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

May 15, 2015International journal of obesity (2005)

Maternal Obesity May Cause Fatty Liver Disease in Offspring by Disrupting Their Daily Biological Rhythms in Mice

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Abstract

Maternal obesity combined with an obesogenic diet in offspring is associated with the development of non-alcoholic fatty liver disease (NAFLD) at 6 months.

Maternal obesity may disrupt the normal rhythmic expression of metabolic genes in the liver of offspring.
Hypermethylation of the BMAL-1 and Per2 gene regions was observed in the liver, which is associated with altered circadian rhythms.
A 24-hour disruption in the expression of pro-inflammatory and fibrogenic mediators was noted in the liver of affected offspring.
These findings suggest that disturbances in circadian rhythms during critical developmental periods could be linked to chronic liver disease later in life.

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BACKGROUND: Maternal obesity increases offspring propensity to metabolic dysfunctions and to non-alcoholic fatty liver disease (NAFLD), which may lead to cirrhosis or liver cancer. The circadian clock is a transcriptional/epigenetic molecular machinery synchronising physiological processes to coordinate energy utilisation within a 24-h light/dark period. Alterations in rhythmicity have profound effects on metabolic pathways, which we sought to investigate in offspring with programmed NAFLD.

METHODS: Mice were fed a standard or an obesogenic diet (OD), before and throughout pregnancy, and during lactation. Offspring were weaned onto standard or an OD at 3 weeks postpartum and housed in 12:12 light/dark conditions. Biochemical and histological indicators of NAFLD and fibrosis, analysis of canonical clock genes with methylation status and locomotor activity were investigated at 6 months.

RESULTS: We show that maternal obesity interacts with an obesogenic post-weaning diet to promote the development of NAFLD with disruption of canonical metabolic rhythmicity gene expression in the liver. We demonstrate hypermethylation of BMAL-1 (brain and muscle Arnt like-1) and Per2 promoter regions and altered 24-h rhythmicity of hepatic pro-inflammatory and fibrogenic mediators.

CONCLUSIONS: 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.

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

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