Maternal obesity programs offspring non-alcoholic fatty liver disease through disruption of 24-h rhythms in mice

Mouralidarane, Angelina; Soeda, Junpei; Sugden, David; Bocianowska, Alina; Carter, R.; Ray, Shuvra; Saraswati, Ruma; Cordero, Paúl; Novelli, Marco; Fusai, Guiseppe; Vinciguerra, Manlio; Poston, Lucilla; Taylor, Paul D.; Oben, Jude A.

doi:10.1038/ijo.2015.85

Cited by 52 publications

(39 citation statements)

References 34 publications

(44 reference statements)

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“…Using a model of HFD in mice, Mouralidarane et al elegantly demonstrated the role of maternal diet in development of offspring NAFLD [30,31]. Likewise, Bruce et al, showed development of steatohepatitis in mice born to HFD-fed dams by 30 wk of age, associated with greater lipogenic genes and mitochondrial dysfunction [10].…”

Section: Discussionmentioning

confidence: 99%

Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations

et al. 2017

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ObjectiveNon-alcoholic fatty liver disease (NAFLD) is an important co-morbidity associated with obesity and a precursor to steatohepatitis. However, the contributions of gestational and early life influences on development of NAFLD and NASH remain poorly appreciated.MethodsTwo independent studies were performed to examine whether maternal over-nutrition via exposure to high fat diet (HFD) leads to exacerbated hepatic responses to post-natal HFD and methionine choline deficient (MCD) diets in the offspring. Offspring of both control diet- and HFD-fed dams were weaned onto control and HFD, creating four groups.ResultsWhen compared to their control diet-fed littermates, offspring of HF-dams weaned onto HFD gained greater body weight; had increased relative liver weight and showed hepatic steatosis and inflammation. Similarly, this group revealed significantly greater immune response and pro-fibrogenic gene expression via RNA-seq. In parallel, 7–8 week old offspring were challenged with either control or MCD diets for 3 weeks. Responses to MCD diets were also exacerbated due to maternal HFD as seen by gene expression of classical pro-fibrogenic genes. Quantitative genome-scale DNA methylation analysis of over 1 million CpGs showed persistent epigenetic changes in key genes in tissue development and metabolism (Fgf21, Ppargc1β) with maternal HFD and in cell adhesion and communication (VWF, Ephb2) in the combination of maternal HFD and offspring MCD diets. Maternal HFD also influenced gut microbiome profiles in offspring leading to a decrease in α-diversity. Linear regression analysis revealed association between serum ALT levels and Coprococcus, Coriobacteriacae, Helicobacterioceae and Allobaculum.ConclusionOur findings indicate that maternal HFD detrimentally alters epigenetic and gut microbiome pathways to favor development of fatty liver disease and its progressive sequelae.

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Section: Discussionmentioning

confidence: 99%

Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations

et al. 2017

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“…In contrast, early in neonatal life light and dark signals presumptively begin to supersede the maternal-driven regulation of the circadian clock (1-3). However, we and others have previously demonstrated that during both fetal and infant developmental time points, a high fat maternal diet appears to have a dominant impact on the molecular regulation of the offspring circadian clock machinery, particularly epigenomic modifications to crucial gene promoter regions of Npas2 (9-11; 56–60). Prior to the studies undertaken herein, it was unknown whether it is maternal signaling, diet, or light/dark cycles that regulated the neonatal and infant circadian directed metabolism.…”

Section: Commentsmentioning

confidence: 92%

Conditional postnatal deletion of the neonatal murine hepatic circadian gene, Npas2, alters the gut microbiome following restricted feeding

O’Neil

Stewart

Chu

et al. 2017

American Journal of Obstetrics and Gynecology

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Background We have recently shown in both non-human primates and in rodents that fetal and neonatal hepatic expression of the circadian transcription factor, Npas2, is modulated by a high fat maternal diet and plays a critical role in establishing life-long metabolic homeostasis. Similarly, we and others have also established the importance of the maternal and early postnatal diet on establishment of the early gut microbiome. Objective We hypothesized that altered circadian gene expression solely in the neonatal liver would result in gut microbiome dysbiosis, especially with diet-induced metabolic stress (i.e., restricted feeding). Using a murine model where we conditionally knock out of Npas2 in the neonatal liver, we aimed to determine the role of the circadian machinery in gut dysbiosis with restricted feeding. Design We collected fecal samples from liver Npas2 conditional knock out (cKO; n=11) and wild type (wt: n=13) reproductive-aged mice before (study day 0) and after the restricted feeding study (study day 17). Extracted DNA was sequenced using the MiSeq Illumina platform using primers specific for the V4 region of the 16S rDNA gene. The resulting sequences were quality filtered, aligned, and assigned taxonomy. Principal coordinate analysis was performed on unweighted and weighted UniFrac distances between samples with Permutation ANOVA to assess clustering significance between groups. Microbial taxa that significantly differ between groups of interest was determined using Linear Discriminate Analysis Effect Size and randomForrest. Results Principal coordinate analysis performed on weighted UniFrac distances between male cKO and wt cohorts revealed that the gut microbiome of the mice did not differ by genotype at the start of the restricted feeding study, but did differ by virtue of genotype at the end of the study (p=0.001). Moreover, these differences could be at least partially attributed to restricted feeding-associated alterations in relative abundance of the Bacteroides genus, which has been implicated as crucial to establishing a healthy gut microbiome early in development. Conclusions Here we have provided an initial key insight into the interplay between neonatal establishment of the peripheral circadian clock in the liver and the ability of the gut microbiome to respond to dietary and metabolic stress. As Npas2 expression in the liver is a target of maternal high fat diet induced metabolic perturbations during fetal development, we speculate that these findings have potential implications in the long term metabolic health of their offspring.

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“…2013; Mouralidarane et al. 2015). However, the precise molecular mechanisms of programming in NAFLD pathogenesis remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Hepatic rhythmicity of endoplasmic reticulum stress is disrupted in perinatal and adult mice models of high-fat diet-induced obesity

Soeda

Cordero

et al. 2016

International Journal of Food Sciences and Nutrition

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We investigated the regulation of hepatic ER stress in healthy liver and adult or perinatally programmed diet-induced non-alcoholic fatty liver disease (NAFLD). Female mice were fed either obesogenic or control diet before mating, during pregnancy and lactation. Post-weaning, offspring from each maternal group were divided into either obesogenic or control diet. At six months, offspring were sacrificed at 4-h intervals over 24 h. Offspring fed obesogenic diets developed NAFLD phenotype, and the combination of maternal and offspring obesogenic diets exacerbated this phenotype. UPR signalling pathways (IREα, PERK, ATF6) and their downstream regulators showed different basal rhythmicity, which was modified in offspring exposed to obesogenic diet and maternal programming. The double obesogenic hit increased liver apoptosis measured by TUNEL staining, active caspase-3 and phospho-JNK and GRP78 promoter methylation levels. This study demonstrates that hepatic UPR is rhythmically activated. The combination of maternal obesity (MO) and obesogenic diets in offspring triggered altered UPR rhythmicity, DNA methylation and cellular apoptosis.

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Maternal obesity programs offspring non-alcoholic fatty liver disease through disruption of 24-h rhythms in mice

Abstract: These data implicate disordered circadian rhythms in NAFLD and suggest that disruption of this system during critical developmental periods may be responsible for the onset of chronic liver disease in adulthood.

Cited by 52 publications

References 34 publications

Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations

Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations

Conditional postnatal deletion of the neonatal murine hepatic circadian gene, Npas2, alters the gut microbiome following restricted feeding

Hepatic rhythmicity of endoplasmic reticulum stress is disrupted in perinatal and adult mice models of high-fat diet-induced obesity

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