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Updated: Nov 22, 2025
Manipulation of Rhythmic Food Intake in Mice Using a Custom-Made Feeding System
Published on: December 16, 2022
Neonatal overfeeding during lactation rapidly and permanently misaligns the hepatic circadian rhythm and programmes
Francesc Ribas-Aulinas1, Silvia Ribo1, Marcela Parra-Vargas1
1Institut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain.
Insights
Early life nutrition challenges can disrupt the liver
Area of Science:
- Metabolic disease research
- Chronobiology
- Developmental biology
Background:
- Childhood obesity is a significant risk factor for adult-onset chronic diseases like type 2 diabetes and cardiovascular disease.
- The molecular mechanisms connecting early adiposity to later metabolic dysfunction remain incompletely understood.
- A mouse model of early adiposity was created using litter size reduction, leading to adult-onset obesity, insulin resistance, and hepatic steatosis.
Purpose of the Study:
- To investigate the molecular pathways linking early developmental stages and childhood obesity to adult hepatic steatosis and insulin resistance.
- To identify key molecular mechanisms underlying the long-term programming of metabolic disease initiated by early-life nutritional insults.
Main Methods:
- Analysis of the hepatic transcriptome in control and small litter (SL) mice using Affymetrix arrays.
- Investigation of core clock gene expression (period and cryptochrome) in the liver and hypothalamus.
- Assessment of the impact of dietary timing interventions (time-restricted feeding) on metabolic parameters and gene expression.
Main Results:
- The hepatic circadian rhythm was significantly deregulated in adult SL mice, with altered expression of core clock genes (period, cryptochrome) persisting from early life.
- This circadian disruption was peripheral, as central hypothalamic clock gene expression remained normal.
- Restricting food intake to the light cycle normalized hepatic triglyceride content by re-aligning peripheral clock genes, implicating period genes in hepatic steatosis regulation via Ppara.
Conclusions:
- Nutritional challenges during early development (birth to postnatal day 30) can misalign the maturing hepatic circadian rhythm, leading to secondary metabolic derangements.
- Time-restricted feeding interventions show promise in improving metabolic health in models of early-life obesity by re-aligning peripheral circadian rhythms.
- The findings highlight the critical role of early-life circadian programming in preventing adult metabolic diseases.
Abstract:
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.
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