Increased placental fatty acid transporter 6 and binding protein 3 expression and fetal liver lipid accumulation in a mouse model of obesity in pregnancy

Díaz, Paula; Harris, J G; Rosario, Fredrick J.; Powell, Theresa L.; Jansson, Thomas

doi:10.1152/ajpregu.00385.2015

Cited by 49 publications

(32 citation statements)

References 59 publications

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“…Previous work has shown hepatic steatosis in fetuses of obese mice (14,43,44), and the current study extends these observations by demonstrating that hepatic steatosis persists in the 3 mo old offspring of obese mice, which was prevented by normalizing circulating maternal ADN levels in late pregnancy. Consistent with the findings in our mouse model, intrahepatic fat is increased in the 1-to 3-wk-old infant of obese mothers with gestational diabetes (45) and in the adolescent offspring of obese mothers (46).…”

Section: Discussionsupporting

confidence: 81%

Normalizing adiponectin levels in obese pregnant mice prevents adverse metabolic outcomes in offspring

et al. 2018

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Infants of obese mothers have an increased risk of developing obesity, insulin resistance, and type 2 diabetes. The underlying mechanisms remain elusive, and no effective interventions to limit the transmission of metabolic disease from the obese mother to her infant are currently available. Obese pregnant women have decreased circulating levels of adiponectin, which is associated with increased placental nutrient transport and fetal overgrowth. We have reported that normalization of adiponectin levels during late gestation reversed placental dysfunction and fetal overgrowth in a mouse model of maternal obesity in pregnancy. In the current study, we hypothesized that adiponectin supplementation during pregnancy in obese mice attenuates the adverse metabolic outcomes in adult offspring. Adult male offspring of obese mice developed obesity, fatty liver, and insulin resistance, with adult female offspring of obese mice having a less pronounced metabolic phenotype. These metabolic abnormalities in offspring born to obese mice were largely prevented by normalization of maternal adiponectin levels in late pregnancy. We provide evidence that low circulating maternal adiponectin is a critical mechanistic link between maternal obesity and the development of metabolic disease in offspring. Strategies aimed at improving maternal adiponectin levels may prevent long‐term metabolic dysfunction in offspring of obese mothers.—Paulsen, M. E., Rosario, F. J., Wesolowski, S. R., Powell, T. L., Jansson, T. Normalizing adiponectin levels in obese pregnant mice prevents adverse metabolic outcomes in offspring. FASEB J. 33, 2899–2909 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 81%

Normalizing adiponectin levels in obese pregnant mice prevents adverse metabolic outcomes in offspring

et al. 2018

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“…Accordingly, fat pad weight in HF dams was higher than CHOW dams despite the lack of body weight differences in our study. It is possible that obese dams may increase placental lipid transport capacity to transfer excess lipid to the fetus .…”

Section: Discussionmentioning

confidence: 99%

Prenatal high‐fat diet alters placental morphology, nutrient transporter expression, and mtorc1 signaling in rat

Song

Sun

Boersma

et al. 2017

Obesity

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Objective: This study aimed to determine how the rat placenta and fetus respond to maternal high-fat (HF) diet during gestation and to identify the possible mechanisms. Methods: Pregnant Sprague-Dawley rats were fed with standard chow (13.5% fat) or HF (60% fat) diet during gestation. Placentas were collected on gestation day 21. Results: HF dams had greater fat mass, higher plasma leptin, lower plasma adiponectin, and impaired glucose tolerance during pregnancy. The placental labyrinth thickness was reduced in both male and female fetuses of HF dams. In HF male placentas, glucose transporter 3 gene expression, system A amino acid transporter (SNAT) 2 gene expression, and SNAT2 protein expression were increased through the activation of the mTORC1 4EBP1 branch. In HF female placentas, gene expression of insulin-like growth factor 2 (IGF2) and IGF2 receptor was elevated compared to placentas of females fed standard chow. Although male and female placentas responded differently to prenatal HF diet exposure, both male and female fetal weight was not altered by maternal HF diet. Conclusions: Placenta responds and adapts to maternal metabolic changes by altering placental layer thickness, mTORC1 signaling, expression of nutrient transporters, and growth factors in a sex-specific manner.Obesity (2017) 25, 909-919.

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“…Evidence exists for increased lipid transport across the placenta in human pregnancies complicated by GDM, as isolated placental cells from pregnancies with GDM have increased expression of genes for fetoplacental lipid metabolism and preferential use of fatty acids as lipogenic substrates 60 . Mice with obesity during pregnancy have increased placental expression of fatty acid transporter proteins 61 and data published in 2016 have confirmed the transfer of maternally derived dietary lipids across the placenta to the fetus 62 . Furthermore, increased fatty acid levels signal the placenta, via Toll like receptor 4 (TLR4), to produce a pro inflammatory response and increase nutrient transport 63–65 .…”

Section: Intrauterine Clues For Nafld Riskmentioning

confidence: 96%

Developmental origins of NAFLD: a womb with a clue

Wesolowski

Kasmi

Jonscher

et al. 2016

Nat Rev Gastroenterol Hepatol

175

167

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Changes in the maternal environment leading to an altered intrauterine milieu can result in subtle insults to the fetus, promoting increased lifetime disease risk and/or disease acceleration in childhood and later in life. Particularly worrisome is that the prevalence of NAFLD is rapidly increasing among children and adults, and is being diagnosed at increasingly younger ages, pointing towards an early-life origin. A wealth of evidence, in humans and non-human primates, suggests that maternal nutrition affects the placenta and fetal tissues, leading to persistent changes in hepatic metabolism, mitochondrial function, the intestinal microbiota, liver macrophage activation and susceptibility to NASH postnatally. Deleterious exposures in utero include fetal hypoxia, increased nutrient supply, inflammation and altered gut microbiota that might produce metabolic clues, including fatty acids, metabolites, endotoxins, bile acids and cytokines, which prime the infant liver for NAFLD in a persistent manner and increase susceptibility to NASH. Mechanistic links to early disease pathways might involve shifts in lipid metabolism, mitochondrial dysfunction, pioneering gut microorganisms, macrophage programming and epigenetic changes that alter the liver microenvironment, favouring liver injury. In this Review, we discuss how maternal, fetal, neonatal and infant exposures provide developmental clues and mechanisms to help explain NAFLD acceleration and increased disease prevalence. Mechanisms identified in clinical and preclinical models suggest important opportunities for prevention and intervention that could slow down the growing epidemic of NAFLD in the next generation.NAFLD is a general term used to describe a broad spectrum of liver abnormalities, ranging from simple, uncomplicated hepatic steatosis to NASH, accompanied by different degrees of Correspondence to J.E.F. jed.friedman@ucdenver.edu. Author contributionsAll authors researched data for the article, provided a substantial contribution to discussion of content, wrote the article, and reviewed and edited the manuscript before submission. Competing interests statementThe authors declare no competing interests. HHS Public AccessAuthor manuscript Nat Rev Gastroenterol Hepatol. Author manuscript; available in PMC 2017 December 12. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript inflammation and fibrosis. NAFLD is increasing in prevalence, especially in adolescents 1 , despite the levellingoff of the obesity epidemic from 2003-2004 to 2013-2014 in children and adolescents aged 2-19 years (REF.2). The most common chronic liver disease worldwide, NAFLD increases the risk of cardiovascular events eightfold and type 2 diabetes mellitus (T2DM) threefold 3 , and is a strong risk factor for hepatocellular carcinoma (HCC) 4 . At the time of paediatric NAFLD diagnosis, 25-50% of children have NASH and 10-25% have advanced fibrosis 5 . For many decades, it was thought that NAFLD was predominantly driven by obesity in the setting of genetic suscep...

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Increased placental fatty acid transporter 6 and binding protein 3 expression and fetal liver lipid accumulation in a mouse model of obesity in pregnancy

Cited by 49 publications

References 59 publications

Normalizing adiponectin levels in obese pregnant mice prevents adverse metabolic outcomes in offspring

Normalizing adiponectin levels in obese pregnant mice prevents adverse metabolic outcomes in offspring

Prenatal high‐fat diet alters placental morphology, nutrient transporter expression, and mtorc1 signaling in rat

Developmental origins of NAFLD: a womb with a clue

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