maternal obesity at conception programs obesity in the offspring

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  • doi: 10.1152/ajpregu.00316.2007294:R528-R538, 2008. First published 21 November 2007;Am J Physiol Regul Integr Comp Physiol

    Thomas M. BadgerKartik Shankar, Amanda Harrell, Xiaoli Liu, Janet M. Gilchrist, Martin J. J. Ronis andoffspringMaternal obesity at conception programs obesity in the

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    http://www.the-aps.org/. Copyright 2008 the American Physiological Society. ISSN: 0363-6119, ESSN: 1522-1490. Visit our website at12 times a year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. levels of biological organization, ranging from molecules to humans, including clinical investigations. It is publishedinvestigations that illuminate normal or abnormal regulation and integration of physiological mechanisms at all

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  • Maternal obesity at conception programs obesity in the offspringKartik Shankar,1,2 Amanda Harrell,1 Xiaoli Liu,1 Janet M. Gilchrist,1,4 Martin J. J. Ronis,1,2and Thomas M. Badger1,3,41Arkansas Childrens Nutrition Center, Little Rock; and Departments of 2Pharmacology and Toxicology, 3Physiology andBiophysics, and 4Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, ArkansasSubmitted 6 May 2007; accepted in final form 19 November 2007

    Shankar K, Harrell A, Liu X, Gilchrist JM, Ronis MJ, BadgerTM. Maternal obesity at conception programs obesity in the offspring.Am J Physiol Regul Integr Comp Physiol 294: R528R538, 2008. Firstpublished November 21, 2007; doi:10.1152/ajpregu.00316.2007.Riskof obesity in adult life is subject to programming during gestation. Toexamine whether in utero exposure to maternal obesity increases therisk of obesity in offspring, we developed an overfeeding-based modelof maternal obesity in rats utilizing intragastric feeding of diets viatotal enteral nutrition. Feeding liquid diets to adult female rats at 220kcal/kg3/4 per day (15% excess calories/day) compared with 187kcal/kg3/4 per day for 3 wk caused substantial increase in body weightgain, adiposity, serum insulin, leptin, and insulin resistance. Lean orobese female rats were mated with ad libitum AIN-93G-fed male rats.Exposure to obesity was ensured to be limited only to the maternal inutero environment by cross-fostering pups to lean dams having adlibitum access to AIN-93G diets throughout lactation. Numbers ofpups, birth weight, and size were not affected by maternal obesity.Male offspring from each group were weaned at postnatal day(PND)21 to either AIN-93G diets or high-fat diets (45% fat calories).Body weights of offspring from obese dams did not differ fromoffspring of lean dams when fed AIN-93G diets through PND130.However, offspring from obese dams gained remarkably greater (P 0.005) body weight and higher %body fat when fed a high-fat diet.Body composition was assessed by NMR, X-ray computerized to-mography, and weights of adipose tissues. Adipose histomorphom-etry, insulin sensitivity, and food intake were also assessed in theoffspring. Our data suggest that maternal obesity at conception leadsto fetal programming of offspring, which could result in obesity inlater life.

    pregnancy; developmental programming; body composition; adiposetissue

    PREVALENCE OF OVERWEIGHT and obesity in the United Statescontinues to rise steadily with one in two adults being over-weight [body mass index, (BMI) 25] and as many as one infive adults ( 60 million individuals) being obese (BMI 30)(14, 35). Prevalence of overweight among children has nearlydoubled in the last two decades (33). Perhaps more alarming isthe steady increase in the risk of overweight even amonginfants (011 mo) (32, 42). This may have critical implica-tions, as overweight in infancy and childhood significantlyincreases the risk of obesity in adulthood (32, 33, 42). Consis-tent with greater numbers of overweight individuals in thepopulation is a remarkable rise in the incidence of obesityamong pregnant women (1, 9, 10, 36, 56). Pregravid over-weight is one of the most common high-risk obstetric condi-tions (8, 25), imparting increased risk of gestational diabetes

    mellitus (GDM), pregnancy-related hypertension, preeclamp-sia, neonatal death, and other labor complications (8, 9, 25, 36).

    While much attention is paid to obesity-related complica-tions during pregnancy, not much is known about the subtleeffects of the obese intrauterine environment on the immediateand long-term health of the offspring. Data from 287,213pregnant women clearly reveal that overweight/obese womenare more likely to give birth to heavier babies (90th percen-tile), consistent with the data that maternal obesity per se, evenafter controlling for gestational diabetes, is associated withtwice higher incidence of heavier babies compared with nono-bese women (8, 27, 30, 41, 44). Data from the Center forDisease Control Pediatric Nutrition Surveillance survey sug-gest that the odds ratios for obese children growing into obeseadults are 2.1 to 8.8 times that of nonoverweight children (32).Hence, greater body weight at birth and weight gain early inlife clearly increases the risk of becoming overweight or obeseas an adult. This suggests that prepregnancy overweight andgestational obesity may lead to a self-reinforcing vicious cycleof excessive weight gain and adiposity that is passed on frommother to successive offspring. While the underlying mecha-nisms of such maternal obesity-induced programming remainunclear, the hypothesis has important implications in explain-ing the rapid rise in obesity.

    Studies of inheritance unambiguously show BMI of childrencorrelate more closely with maternal BMI than paternal BMI,suggesting that in addition to the genetic influences, the ma-ternal in utero environment may contribute to the developmentof obesity in the offspring (12, 54). Hence, developing animalmodels to precisely delineate in utero influences in metabolicprogramming of obesity is critical to our understanding ofunderlying mechanisms of how increased susceptibility ispassed onto the offspring. In the present report, we examinedeffects of obesity specifically at conception on the program-ming of obesity in the offspring. We have controlled for directmaternal and paternal genetic influences by developing amodel of overnutrition-driven maternal obesity so as to exam-ine only the metabolic effects of obesity on offspring health.Furthermore, by use of cross-fostering, we have excludeddirect influences of maternal obesity on nursing offspring. Ourdata strongly suggest that exposure to maternal obesity in uteroleads to metabolic programming, which results in increasedsusceptibility to obesity in the offspring.

    MATERIALS AND METHODS

    Animals and chemicals. Female Sprague-Dawley rats (150175 g)were obtained from Charles River Laboratories (Wilmington, MA).

    Address for reprint requests and other correspondence: Kartik Shankar,Arkansas Childrens Nutrition Center, 1212 Marshall St., Slot 512-20B, LittleRock, AR 72202 (e-mail: ShankarKartik@uams.edu).

    The costs of publication of this article were defrayed in part by the paymentof page charges. The article must therefore be hereby marked advertisementin accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    Am J Physiol Regul Integr Comp Physiol 294: R528R538, 2008.First published November 21, 2007; doi:10.1152/ajpregu.00316.2007.

    0363-6119/08 $8.00 Copyright 2008 the American Physiological Society http://www.ajpregu.orgR528

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  • Animals were housed in an American Association for Accreditation ofLaboratory Animal Care-approved animal facility. Protocols for ani-mal maintenance and experimental treatments were conducted inaccordance with the ethical guidelines for animal research estab-lished and approved by the Institutional Animal Care and UseCommittee at the University of Arkansas for Medical Sciences.Unless otherwise specified, all chemicals were obtained fromSigma-Aldrich (St. Louis, MO).

    Experimental protocol. Virgin female Sprague-Dawley rats wereintragastrically cannulated and allowed to recover for 10 days aspreviously described (3, 5, 6, 26, 45, 46). Rats were fed a liquid diet[20% protein (casein), 35% carbohydrate (dextrose and maltodextrin),and 45% fat (corn oil)] at National Research Council recommendedcaloric intake of 187 kcal/kg3/4 per day (referred to as lean dams) orwere overfed an obesegenic liquid diet (20% protein, 75% carbohy-drate, 5% fat) at 220 kcal/kg3/4 per day (15% excess, referred to asobese dams). Diets met caloric and nutritional guidelines recom-mended by the National Research Council, have been describedpreviously (3, 5, 6), and have been utilized by our group in a numberof studies (4, 19, 26, 43, 45, 46). In preliminary experiments, weobserved that while feeding at 187 kcal/kg3/4 per day mirrored bodyweight gains of ad libitum-fed controls (data not shown), feeding at220 kcal/kg3/4

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