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Vitamin C Inhibits the Metabolic Changes Induced by Tet1 Insufficiency Under High Fat Diet Stress
Yangmian Yuan1, Chengyu Liu2,3, Xingrui Chen1
1Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
Scope:
DNA methylation contributes to obesity, but the role of the DNA demethylase ten-eleven translocation protein 1 (Tet1) in obesity remains unclear. Vitamin C is a cofactor for the Tet family of proteins, but whether vitamin C can be used to treat obesity via Tet1 awaits clarification.
Methods And Results:
Tet1+/+ and Tet1+/- mice are fed a high fat diet (HFD). Higher weight gain and more severe hepatic steatosis, accompanied by reduced 5-hydromethylcytosine (5hmC) levels, are found in the white adipose tissue and liver of Tet1+/- mice. Accumulated lipids are observed in palmitic acid or oleic acid treated primary hepatocytes derived from Tet1+/- mice, which are rescued by Tet1 overexpression or vitamin C treatment. Bisulfite sequencing reveals higher DNA methylation levels on lipolysis related genes in the liver of Tet1+/- mice. Notably, oral intake of vitamin C normalizes DNA methylation levels, promotes lipolysis, and decreases obesity in HFD-fed Tet1+/- mice.
Conclusions:
The results reveal a novel function of Tet1 in obesity and provide a new mechanism for the beneficial role of vitamin C in metabolic diseases through enhanced Tet1 activity.
Insights
The DNA demethylase ten-eleven translocation protein 1 (Tet1) plays a role in obesity. Vitamin C treatment improved obesity in mice by enhancing Tet1 activity, suggesting a new therapeutic approach for metabolic diseases.
Area of Science:
- Epigenetics
- Metabolic Diseases
- Molecular Biology
Background:
- DNA methylation is implicated in obesity.
- The specific role of ten-eleven translocation protein 1 (Tet1), a DNA demethylase, in obesity is not well understood.
- Vitamin C acts as a cofactor for Tet proteins, but its therapeutic potential in obesity via Tet1 requires clarification.
Purpose of the Study:
- To investigate the role of Tet1 in obesity.
- To explore the mechanism by which Vitamin C may treat obesity through Tet1.
- To determine the impact of Tet1 deficiency on metabolic parameters in mice fed a high-fat diet.
Main Methods:
- Tet1 heterozygous (Tet1+/-) and wild-type (Tet1+/+) mice were fed a high-fat diet (HFD).
- Levels of 5-hydroxymethylcytosine (5hmC) and DNA methylation were assessed in adipose tissue and liver.
- Lipid accumulation in primary hepatocytes was analyzed, and the effects of Tet1 overexpression and Vitamin C treatment were evaluated.
- Lipolysis-related genes were examined for DNA methylation changes.
Main Results:
- Tet1+/- mice exhibited increased weight gain and hepatic steatosis compared to Tet1+/+ mice under HFD.
- Reduced 5hmC levels were observed in the white adipose tissue and liver of Tet1+/- mice.
- Primary hepatocytes from Tet1+/- mice showed increased lipid accumulation, which was reversed by Tet1 overexpression or Vitamin C.
- Bisulfite sequencing indicated higher DNA methylation in lipolysis-related genes in Tet1+/- mouse livers.
- Oral Vitamin C administration normalized DNA methylation, enhanced lipolysis, and reduced obesity in HFD-fed Tet1+/- mice.
Conclusions:
- Tet1 has a novel function in regulating obesity.
- Enhanced Tet1 activity by Vitamin C provides a new mechanism for its beneficial effects in metabolic diseases.
- This study suggests Vitamin C as a potential therapeutic agent for obesity by modulating Tet1 activity.
