maternal high-fat intake predisposes nonalcoholic fatty liver disease in c57bl/6 offspring
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Tspefrostefibrosis and liver failure.1 The conditionsincluatomacrovesicular or a mix betweenmicro-
anlobopthesinThese changes include alterations in
tion of a scar (fibril-forming) matrix,ninotsig
whpopawhsiofurther increasing hepatic FFA synthesis.
oxidized by enzymes in peroxisomes,
ReUnMoBiomedical Center, Rio de Janeiro, Brazil205
Research www.AJOG.orgglyceride depots are also delivered to theliver, taken up by hepatocytes, and con-verted into triglycerides.4
De novo lipogenesis is another factorthat leads to steatosis in NAFLD, a pro-cess regulated by transcription factorsthat are activated by insulin, particularlysterol regulatory element binding pro-tein (SREBP)-1c.5 The high insulin levels
novo synthesis and catabolism inhepatocytes.4
Some models, such as nonhuman pri-mate and murine, are used to correlatethe intrauterine environment and devel-opment of NAFLD.10,11 Different mech-anisms are involved in the offspringinsult because of adversematernal nutri-tion. Up-regulation of specific placental
Laboratory of Morphometry andrdiovascular Morphology is supported byzilian agencies CNPq (National Council forence and Technology, www.cnpq.br) anderj (Rio de Janeiro Foundation forsearch, www.faperj.br).
2-9378/$36.00010 Mosby, Inc. All rights reserved.which results in wideDisse and loss of endTransport across thehence reduced, leadinof hepatic function.3
InNAFLD, triglycesynthesized from fattyare numerous potenused to generate trietary FAs are a main srived from lipolysis o
te University of Rio de Janeiro,medical Center, Institute of Biology,oratory ofMorphometry andrdiovascularMorphology, Rio de Janeiro,zil.
ceived March 11, 2010; revised May 25,0; accepted June 17, 2010.
prints: Marcia B. Aguila, RD, PhD, Stateiversity of Rio de Janeiro, Laboratory ofrphometry and Cardiovascular Morphology,increase the expression: 10.1016/j.ajog.2010.06.042
Ng of the space ofhelial fenestrae.nusoidal wall isto deterioration
es are ultimatelyids (FAs). Theresources of FAscerides, but di-rce. The FAs de-ipose tissue tri-
mitochondria, and the endoplasmic re-ticulum (microsomes).8 Regardless ofthe source of FAs that hepatocytes use toproduce triglycerides, this triglyceride isnormally packaged into lipoproteins inthe hepatocyte endoplasmatic reticulumand then exported to adipose depots forstorage.9 Therefore, accumulation of fatin the liver leads to an excessive deliveryof FFAs from visceral adipose tissue intothe liver and from a misbalance in dee qua non of NAFLD patients in-des macro- and microvesicular ste-sis and in NASH patients include
both cellular responses and extracellularmatrix composition. Activation of thehepatic stellate cells leads to accumula-
FAsmay also accumulate within hepa-tocytes because their metabolism is im-paired. In healthy hepatocytes, FAs areSIC SCIENCE: OBSTETR
aternal high-fat intatty liver disease in Cnca M. Gregorio, RD, PhD; Vanessa Sourlos A. Mandarim-de-Lacerda, MD, PhD
JECTIVE: This work aimed to verify the hypothe of high-fat diet in critical periods of pregnancpredisposes nonalcoholic fatty liver disease ipring.
UDY DESIGN: Male pups were divided into 5ndard chowfed dams; (2) G, from high-fating the gestation (G) period; (3) L, from HF-fedon (L) period; (4) GL, from HF-fed dams duringon (GL) periods; and (5) GL/HF, from HF-fed ding an HF diet from postweaning to adulthooss, plasma blood, and liver structure.
this article as: Gregorio BM, Souza-Mello V, CarvJ Obstet Gynecol 2010;203:495.e1-8.
he term nonalcoholic fatty liver dis-ease (NAFLD) is used to describe a
ctrum of structural findings rangingm simple steatosis to nonalcoholicatohepatitis (NASH) with progressiveS
e predisposes nonal7BL/6 offspringMello, RD, PhD; Jorge J. Carvalho, PhD;arcia B. Aguila, RD, PhD
s that maternal in-nd/or suckling pe-ult C57BL/6 mice
ups: (1) SC, fromw (HF)fed damsms during the lac-gestation and lac-during GL, main-
We analyzed body
RESULTS: The G offsprintransporter-2 expressionand mainly in GL/HF offtein-1c expression was h
CONCLUSION: Programmremodeling in the liver of
Key words: fatty liver, feultrastructure, maternal
JJ, et al. Maternal high-fat intake predisposes no
d macrovesicular steatosis with mildular inflammation.2 As fibrosis devel-s, changes occur within the subendo-lial space and within the hepaticusoid.of SREBP-1c, nu
OVEMBER 2010 Americanoholic
howed insulin resistance and lower glucoseepatic steatosis was present in the G, L, GL,ng. Sterol regulatory element-binding pro-er in G, GL, and GL/HF offspring.
g by HF chow predisposes hepatic adverseult offspring.
programming, liver steatosis, liver-fat diet
coholic fatty liver disease in C57BL/6 offspring.
ich increases the expression of all li-genic enzymes, thus increasing he-tic free fatty acid (FFA) synthesis,ich also increases the hepatic expres-n of all hepatic lipogenic genes,6,7 thustrient transporter isoforms consti-
Journal of Obstetrics& Gynecology 495.e1
Research Basic Science: Obstetrics www.AJOG.org
49es a mechanism linking maternalh-fat (HF) diet and obesity to fetalergrowth12 and modulates the off-ing glucose homeostasis.13 Therefore,s study aimed to investigate how theternal intake of HF diet in differenttical periods of pregnancy and/orkling period influences carbohy-
IGURE 1ormation of the groups
estation; GL, maternal HF diet during gestation and lactation; HF,
gorio. Hepatic adverse remodeling by HF programming. Am
IGURE 2ody mass evolution (mean and SEM
e-way ANOVA and post-hoc test of Tukey: in sigVA, analysis of variance; G, gestation; GL, maternal HF diet dudard chow.
gorio. Hepatic adverse remodeling by HF programming. Am5.e2 American Journal of Obstetrics& Gynecologytes metabolism alterations andFLD in adulthood offspring.
ATERIALS AND METHODSimals and dietperimental protocols were approvedthe local committee according to con-
-fat chow; L, lactation; SC, standard chow.
stet Gynecol 2010.
d cases with the same symbols, P .05.gestation and lactation; HF, high-fat chow; L, lactation; SC,
stet Gynecol 2010.loa
NOVEMBER 2010tional guidelines for experimenta-nwith animals.14 Animals weremain-ned under controlled conditions ofperature and humidity, and 12 hour
rk, 12 hour light cycle, with free accesswater and food. C57BL/6 virgin ma-e females were cagedwithmales over-ht, and mating was confirmed thext morning (vaginal plug). Then fe-les were allocated to be fed either andard chow (SC; 17% fat, 19% pro-n, and 64% carbohydrate, equivalent16.5 kJ/g) or aHF chow (49% fat, 19%tein, and 32% carbohydrate, equiva-t to 20.7 kJ/g, 25.5% more energyn the SC diet). Both diets, includingmicronutrientmineralmix, followedAmerican Institute of Nutrition rec-mendation (AIN-93G).15
F feeding was targeted to specific pe-ds in gestation (G) and/or (L) lacta-n (Figure 1): G (HF diet was takenring the gestation); L (HF diet wasen during lactation); GL (HF diet wasen in both gestation and lactation),d GL/HF (HF diet was taken in bothtation and lactation and continuedm postweaning until 3 months old).mediately after delivery, litters werejusted to 6 animals per mother (to as-e adequate and standardized nutri-n until weaning), and at weaning, 1le pup per litter was randomly as-ned to form the groups of studyanimals/group).ffspring body mass evolution wasnitored until the euthanasia. Food in-e was estimated by subtracting theount of food left on the grid and theount of spilled food from the initialight of food supplied. Energy intakesre calculated based on energetic valuediets. Feed efficiency was calculated asms of the body mass gain per kilo-les of food consumed per animal.
l glucose tolerance testTT) and plasma insulinTT was made at 3 months old with
% glucose in sterile saline (0.9%Cl) (1 g/kg body mass [BM]) ad-nistered by orogastric gavage after 6urs of a fasting period. Blood wasllected from the tail vein at 0, 15, 30,, and 120 minutes after the glucosenalering
J Obd, and blood glucose was measured
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www.AJOG.org Basic Science: Obstetrics Researching a glucometer (Accu-Chek;che, Sao Paulo, Brazil. The analysisnsidered the area under the curve toess glucose intolerance (Prism ver-n 5.03 for Windows; GraphPadftware, San Diego, CA).lasma insulin concentrations wereasured by radioimmunoassay usingouse insulin radioimmunoassay kittalog #RI-13K; Linco Research, Starles, MO). All samples were ana-ed in a double assay, for which theraassay coefficient of variation was%. Insulin res