and show that exposure to exercise during IUGR individuals’ life improves metabolic outcomesbut less effect was seen on muscle architecture or function.

� Please cite this article as: Bischoff AR, Cunha FS, Molle RD, Maróstica PJ, Silveira PP. Is willingness to exercise programmed intero? Reviewing sedentary behavior and the benefits of physical activity in intrauterine growth restricted individuals. J Pediatr (Rio J).018;94:582---95.∗ Corresponding author.

E-mail: adrianne.bischoff@sickkids.ca (A.R. Bischoff).

ttps://doi.org/10.1016/j.jped.2017.12.015021-7557/© 2018 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-NDicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Fetal programming of energy expenditure 583

Conclusions: Alterations in muscle strength and metabolism, as well as altered aerobic perfor-mance, may predispose IUGR individuals to be spontaneously less physically active, suggestingthat this population may be an important target for preventive interventions. Although veryheterogeneous, the different studies allow us to infer that physical activity may have beneficialeffects especially for individuals that are more vulnerable to metabolic modifications such asthose with IUGR.© 2018 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. This is an openaccess article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PALAVRAS-CHAVEDOHaD;RCIU;Atividade física;Comportamentosedentário

A vontade de se exercitar é programada ainda no útero? Análise do comportamentosedentário e dos benefícios da atividade física em indivíduos com crescimentointrauterino restrito

ResumoObjetivo: A literatura sugere que um feto se adaptará às adversidades externas ao apri-morar seu gasto energético para melhorar a sobrevida, o que leva, em última instância, àprogramacão do consumo e gasto energético do indivíduo. Apesar de análises recentes teremfocado na programacão fetal do consumo energético e preferências alimentares, ainda háalguma comprovacão de que as adversidades fetais estão associadas aos baixos níveis de ativi-dade física. Portanto, visamos analisar: a) a comprovacão de uma associacão entre nascer comrestricão de crescimento intrauterino (RCIU) e sedentarismo durante o curso de vida e b) os pos-síveis benefícios da atividade física sobre os fatores de risco cardiometabólico dessa populacão.Fontes: PubMed, Scielo, Scopus e Embase.Resumo dos achados: A maior parte dos estudos clínicos que usaram medidas objetivas nãoconstatou associacão entre RCIU e os níveis de atividade física, ao passo que a maior partedos estudos que usaram questionários de autorrelato revelou essas relacões, principalmente noque diz respeito à atividade física de lazer. Estudos experimentais corroboram a existência deprogramacão fetal de atividade física e mostram que a exposicão a exercícios durante a vidade indivíduos com RCIU melhora os resultados metabólicos, porém menos efeito foi visto sobrea arquitetura ou funcão muscular.Conclusões: Alteracões na forca muscular e no metabolismo, bem como o desempenho aeróbicoalterado, podem predispor indivíduos com RCIU a serem espontaneamente menos ativos fisica-mente, sugere que essa populacão pode ser um importante alvo de intervencões preventivas.Apesar de muito heterogêneos, os diferentes estudos nos possibilitam deduzir que a atividadefísica pode ter efeitos benéficos principalmente em indivíduos mais vulneráveis a modificacõesmetabólicas, como aqueles com RCIU.© 2018 Sociedade Brasileira de Pediatria. Publicado por Elsevier Editora Ltda. Este e um artigoOpen Access sob uma licenca CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Introduction

The Developmental Origins of Health and Disease (DOHaD)concept aims to study the consequences that adverse eventsoccurring during early phases of human development haveon disease and health patterns over the life course.1,2

Another interesting aspect related to this field of researchrelates to the programming of a behavior, such as foodintake, feeding preferences or willingness to engage inphysical activities, which ultimately may contribute to thedevelopment of such diseases. While most of DOHaD fieldhas focused on how fetal programming may affect histo-logical, anatomical or metabolic markers, it is intriguing to

think that neurobiological changes that affect behaviors mayalso be equally affected by adversity in vulnerable periodssuch as fetal life/infancy/adolescence. Behaviors involving‘‘will’’ or ‘‘choices’’ are usually closely associated to free

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ill in human nature, and it may be uncomfortable to sug-est that this may be shaped by neurologic and geneticeterminants and influenced by the environment.3 Is it pos-ible that the biological parameters can define our ownree selves? As stated by David Goldman, ‘‘individual freeill, and by extension the autonomy of groups of people,re parameters whose existence can be derived from thenheritance of cognitive structures and variation in thesetructures due to neurodevelopmental adaptation’’.3

One way to measure intrauterine adversity relates tooor fetal growth. Intrauterine growth restriction (IUGR)s the inability of the fetus to achieve its full potentialrowth4 which can be caused by, but not restricted to, pla-ental insufficiency,5,6 maternal malnutrition and smoking,7

ongenital infections and anomalies, drugs, obesity andhromosomal abnormalities.4,8 The estimated burden ofUGR is very high considering that in low and middle-income

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ountries, for instance, IUGR accounts for 27% of live births.9

dditionally, IUGR has been linked to non-communicable dis-ases later in life, such as metabolic syndrome,2,10,11 type IIiabetes11 and cardiovascular diseases.12

The thrifty phenotype hypothesis proposes that the fetusdapts to surrounding adversities (e.g. lack of nutrients)y optimizing its use of energy to improve survival.1,2

his ultimately leads to the programming of the individ-al’s energy intake and expenditure.13---15 Regarding energyntake, our group has spent the last few years studyinghe programming of food preferences toward highly caloricalatable foods.16---21 On the other hand, it is interesting tocknowledge that adverse events in the early developmentan cause behavioral consequences. When considering thexpenditure, there is also evidence that this population mayave diminished physical activity levels,22,23 contributing toncreased storage and consequent predisposition to alteredetabolic states.Experimental studies have shown that IUGR offspring are

ess active when compared to those born with normal birtheight.23---25 Evidence of lower levels of leisure-time physi-al activity and increased levels of sedentary behavior havelready been demonstrated by some clinical studies,22,26---30

hile others have reported controversial results, withoutny association between low birth weight and lower levelsf physical activity.31---36

Additionally, considering the detrimental effects of IUGRater in life, some studies have also focused on the potentialenefits that physical activity can have on metabolic out-omes of this at-risk population.37 It appears that exerciseay attenuate cardiometabolic risk factors such as glucose

ntolerance,29 insulin resistance38 and poor lipid profile39

specially in the IUGR population in which these risk factorsre more prevalent.

In this review we summarize the available clinical andxperimental evidence regarding: (1) the effects of IUGRn sedentary behavior and physical activity levels, and (2)he potential benefits of exercise interventions to attenuateegative cardiometabolic effects of IUGR. Furthermore, wexplore some mechanisms that are likely implicated in thesessociations.

linical evidence of the fetal programming ofnergy expenditure

he general environmental message during intrauterine lifef an IUGR fetus is of a paucity of nutrients, therefore organsnd systems are programmed to save energy.15 The fetalrogramming of energy expenditure, including diminishedhysical activity levels and body lean mass, saves energy forrowth and fat accumulation. Additionally, muscle strengths directly associated with physical activity levels,40 so its likely that IUGR individuals may exercise less because ofacking appropriate musculature.41,42

There is a large heterogeneity in the literature regardinghe study of variables related to sedentarism and physicalctivity. While some studies use objective measurements,

uch as accelerometer, others use self-reported question-aires and measures such as leisure time physical activityLTPA). Accelerometer, for instance, can estimate totalctivity with an average counts per minute (cpm) over

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he valid measurement period.43,44 The cut off to defineoderate to vigorous physical activity also uses the aver-

ge cpm but in terms of time spent each day on suchctivity.45 Nonobjective measurements include LTPA, mea-ured through questionnaires that evaluate the frequencynd duration of different conditioning (such as running,wimming) and non-conditioning (such as gardening, house-old work) activities.46,47 Different questionnaires have beenalidated for different time frames, ranging from a recallime of 1 week48 to 12 months.47

Sedentarism is defined according to the time spentn physical activity and the cut off points are also vari-ble among the different studies, ages and methodologiessed. For instance, in adolescents a sedentary lifestyle isonsidered as less than 300 min of physical activity pereek measured through questionnaires49 whereas in adults

t is considered as less than 150 min per week.30 Differ-nt studies convert questionnaire responses into Metabolicquivalent of Task (MET)-min/week and use METs cutoffso define sedentarism.22 Similarly, sedentary behavior haseen defined as <100 cpm in children using accelerometer.50

herefore, when considering the different studies, onehould keep in mind the specific concepts and constructseing evaluated. We separate the studies into those usingbjective and self-reported questionnaire data, and there-fter discuss the potential benefits of physical activity toUGR individuals. Table 1 summarizes the main characteris-ics of the clinical studies.

tudies using objective measures to assess thessociation between IUGR and physical activity

ehoe et al. evaluated accelerometer measures in children6 to 10 year-olds) in rural India. There were 8% of small forestational age (SGA) children in the sample (considered as

birth weight of <2.5 kg) and birth weight varied from 1.57o 4.75 kg. There were no significant associations betweenny of the anthropometric measures at birth and the phys-cal activity variables.36 It is interesting to notice that inhis study socio economic status was negatively associatedith physical activity. Although the data were not shown,

he authors described that separate analysis for SGA andreterm were conducted and that there was a trend forGA to be less active. It seems to us that the definition ofGA was not adequate and the use of other definitions forGA (i.e.: smaller than 10th percentile or birth weight ratio0.85) would result in a larger proportion of low birth weightor a given gestational age in the population described.

The ALSPAC (Avon Longitudinal Study of Parents andhildren) cohort included a large sample of school-agedhildren and there was no relationship between physicalctivity levels, measured through accelerometer, and any ofhe neonatal anthropometrics measurements (birth weight,onderal index, head circumference) or gestational age.43

irth weight was used as a continuous variable but the studyid not categorize individuals as SGA or IUGR.

Another study included four birth cohorts from Europeanountries and Brazil32 and found no significant associationetween birth weight and objectively measured physicalctivity. The cohort from Brazil that was included in this

Fetal programming of energy expenditure 585

Table 1 Summary of clinical studies evaluating the relationship between IUGR and physical activity/sedentarism.

Author/year(referencenumber)

Age in years(number ofparticipants)

Tool Definitions Outcome

Objectively measuredKehoe,201236

6---10 (449) Accelerometer for 7 days <100 cpm: sedentary behavior100---2291 cpm: light activity2292---4007 cpm: moderateactivity>4008 cpm: vigorous activity

No associations betweenbody size and skinfoldthickness at birth andphysical activity levels

Mattocks,200743

11---12 (5451) Accelerometer for 7days + record ofswimming/cycling time

>3600 cpm: moderate tovigorous activity

BW has no influence inphysical activity levels

Ridgway,201132

9---15 (4170) Accelerometer ≥ 3 days <100 cpm: sedentary time>2000 cpm: moderate andvigorous activity

No association betweenBW and total physicalactivity. One cohortshowed a associationbetween higher BW andlower levels of totalphysical activity

Kaseva,201551

22---30 (104) Accelerometer ≥ 3 days <320 cpm, <1.5 METs:sedentary time1048---1624 cpm, 3---6 METs:moderate PA>1624, >6 METs: vigorous PA≥1048 cpm, ≥3 METs:moderate-to-vigorous PA

No significant differencein physical activity levelsor sedentary time inVLBW compared to termcontrols (same cohort asKajantie, 2010)28

Hildebrand,201531 andEkelund,201252

6---18 (10,793) Accelerometer <100 cpm: sedentary time>3000 cpm:moderate-to-vigorous PA

BW positively associatedwith sedentary time

vanDeutekom,201453

8---9 (183) Accelerometer >3000 cpm: moderate activityMinutes sedentary per day

LBW was not associatedwith either physicalactivity or sedentarytime

QuestionnairesKaseva,201247

22---30 (195) 12 month recallquestionnaire

Conditioning LTPA (running,skiing, swimming),non-conditioning LTPA(household work, gardening,shoveling snow), PA fromcommuting to work. Frequency,duration and average intensity

VLBW undertake lessleisure-time physicalactivity (same cohort asKajantie, 2010)28

Kajantie,201028

18.5---27.1 (351) Questionnaire Occupational, commuting, andleisure-time non-conditioningphysical activity. Frequency,duration and intensity.

VLBW exercise less thanadults born at term(30% vs 0% were SGA inthe VLBW sample)

Andersen,200926

14---74 (43,482) LTPA Questionnaire Duration, frequency and/orintensity

Reverse U-shapedassociation between BWand leisure time physicalactivity

586 Bischoff AR et al.

Table 1 (Continued)

Author/year(referencenumber)

Age in years(number ofparticipants)

Tool Definitions Outcome

Fernandes,201022

22---23 (2057) 1 week recallquestionnaire

Active: >7 days of combinedactivities reaching at least 3000 METsor intense activity for at least 3 daysreaching a minimum of 1500 METs;Sufficiently active: ≥5 days ofcombined activities reaching at least600 METs or >5 days of walking for aminimum of 30 min/day or >5 days ofmoderate activity for at least30 min/day or >3 days of intenseactivity for at least 20 min/day;Sedentary: when the level of physicalactivity was below the abovedescriptions

LBW is a risk factor forsedentary behavior

Azevedo,200830

21---23 (4297) 1 week recallquestionnaire

Sedentary: <150 min/week of PA BW inversely associatedwith sedentarism only inwomen

Hallal,200649

10---12 (4453) Questionnaire Sedentary lifestyle: <300 min/weekof PA

Lower BW associatedwith increased sedentarytime

Elhakeem,201654

13---68 (2739) LTPA Questionnaire Inactive: no participation in LTPA;Moderately: up to four times in LTPA;Regularly active: five or more timesin LTPA (in the previous month at age36 years, per month at age 43 years,and in the previous 4 weeks at ages53, 60---64, and 68 years).

LBW was associated withlower ability in schoolsports and withnonparticipation in LTPAacross adulthood.

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IUGR, intrauterine growth restriction; cpm, counts per minute; BWVLBW, very low birth weight; LTPA, leisure time physical activity;

tudy revealed results in the opposite direction, with higherirth weight being associated with lower levels of activity.32

Kaseva et al. used the same methodology withccelerometer to objectively measure physical activity lev-ls in a cohort (Helsinki Study) of very low birth weightVLBW) (<1500 g) young adults.51 Overall there were noifferences in physical activity levels or sedentary timeetween VLBW and control participants.

Hildebrand et al.31 and Ekelund et al.52 used the Inter-ational Children’s Accelerometry Database and found thatirth weight was positively associated with sedentary timend with waist circumference.31 There were no data regard-ng gestational age, so the authors could not differentiateetween low birth weight caused by IUGR or by prema-urity. In 2014 van Deutekom et al. described that birtheight was not related to either physical activity or seden-

ary behavior.53

tudies using self-report questionnaires to assesshe association between IUGR and physical activity

wo other studies were performed in the previouslyescribed Helsinki cohort,28,47 but assessed physical activ-ty through questionnaires of LTPA. The study by Kasevat al. found markedly reduced LTPA in VLBW adults when

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th weight; MET, metabolic equivalent task; PA, physical activity; small for gestational age.

ompared to controls.47 Kajantie et al. described similarndings.28 When asked about the amount of time spent inhysical activity during their leisure time, VLBW individualsad significant less time devoted to LTPA when compared toontrols (35% versus 25%). It is important to notice that theLBW sample included 30% SGA, while the control samplead no SGAs. Subgroup analysis comparing VLBW SGA andLBW born appropriate for gestational age (AGA) revealedo differences in any of the physical activity variables, norirth weight SD score and gestational age as continuousariables within the VLBW group. In this study, IUGR doesot seem to be implicated in the findings and it is likely thathe association is attributable to prematurity.28

In a sample of both children and adults born IUGR, teach-rs reported lower ability in sports in 13 year-olds and lowerelf-reported LTPA in adulthood.54 A meta-analysis by Ander-en et al.26 included a wide range of age groups, from 14 to4 years old, derived from 13 Nordic cohorts. Both low andigh birth weight were associated with lower LTPA levels inomen and men.

Some studies explored other possible factors interacting

ith birth weight to influence sedentary behavior levels,

uch as education and socioeconomic status. A cohort ofoung adults by Fernandes et al. found an associationetween sedentary and LBW conditioned to individuals who

Fetal programming of energy expenditure 587

Table 2 Physical activity levels effects on metabolic outcomes of LBW/IUGR.

Author/year Age in years (number of participants) Outcome

Aoyama, 201356 20---64 (379) BW and cardiorespiratory fitness inversely associatedwith HOMA-IR

Eriksson, 200429 65---75 (500) Regular and moderate exercise protects against glucoseintolerance in elderly people with increased risk ofdeveloping Type 2 diabetes (born with LBW)

Labayen, 201359 12---17 (538) Meeting the physical activity recommendations mayattenuate the negative effect of LBW on serum leptinlevels

Laaksonen, 200338 42---60 (462) Regular vigorous leisure-time physical activity or goodcardiorespiratory fitness seems to attenuate theassociation of LBW with insulin resistance and metabolicsyndrome

Madsen, 201558 19---21 (117) LBW benefits metabolically from exercise training to anextent comparable with NBW controls

Ortega, 201160 12---17 (846) Higher levels of physical activity may attenuate theadverse effects of LBW on insulin sensitivity inadolescents

Redmond, 201339 20 (36) Low Ponderal Index have poorer lipid profile andimprove values with training

Ridgway, 201157 9---15 (1254) Physical activity does not modify the associationbetween LBW and insulin resistance

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have higher educational levels.22 Another Brazilian cohortrevealed an inverse association between birth weight andLTPA in women but found that socioeconomic status was alsorelated to exercise levels.30 Hallal et al. had similar conclu-sions to lower birth weight being associated with sedentarybehavior at 10---12 years old. Other risk factors for seden-tary behavior were higher maternal education and familyincome, similarly to the other two studies described. Fromthe different studies, it is possible to apprehend that socio-economic variables (both income and education) deeplyaffect the association between birth weight and sedentarybehavior, either when comparing different social extractswithin a specific community or when comparing studies per-formed in countries from diverse economic profile.

Benefits of physical activity in IUGR individuals

In 2014 Gatford et al. comprised a review of clinical andexperimental evidence that exercise can improve metabolicoutcomes after IUGR.55 It is clear that IUGR adults bene-fit from physical activity when it comes to cardiometabolicoutcomes but it is still unclear whether these benefitsare different when comparing IUGR to normal birth weightindividuals. Table 2 summarizes the main evidence aboutcardiometabolic effects of exercise in IUGR individuals.

Aoyama et al. studied 379 adults (20---64 years), evaluat-ing their homeostasis model assessment of insulin (HOMA-IR)and cardiorespiratory fitness. Lower birth weight andcardiorespiratory fitness were associated with increased

HOMA-IR, while BMI and abdominal circumference werepositively associated with HOMA-IR. Further analysis usingHOMA-IR as an independent variable, adjusted for cardiores-piratory fitness, little modified the association between

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BW, low birth weight; NBW, normal birth weight.

irth weight and insulin resistance. Lifestyle factors may beore important than birth weight since the major predictor

f insulin resistance was cardiorespiratory fitness.56

Ridgway et al. evaluated a younger population (9---15ears) with accelerometer measurements to verify whetherhysical activity and aerobic fitness could modify the associ-tion between birth weight and metabolic outcomes. Birtheight was not associated with fasting insulin, except when

he model was adjusted for adolescent waist circumference.he data were little modified even after further adjustmentor time spent exercising.57 It is possible that the young agef evaluation may play a role in these findings, consideringhat changes in metabolism may still not be present at thisge.

One study conducted in India included young healthy men18---22 years), excluding obese and those using medicationshat could alter the glucose profile, for a bicycle-basedntervention over 6 weeks in order to evaluate changesn glucose metabolism. Approximately half of the sampleomprised men born with LBW. Baseline data revealed noignificant differences in either fasting plasma glucose ornsulin levels between LBW and normal birth weight groups.asting plasma insulin levels, HOMA-IR and insulin secre-ion (HOMA-IS) improved equally after the intervention inoth groups.58 One limitation is that the study selected onlyealthy individuals. Since IUGR is a known risk factor foretabolic syndrome2,10,11 and type II diabetes,11 the exclu-

ion of individuals with altered metabolic states (obese andhose using medications) may lead to the false conclusionhat they would not benefit even more from an exercise

ntervention.

Redmond et al. evaluated differential outcomes of anxercise intervention in the metabolic profile of adults bornmall for gestational age. Individuals born with normal birth

588 Bischoff AR et al.

Table 3 Summary of the experimental data linking IUGR and physical activity levels.

Author/year Sex Age Species Tool Outcome

Baker, 201562 Male andfemale

40 days Agoutiviableyellow mice

PA measured by beambreaks: activity,ambulatory movementalong the length of thecage and rearing.

IUGR female exerciseless and have increasedadiposity

Bellinger,200625

Male andfemale

13 months Wistar rats Infra-red beams tomonitor animal motion

Decreased locomotoractivity in animals bornfrom dams fed with alow protein diet

Corvino, 201569 Female 90 days Wistar rats Swimming three timesper week

Glucose intolerance wasreversed in IUGRexposed to a swimmingprogram

Corvino, 201770 Female 90 days Wistar rats Swimming three timesper week

Enhanced peripheralinsulin sensitivity inexercised female rats.

Cunha, 201523 Male andFemale

60 days Sprague-Dawleyrats

Spontaneous activity inrunning wheels

Both undernutrition andovernutrition inpregnancy leads to LBW.LBW animals exerciseless.

de MeloMontenegro,201268

Male 8 weeks Wistar rats Exercise training on amotorized treadmill

Physical activityattenuates effects ofIUGR on the leptincontent in visceraladipose tissue

Garg, 200965 Male andFemale

60 days Sprague-Dawleyrats

Exercise training on amotorized treadmill

Exercise training in IUGRoffspring improvesinsulin sensitivity

Huber, 200989 Male andfemale

250 days Wistar rats Forced exercise inrunning wheels

Daily exercise decreasesadiposity in IUGRoffspring

Kaur, 201663 Male andfemale

240 days Merino×BorderLeicesterewes

Spontaneous ambulatoryactivity measured with aGarmin attached to acollar

Spontaneous ambulatoryactivity negativelycorrelated with birthweight in females

Laker, 201275 Male 24 weeks Wistar rats Exercise training on amotorized treadmill

Exercise for IUGR doesnot alter deficits inskeletal muscle markersof mitochondrialbiogenesis in adulthood

Laker, 201166 Male 9---24 weeks Wistar---Kyotorats

Exercise training on amotorized treadmill

Exercise preventscompromised pancreatic�-cell mass later in life

Leandro,201271

Male 60 days Wistar rats Exercise training on amotorized treadmill

Physical activity revertsthe effects of a perinatallow-protein diet on theproportion of fiber typesin skeletal muscle

Maux, 200974 Male 16 weeks Wistar rats Exercise training on amotorized treadmill

Physical activity did notmodify structuralalterations on thecommon left carotid andhorizontal aorta arterieswall

Fetal programming of energy expenditure 589

Table 3 (Continued)

Author/year Sex Age Species Tool Outcome

Miles, 200964 Male andfemale

250---365days

Wistar rats Running over levelpressing for food

IUGR rats have greaterpreference for runningover lever pressing forfood

Miles, 200967 Male andfemale

150 days Wistar rats Forced exercise inrunning wheels

Exercise preventsobesity in IUGRoffspring.

Oliveira, 201472 Male 8---18 weeks Wistar rats Exercise training on amotorized treadmill

Aerobic exercisepromotes beneficialcardiovascularadaptations in IUGR

Reyes, 201573 Male andfemale

10---16weeks

Sprague-Dawleyrats

Exercise training on amotorized treadmill

Aerobic exerciseimproved vasodilation inmuscle arteries in IUGRmales

Vickers, 200324 Male andfemale

420 days Wistar rats Optimax behavioraltesting apparatus

IUGR offspring weresignificantly less activethan controls. Postnatalhypercaloric dietexacerbated thesedentary behavior.

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IUGR, intrauterine growth restriction; LBW, low birth weight.

weight had a better pre-training lipid profile (particularlytotal and LDL cholesterol). Following training, group dif-ferences between total and LDL cholesterol disappeared.The increased risk of chronic diseases in those born withIUGR may be attenuated through lifestyle changes such asimplementing an exercise routine.39

Among the studies showing beneficial effects of exer-cise, Eriksson et al. evaluated older adults and showed thatfrequent or moderate weekly exercise was associated withbetter glucose tolerance and this effect was even strongeramong those born with small size at birth. Furthermore, menthat were born small exercised more in adulthood than theircontrols, which could be interpreted as an adaptive responseof survival of the fittest in this high-risk group.29 Also investi-gating adults, Laaksonen et al. found that small size at birthwas associated with metabolic syndrome features even priorto the development of diabetes or cardiovascular disease.The association was no longer present when regular vigor-ous LTPA or good cardiorespiratory fitness were taken intoconsideration.38

Two studies in adolescents were favorable to physicalactivity as an attenuator of altered metabolic outcomes forthose born small.59,60 The first one found that as birth weightdecreases, leptin levels increase in girls not meeting thephysical activity recommendations (≥60 min/day of moder-ate to vigorous physical activity). There was no associationbetween leptin levels and birth weight in those meetingthe physical activity recommendations.59 Serum leptin lev-els are increased in obese people, who seem to develop aleptin resistance status, and it has already been shown that

LBW is associated with higher serum leptin levels in femaleadolescents.61 The second article showed that higher levelsof physical activity played a role in altering the associationbetween LBW and HOMA-IR.60

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Although the cohorts and studies are heterogeneous inerms of many variables such as age, country of origin andype of physical activity, it seems that physical training mayave beneficial effects especially for individuals that areore vulnerable to metabolic modifications such as thoseorn with LBW.

xperimental evidence

he effects of intrauterine growth restriction onhysical activity levels

imilarly to what was described in the clinical studies,xperimental evidence also suffers from heterogeneity inhe methodology used to assess physical activity. Spon-aneous physical activity is measured either by filminghe cage, by infrared spectroscopy or by digital counterttached to running wheels. Table 3 summarizes the mainharacteristics of the outcomes of experimental studies.

In order to identify changes in physical activity levelsmong female mice that were born IUGR, Baker et al. testednimals born from lean and obese dams, with all animalseing fostered to lean dams. IUGR was noted in the off-pring of obese dams. Female animals born from obeseams had reduced levels of spontaneous physical activ-ty and energy expenditure, with increased rates of adultbesity.62 Kaur et al. induced IUGR through surgical manip-lation of endometrial placental attachment sites of ewesnd measured spontaneous physical activity in the offspring.

lacental restriction and low birth weight were associatedith greater spontaneous ambulatory activity.63

Cunha et al. evaluated spontaneous physical activity inats born with IUGR (dams receiving a 50% food restricted

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iet from day 10 of pregnancy until birth) versus rats bornrom dams receiving an ad libitum diet and rats born fromams receiving high-fat diet. Both extreme groups (50% foodestricted and high fat diets during pregnancy) had IUGRups at birth, and both had different physical activity levelshen compared to controls. However, there were oppositeffects in different sexes: females from the extreme groupsad increased physical activity in comparison to controls,hile males from the extreme groups showed decreasedctivity in relation to controls.23 Considering that alterationsn the mesolimbic system could be a possible mechanism toxplain the effect observed in physical activity, D2 recep-ors in the dorsal striatum were assessed, and females fromhe food restricted group had decreased striatal D2 receptorevels when compared to the control group.23

Bellinger et al. fed pregnant rats with either a control or low protein diet in different gestational periods (early, midr late). Offspring locomotor activity was measured with annfrared sensor array. A low protein diet in all gestationaleriods was significantly associated with lower locomotorctivity in female offspring, while in male offspring theffect was observed only when the low protein diet wasffered in early pregnancy.25

Vickers et al. compared adult rats born from dams sub-itted to an undernourished diet during pregnancy versus

ontrols. IUGR animals (born from dams receiving an under-ourished diet during pregnancy) were more sedentary whenompared to controls, regardless of the postnatal diet (stan-ard or hypercaloric). The effect occurred in both gendersut was more pronounced in males.24 In the study byiles et al., the animals were given the choice betweenheel running and pressing a response lever for food.

UGR offspring (born from undernourished dams) revealed greater preference for exercise when compared to ad libi-um offspring.64

xercise intervention to attenuate metabolicutcomes of IUGR in animals

arg et al. conducted a trial of early exercise training tonalyze its effect on glucose kinetics. Pregnant rats wereivided to receive either a normal or a restricted diet duringays 11---21 of gestation. An exercise training interventionn the offspring was able to suppress glucose-stimulatednsulin production and hepatic glucose production, leadingo an overall improvement on insulin sensitivity.65 A shorteriod of exercise training in pups was associated with sig-ificant increases in �-cell mass for all animals and this earlyxercise restored �-cell mass to control levels in IUGR off-pring. However, insulin secretion was not altered by thentervention.66

Miles et al. was able to demonstrate that daily exer-ise in adult IUGR rats prevented the development ofbesity. Although IUGR offspring had increased adiposityompared to controls, insulin resistance was not observed.aily physical activity prevented the development of obe-ity and had positive effects on metabolic parameters in

UGR offspring.67 In a different study, physical activity alsoffected leptin content of the adipose tissue in IUGR rats.ffspring from low-protein diet fed dams had increased lep-in in the visceral tissue but this was reversed by exercise.68

aaaF

Bischoff AR et al.

wimming in IUGR rats also prevented glucose intolerancerom developing as well as reducing adiposity in anotherample.69 Adult IUGR female rats exercised continuouslyor 60 min during pregnancy also had enhanced peripheralnsulin sensitivity although in this sample this was associatedith IUGR in the offspring.70

Other interesting effects of physical activity in IUGR ratsoncern the proportion of muscle fibers,71 improvements inngiotensin II-induced vasoconstriction, alterations relatedo superoxide levels72 and improvements in endothelium-erived hyperpolarization-mediated vasodilation in musclerteries.73 In contrast, study by Maux et al. found that mod-rate physical training did not modify structural changesssociated with malnutrition on the common left carotid andorizontal aorta arteries wall.74 Using a different method-logy with bilateral uterine vessel ligation or sham surgeryn pregnant dams to induce IUGR, Laker et al. did not findny reprogramming effects related to exercise in skeletaluscle markers of mitochondrial biogenesis in adulthood.75

Therefore, from the different experimental studies, its possible to infer that there is evidence to support thexistence of a fetal programming effect on physical activ-ty/sedentary behavior later in life. In addition, exposureo exercise during the life course seems to be able toevert some of the detrimental effects of being born IUGR,specially regarding metabolic outcomes, although less con-istent reversion is seen on the damages found on musclerchitecture or function.

echanisms

ome of the possible mechanisms implied in the above-entioned alterations in physical activity levels in IUGRere already described among the experimental results

Table 3). There are other articles focusing on these mecha-isms in clinical studies that will be described here (Table 4).

The most commonly studied mechanism involves changesn muscle strength. As previously stated, poorer muscletrength is associated with less physical activity levels.he positive association between birth weight and hand-rip strength has been described in different age groups:n childhood,76,77 young adults,41 adults and elderly.78---81 Lowuscle strength has already been associated with metabolic

isk factors such as blood pressure, HOMA-IR and triglyc-rides in school-aged children.82 Dodds et al. conducted aystematic review and meta-analysis and found 19 studiesonfirming this association, which is maintained across theife course.42 Each kilogram increase in birth weight resultedn a 2.07 kg and 1.59 kg increase in muscle strength in mennd women respectively.

One study concluded that poor fetal growth affectsuscle force generation, based on the findings of lower

rip strength, lower maximal isometric voluntary contrac-ion of the quadriceps femurs, increased rates of fatiguere- and post-training and decreased training response inhose born with low ponderal index.41 Jensen et al. investi-ated changes in skeletal muscle morphology and showed an

ltered proportion of different muscle fibers in young IUGRdults. It was hypothesized that increased fiber size may ben early marker of insulin resistance in this population.83

urthermore, Brons et al. evaluated the effects of LBW on

Fetal programming of energy expenditure 591

Table 4 Proposed mechanisms implied in the association between IUGR and lower physical activity levels.

Mechanism Author/year Main findings

Altered cardiovascular/aerobicperformance

Baraldi, 199093 Higher energy cost of running in SGABoreham, 200192 Higher birth weight, higher fitness scoreCafiero, 201490 Decreased cardiovascular fitness in SGALawlor, 200891 Birth weight, length and ponderal index positively

associated with cardiorespiratory fitnessReyes, 201594 Reduced baseline cardiac performance in male IUGR

offspring and increased superoxide generationAltered muscle strength Brutsaert, 201141 Low ponderal index at birth associated with lower grip

strength, lower maximal isometric voluntarycontraction, increased rate of fatigue and decreasedtraining response

Dodds, 201242 Birth weight positively associated with greater musclestrength

Inskip, 200778 Increased grip strength with higher birth weightKuh, 200280 Birth weight associated with adult grip strengthMoura-Dos-Santos, 201377 Decreased handgrip strength and running speed

performance in LBWRidgway, 200979 Birth weight positively associated with muscle strength

and aerobic fitnessYlihärsilä, 200781 Birth weight associated with grip strength and increased

adult lean massvan Deutekom, 201576 Birth weight positively associated with handgrip

strength. Impaired aerobic and neuromuscular fitness inLBW

Muscle metabolism, gene expressionand histologic alterations

Brons, 200884 Normal in vivo mitochondrial function and expression ofoxidative phosphorylation genes in low birth weight.

Brutsaert, 201285 Plasma lactate after exercise as well as in response totraining (but not aerobic capacity are dependent onponderal index.

Friedrichsen, 201286 CD68 expression increased in low birth weight, oxidativephosphorylation genes decreased in low birth weightand negatively correlated with CD69 expression. MPC1and NF-�B activity unaffected. None of theinflammatory markers correlated with insulin sensitivity.

Jensen, 200783 Changes in muscle fiber composition and sizeMortensen, 201487 More sensitive AMPK systemMortensen, 201388 Bed rest is related to decreased insulin-stimulated Akt

phosphorylation and to increased AMPK �1 and �3protein expression; insulin response of A5160phosphorylation is decreased both pre- and post-bedrest.

age;

ated

asicasl

t

IUGR, intrauterine growth restriction; SGA, small for gestational

NF-�B, nuclear factor-�B; AMPK, adenosine monophosphate-activ

mitochondrial dysfunction in skeletal muscle. The study con-firmed previous findings of abnormal glucose metabolism inLBW individuals. However, there was no indication that mito-chondrial dysfunction could be the key to explaining themetabolic defects underlying insulin resistance.84

Other articles found differences in lactate mus-cle metabolism,85 CD68 mRNA expression suggestingmacrophage infiltration and reduced oxidative phosphoryla-tion (OXPHOS) gene expression when exposed to bed rest,86

87

as well as skeletal muscle insulin signaling. Mortensenet al. suggested that LBW could have a more sensitiveAMPK (AMP-activated protein kinase) system, supportedby the evidence of an increased exercise-induced AMPK

cato

LBW, low birth weight; MPC1, monocyte chemotactic protein-1;protein kinase.

ctivation as well as increased effects on the down-tream target ACC2 (acetyl coenzyme A carboxylase 2)n LBW subjects.88 Additionally, Ylihärsilä et al. con-luded that LBW is associated with lower lean mass indult life and this contributes to the risk of relativearcopenia and the related functional inability later inife.81

In another study, prenatal undernutrition caused a reduc-ion in muscle fiber size. Exercise did not affect fiber type

omposition. The activity of enzymatic markers of oxidativend glycolytic pathways was significantly different in thosehat were born IUGR. Overall, physical activity preventedbesity in IUGR offspring.89

592 Bischoff AR et al.

Fetalprogramming

Gene expressionAltered

cardiometabolic statusAltered muscle strength

and metabolismMuscle histologic

alterations

Sedentarybehavior

Age Culture Sleep quality ExposureNeighborhood

safetySocioeconomic

statusScreen time/

indoor activities

Figure 1 Fetal programming alters gene expression, cardiometabolic status, muscle strength, metabolism and histology, leadingto altered physical activity levels in individuals with IUGR. Age, culture, exposure, sleep quality, socioeconomic status, neighborhoodsafety, screen time and indoor activities also moderate the association between birth weight and sedentary behavior.

Lack of insulin

DM

ObesityHPA axis dysfunction

↑ Oxidative stress

Insulin resistance

Hyperglycemia

Neuroplasticity Hippocampalneurogenesis

Peripheral fataccumulation

Appetite

Preference forpalatable foods

EXERCISE

?

F indiva ctions re in

pwLcrctcisaeI

C

Aew

ihcmpsecas

nhcet

igure 2 Exercise may act in specific vulnerabilities that IUGRdiposity, as well as hypothalamus---pituitary---axis (HPA) dysfunuch as increasing neurogenesis and neuroplasticity and therefo

Finally, some authors described a decreased cardiores-iratory/aerobic capacity in those born with low birtheight.79,90---92 Van Deutekom et al. results indicate thatBW and accelerated infant growth might negatively affecthildhood aerobic and neuromuscular fitness.76 Otherseported that the energy cost of running was higher amonghildren born preterm SGA when compared to term con-rols, with no differences between preterm AGA and termontrols.93 Running speed performance was also diminishedn another sample of LBW children.77 Experimental datahowed reduced cardiac performance in male IUGR offsprings well as increased superoxide generation.94 Fig. 1 delin-ates the factors affecting physical activity levels related toUGR.

onclusions and future directions

s Gatford et al. have previously pointed out, there is somevidence linking IUGR to altered physical activity levels asell as describing potential beneficial outcomes of exercise

hnn(

iduals have, such as their increased risk for type II diabetes and. Moreover, exercise acts in several brain areas and processes,fluences behavior. Adapted and modified from Yi.96

ntervention on metabolic outcomes, however few studiesave been conducted and results are mixed.55 Most clini-al studies have focused on cardiovascular performance anduscle alterations that could help explain the decreasedhysical activity levels in this population. Experimentaltudies, on the other hand, have gone somewhat further,xploring changes in insulin sensitivity, leptin secretion, vas-ular and muscle structure and function. Still, little is knownbout the neurobiological mechanisms that may influenceedentary behavior.

Exercise benefits a whole range of human conditions,ot only related to physical health, but also mentalealth. Physical activity, either aerobic, resistance oroordination training, benefits cognitive function in thelderly.95 It also increases brain connectivity betweenhe frontal, posterior, and temporal cortices, affects

ippocampal volume and serum levels of brain-derivedeurotrophic factor (BDNF), a mediator of neuroge-esis in the dentate gyrus of the hippocampus95,96

Fig. 2).

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Fetal programming of energy expenditure

From a neurobiological standpoint, exercise influencescortisol, endocannabinoids, BDNF, dopamine and serotoninreleases. The stress response associated with exerciseinduces inhibitory effects from the secreted cortisol uponthe hypothalamus and pituitary through medial prefrontalcortex receptors and reduces stress-induced overexcitabil-ity of the amygdala. Additionally, by reducing the amountof competitive amino acids through muscle uptake, aero-bic exercise increases tryptophan’s chances of crossing theblood---brain barrier, and so has the potential to increaseserotonin, an important neurotransmitter for emotional pro-cessing, satiety and memory functions.97 These are some ofthe potential targets of future research, especially explor-ing the neurobiological effects of exercise in vulnerablepopulations such as those born IUGR. Therefore, furtherresearch would benefit from targeting IUGR individuals forstructured interventions in well-designed, large-scale lon-gitudinal studies, to investigate the potential benefits ofphysical training. In addition, basic neurobiological inves-tigations detailing the effects of exercise specifically in thisgroup could unravel mechanisms that would better tailorsuch interventions.

Conflicts of interest

The authors declare no conflicts of interest.

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