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DIDO is necessary for adipogenesis promoting diet-induced obesity [I]

ABSTRACT: Rates of overweight and obesity continue to rise in the population worldwide. Obesity reduces life expectancy because it is an important predisposing factor for cancer, cardiovascular diseases and diabetes mellitus. Adipose tissue (AT), the main organ for fat storage with endocrine capacity, plays fundamental roles in systemic metabolism and in obesity-related diseases. Adiposity and lipodystrophy are associated with metabolic disorders, indicating that normal AT function is required for metabolic health. Dido1 is a marker gene for stemness and gene-targeting experiments compromised several functions from cell division to embryonic stem cell differentiation, in vivo and in vitro. Using animals carrying a DIDO mutant without the N-terminal, we report that these mice display a lean phenotype with reduced adipose tissue and hypolipidemia even when fed with an obesogenic diet. The phenotype related to impaired adipogenesis, partially corrected by transcription factors C/EBPα or PPARγ expression and to hypothermia subsequent to dermal fat thinning. Deep sequencing of the epididymal white fat (Epi WAT) transcriptome shows the role of Dido1 in the control of cellular lipases. The molecular analysis involves Dido1 in orchestrating adipogenesis and altogether offers a model different from described lipodystrophies in mice and pioneers a new path to understand obesity and identify mechanism for obesity intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE195908 | GEO | 2024/01/09

REPOSITORIES: GEO

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Project description:Background/Objectives: Obese subjects have increased number of enlarged fat cells which are reduced in size but not number in post-obesity. We performed DNA methylation profiling in fat cells with the aim of identifying differentially methylated DNA sites (DMS) linked to adipose hyperplasia (many small fat cells) in post-obesity. Subjects/Methods: Genome-wide DNA methylation was analyzed in abdominal subcutaneous fat cells from 16 women examined two years after gastric bypass surgery at a post-obese state (BMI 26±2 kg/m2, mean±s.d.) and 14 never-obese women (BMI 25±2 kg/m2). Gene expression was analyzed in subcutaneous adipose tissue from 9 women in each group. In a secondary analysis, we examined DNA methylation and expression of adipogenesis genes in 15 and 11 obese women, respectively. Results: The average degree of DNA methylation of all analyzed CpG-sites was lower in fat cells from post-obese as compared to never-obese women (P=0.014). 8,504 CpG sites were differentially methylated in fat cells from post-obese versus never-obese women (false discovery rate 1%). DMS were under-represented in CpG-islands and surrounding shores. The 8,504 DMS mapped to 3,717 unique genes; these genes were over-represented in cell differentiation pathways. Notably, 27% of genes linked to adipogenesis (i.e. 35 of 130) displayed DMS (adjusted P=10−8) in post-obese versus never-obese women. Next, we explored DNA methylation and expression of genes linked to adipogenesis in more detail in adipose tissue samples. DMS annotated to adipogenesis genes were not accompanied by differential gene expression in post-obese compared to never-obese women. In contrast, adipogenesis genes displayed differential DNA methylation accompanied by altered expression in obese women, Conclusions: Global CpG hypomethylation and overrepresentation of DMS in adipogenesis genes in fat cells may contribute to adipose hyperplasia in post-obese women. Post obese=16, Control group=14.

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DIDO is necessary for adipogenesis promoting diet-induced obesity [I]

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