Neonatal overfeeding during lactation rapidly and permanently misaligns the hepatic circadian rhythm and programmes adult NAFLD
Childhood obesity is a strong risk factor for adult obesity, type 2 diabetes, and cardiovascular disease. The mechanisms that link early adiposity with late-onset chronic diseases are poorly characterised. We developed a mouse model of early adiposity through litter size reduction. Mice reared in sm...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-03-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877821000028 |
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| author | Francesc Ribas-Aulinas Silvia Ribo Marcela Parra-Vargas Antonio Fernández-Pérez Judith Cebrià Maria Guardiola-Perello Marta Ramon-Krauel Carles Lerin Ruben Diaz Susana G. Kalko Mario Vallejo Antoni Díez-Noguera Trinitat Cambras Josep C. Jimenez-Chillaron |
| author_facet | Francesc Ribas-Aulinas Silvia Ribo Marcela Parra-Vargas Antonio Fernández-Pérez Judith Cebrià Maria Guardiola-Perello Marta Ramon-Krauel Carles Lerin Ruben Diaz Susana G. Kalko Mario Vallejo Antoni Díez-Noguera Trinitat Cambras Josep C. Jimenez-Chillaron |
| author_sort | Francesc Ribas-Aulinas |
| collection | DOAJ |
| description | Childhood obesity is a strong risk factor for adult obesity, type 2 diabetes, and cardiovascular disease. The mechanisms that link early adiposity with late-onset chronic diseases are poorly characterised. We developed a mouse model of early adiposity through litter size reduction. Mice reared in small litters (SLs) developed obesity, insulin resistance, and hepatic steatosis during adulthood. The liver played a major role in the development of the disease. Objective: To gain insight into the molecular mechanisms that link early development and childhood obesity with adult hepatic steatosis and insulin resistance. Methods: We analysed the hepatic transcriptome (Affymetrix) of control and SL mice to uncover potential pathways involved in the long-term programming of disease in our model. Results: The circadian rhythm was the most significantly deregulated Gene Ontology term in the liver of adult SL mice. Several core clock genes, such as period 1–3 and cryptochrome 1–2, were altered in two-week-old SL mice and remained altered throughout their life course until they reached 4–6 months of age. Defective circadian rhythm was restricted to the periphery since the expression of clock genes in the hypothalamus, the central pacemaker, was normal. The period-cryptochrome genes were primarily entrained by dietary signals. Hence, restricting food availability during the light cycle only uncoupled the central rhythm from the peripheral and completely normalised hepatic triglyceride content in adult SL mice. This effect was accompanied by better re-alignment of the hepatic period genes, suggesting that they might have played a causal role in mediating hepatic steatosis in the adult SL mice. Functional downregulation of Per2 in hepatocytes in vitro confirmed that the period genes regulated lipid-related genes in part through peroxisome proliferator-activated receptor alpha (Ppara). Conclusions: The hepatic circadian rhythm matures during early development, from birth to postnatal day 30. Hence, nutritional challenges during early life may misalign the hepatic circadian rhythm and secondarily lead to metabolic derangements. Specific time-restricted feeding interventions improve metabolic health in the context of childhood obesity by partially re-aligning the peripheral circadian rhythm. |
| first_indexed | 2024-12-17T22:30:40Z |
| format | Article |
| id | doaj.art-6a24126da33d484e9ce05d40ed7abc8e |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-17T22:30:40Z |
| publishDate | 2021-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-6a24126da33d484e9ce05d40ed7abc8e2022-12-21T21:30:12ZengElsevierMolecular Metabolism2212-87782021-03-0145101162Neonatal overfeeding during lactation rapidly and permanently misaligns the hepatic circadian rhythm and programmes adult NAFLDFrancesc Ribas-Aulinas0Silvia Ribo1Marcela Parra-Vargas2Antonio Fernández-Pérez3Judith Cebrià4Maria Guardiola-Perello5Marta Ramon-Krauel6Carles Lerin7Ruben Diaz8Susana G. Kalko9Mario Vallejo10Antoni Díez-Noguera11Trinitat Cambras12Josep C. Jimenez-Chillaron13Institut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, SpainInstitut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, SpainInstitut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, SpainInstituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid y Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, Madrid, SpainInstitut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, SpainInstitut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, SpainInstitut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain; Departament de Medicina, Facultat de Medicina, Universitat de Barcelona, SpainInstitut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, SpainInstitut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain; Departament de Medicina, Facultat de Medicina, Universitat de Barcelona, SpainMoebius Research Ltd, London, UKInstituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid y Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, Madrid, SpainDepartament de Bioquímica i Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, SpainDepartament de Bioquímica i Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, SpainInstitut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain; Corresponding author. Institut de Recerca Sant Joan de Déu (Children's Hospital Barcelona), Endocrine Division, Santa Rosa 39-57, 4a Planta, Esplugues de Llobregat, Barcelona, 08950, Spain.Childhood obesity is a strong risk factor for adult obesity, type 2 diabetes, and cardiovascular disease. The mechanisms that link early adiposity with late-onset chronic diseases are poorly characterised. We developed a mouse model of early adiposity through litter size reduction. Mice reared in small litters (SLs) developed obesity, insulin resistance, and hepatic steatosis during adulthood. The liver played a major role in the development of the disease. Objective: To gain insight into the molecular mechanisms that link early development and childhood obesity with adult hepatic steatosis and insulin resistance. Methods: We analysed the hepatic transcriptome (Affymetrix) of control and SL mice to uncover potential pathways involved in the long-term programming of disease in our model. Results: The circadian rhythm was the most significantly deregulated Gene Ontology term in the liver of adult SL mice. Several core clock genes, such as period 1–3 and cryptochrome 1–2, were altered in two-week-old SL mice and remained altered throughout their life course until they reached 4–6 months of age. Defective circadian rhythm was restricted to the periphery since the expression of clock genes in the hypothalamus, the central pacemaker, was normal. The period-cryptochrome genes were primarily entrained by dietary signals. Hence, restricting food availability during the light cycle only uncoupled the central rhythm from the peripheral and completely normalised hepatic triglyceride content in adult SL mice. This effect was accompanied by better re-alignment of the hepatic period genes, suggesting that they might have played a causal role in mediating hepatic steatosis in the adult SL mice. Functional downregulation of Per2 in hepatocytes in vitro confirmed that the period genes regulated lipid-related genes in part through peroxisome proliferator-activated receptor alpha (Ppara). Conclusions: The hepatic circadian rhythm matures during early development, from birth to postnatal day 30. Hence, nutritional challenges during early life may misalign the hepatic circadian rhythm and secondarily lead to metabolic derangements. Specific time-restricted feeding interventions improve metabolic health in the context of childhood obesity by partially re-aligning the peripheral circadian rhythm.http://www.sciencedirect.com/science/article/pii/S2212877821000028Developmental origins of health and disease (DOHaD)Childhood obesityCircadian rhythmLitter size reductionTime-restricted feeding (TRF)Non-alcoholic fatty liver disease (NAFLD) |
| spellingShingle | Francesc Ribas-Aulinas Silvia Ribo Marcela Parra-Vargas Antonio Fernández-Pérez Judith Cebrià Maria Guardiola-Perello Marta Ramon-Krauel Carles Lerin Ruben Diaz Susana G. Kalko Mario Vallejo Antoni Díez-Noguera Trinitat Cambras Josep C. Jimenez-Chillaron Neonatal overfeeding during lactation rapidly and permanently misaligns the hepatic circadian rhythm and programmes adult NAFLD Molecular Metabolism Developmental origins of health and disease (DOHaD) Childhood obesity Circadian rhythm Litter size reduction Time-restricted feeding (TRF) Non-alcoholic fatty liver disease (NAFLD) |
| title | Neonatal overfeeding during lactation rapidly and permanently misaligns the hepatic circadian rhythm and programmes adult NAFLD |
| title_full | Neonatal overfeeding during lactation rapidly and permanently misaligns the hepatic circadian rhythm and programmes adult NAFLD |
| title_fullStr | Neonatal overfeeding during lactation rapidly and permanently misaligns the hepatic circadian rhythm and programmes adult NAFLD |
| title_full_unstemmed | Neonatal overfeeding during lactation rapidly and permanently misaligns the hepatic circadian rhythm and programmes adult NAFLD |
| title_short | Neonatal overfeeding during lactation rapidly and permanently misaligns the hepatic circadian rhythm and programmes adult NAFLD |
| title_sort | neonatal overfeeding during lactation rapidly and permanently misaligns the hepatic circadian rhythm and programmes adult nafld |
| topic | Developmental origins of health and disease (DOHaD) Childhood obesity Circadian rhythm Litter size reduction Time-restricted feeding (TRF) Non-alcoholic fatty liver disease (NAFLD) |
| url | http://www.sciencedirect.com/science/article/pii/S2212877821000028 |
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