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Intergenerational Inheritance of Hepatic Steatosis in a Mouse Model of Childhood Obesity: Potential Involvement of Germ-Line microRNAs

Nutrients · 10 authors, 5 centres

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TL;DR

This preclinical mouse study used litter size reduction to model childhood obesity and found that paternal overnutrition led to hepatic steatosis in offspring, with transcriptomic analysis pointing to circadian rhythm and lipid metabolism pathways. The study suggests that two specific sperm-borne microRNAs (miR-547 and miR-201) may be involved in this intergenerational transmission, while DNA methylation changes were not found to be inherited or directly linked to the offspring's liver gene expression.

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BACKGROUND

Childhood obesity is a risk factor for chronic diseases, and evidence suggests early-life nutritional imbalances can influence subsequent generations. This study used a mouse model of early adiposity (childhood obesity) induced by litter size reduction to explore the mechanisms of intergenerational inheritance of hepatic steatosis. Methods: Male mice from small litters (SL-F0) were mated with control females to produce F1 offspring. Hepatic gene expression was analyzed via microarrays, and epigenetic mechanisms were investigated through DNA methylation microarrays and small RNA sequencing of sperm and liver tissue. Results: SL-F1 offspring developed hepatic steatosis (elevated triglycerides and cholesterol). Transcriptomic analysis identified deregulated circadian rhythm and lipid metabolism pathways. DNA methylation changes in SL-F0 sperm were not found in SL-F1 liver, suggesting no direct inheritance. However, two microRNAs (miR-547 and miR-201) were differentially expressed in SL-F0 testes and are predicted to target lipid-related genes in hepatocytes. Limitations: The study is limited to male mice, and the functional role of the identified miRNAs in offspring development and adult liver metabolism requires further validation. The link between circadian rhythm disruption and hepatic steatosis in F1 mice is not fully established. Implications: The findings support a potential role for paternal germline microRNAs in the intergenerational transmission of metabolic dysfunction, highlighting a non-genetic mechanism for the inheritance of hepatic steatosis.

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preclinical research

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ORIGINAL PAPER

PMC10005268

Intergenerational Inheritance of Hepatic Steatosis in a Mouse Model of Childhood Obesity: Potential Involvement of Germ-Line microRNAs

Nutrients

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ABSTRACT

Abstract Childhood obesity increases the risk of developing metabolic syndrome later in life. Moreover, metabolic dysfunction may be inherited into the following generation through non-genomic mechanisms, with epigenetics as a plausible candidate. The pathways involved in the development of metabolic dysfunction across generations in the context of childhood obesity remain largely unexplored. We have developed a mouse model of early adiposity by reducing litter size at birth (small litter group, SL: 4 pups/dam; control group, C: 8 pups/dam). Mice raised in small litters (SL) developed obesity, insulin resistance and hepatic steatosis with aging. Strikingly, the offspring of SL males (SL-F1) also developed hepatic steatosis. Paternal transmission of an environmentally induced phenotype strongly suggests epigenetic inheritance. We analyzed the hepatic transcriptome in C-F1 and SL-F1 mice to identify pathways involved in the development of hepatic steatosis. We found that the circadian rhythm and lipid metabolic process were the ontologies with highest significance in the liver of SL-F1 mice. We explored whether DNA methylation and small non-coding RNAs might be involved in mediating intergenerational effects. Sperm DNA methylation was largely altered in SL mice. However, these changes did not correlate with the hepatic transcriptome. Next, we analyzed small non-coding RNA content in the testes of mice from the parental generation. Two miRNAs (miR-457 and miR-201) appeared differentially expressed in the testes of SL-F0 mice. They are known to be expressed in mature spermatozoa, but not in oocytes nor early embryos, and they may regulate the transcription of lipogenic genes, but not clock genes, in hepatocytes. Hence, they are strong candidates to mediate the inheritance of adult hepatic steatosis in our murine model. In conclusion, litter size reduction leads to intergenerational effects through non-genomic mechanisms. In our model, DNA methylation does not seem to play a role on the circadian rhythm nor lipid genes. However, at least two paternal miRNAs might influence the expression of a few lipid-related genes in the first-generation offspring, F1. Keywords: circadian rhythm, intergenerational epigenetic inheritance, childhood obesity, litter size reduction, DNA methylation, small non-coding RNAs

CITATION EXPORT

Francesc Ribas-Aulinas, Sílvia Ribo, Eduard Casas et al.. Intergenerational Inheritance of Hepatic Steatosis in a Mouse Model of Childhood Obesity: Potential Involvement of Germ-Line microRNAs. Nutrients. (2023). https://doi.org/10.3390/nu15051241

AUTHORS

10 · 5 CENTRES

Francesc Ribas-Aulinas, Sílvia Ribo, Eduard Casas, Marta Mourin-Fernandez, Marta Ramon-Krauel, Ruben Diaz, Carles Lerin, Susana G Kalko, Tanya Vavouri, Josep C Jimenez-Chillaron

1Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues, 08950 Barcelona, Spain
2Josep Carreras Leukemia Research Institute (IJC), 08916 Badalona, Spain
3Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
4Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain
5School of Medicine, University of Barcelona, L’Hospitalet, 08907 Barcelona, Spain

Francesc Ribas-Aulinas, Sílvia Ribo, Eduard Casas et al.. Intergenerational Inheritance of Hepatic Steatosis in a Mouse Model of Childhood Obesity: Potential Involvement of Germ-Line microRNAs. Nutrients. (2023). https://doi.org/10.3390/nu15051241