{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:57:52Z","timestamp":1790816272613,"version":"4.1.0"},"reference-count":76,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T00:00:00Z","timestamp":1677628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The European Foundation for the Study of Diabetes\/Lilly","award":["SAF2017-84542-R"],"award-info":[{"award-number":["SAF2017-84542-R"]}]},{"name":"The European Foundation for the Study of Diabetes\/Lilly","award":["62167"],"award-info":[{"award-number":["62167"]}]},{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad, Spain (MINECO)","doi-asserted-by":"publisher","award":["SAF2017-84542-R"],"award-info":[{"award-number":["SAF2017-84542-R"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad, Spain (MINECO)","doi-asserted-by":"publisher","award":["62167"],"award-info":[{"award-number":["62167"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Templeton Foundation","award":["SAF2017-84542-R"],"award-info":[{"award-number":["SAF2017-84542-R"]}]},{"name":"The Templeton Foundation","award":["62167"],"award-info":[{"award-number":["62167"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/nu15051241","type":"journal-article","created":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T03:03:48Z","timestamp":1677639828000},"page":"1241","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Intergenerational Inheritance of Hepatic Steatosis in a Mouse Model of Childhood Obesity: Potential Involvement of Germ-Line microRNAs"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7672-4775","authenticated-orcid":false,"given":"Francesc","family":"Ribas-Aulinas","sequence":"first","affiliation":[{"name":"Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Esplugues, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8983-827X","authenticated-orcid":false,"given":"S\u00edlvia","family":"Ribo","sequence":"additional","affiliation":[{"name":"Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Esplugues, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6001-1276","authenticated-orcid":false,"given":"Eduard","family":"Casas","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukemia Research Institute (IJC), 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Mourin-Fernandez","sequence":"additional","affiliation":[{"name":"Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Esplugues, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Ramon-Krauel","sequence":"additional","affiliation":[{"name":"Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Esplugues, 08950 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben","family":"Diaz","sequence":"additional","affiliation":[{"name":"Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Esplugues, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carles","family":"Lerin","sequence":"additional","affiliation":[{"name":"Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Esplugues, 08950 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6701-0233","authenticated-orcid":false,"given":"Susana G.","family":"Kalko","sequence":"additional","affiliation":[{"name":"Vall d\u2019Hebron Research Institute (VHIR), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2352-9049","authenticated-orcid":false,"given":"Tanya","family":"Vavouri","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukemia Research Institute (IJC), 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep C.","family":"Jimenez-Chillaron","sequence":"additional","affiliation":[{"name":"Institut de Recerca Sant Joan de D\u00e9u (IRSJD), Esplugues, 08950 Barcelona, Spain"},{"name":"School of Medicine, University of Barcelona, L\u2019Hospitalet, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1001\/jama.2010.1635","article-title":"Association of Adolescent Obesity with Risk of Severe Obesity in Adulthood","volume":"304","author":"The","year":"2010","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ijo.2011.186","article-title":"Childhood Obesity and Risk of the Adult Metabolic Syndrome: A Systematic Review","volume":"36","author":"Lloyd","year":"2012","journal-title":"Int. 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