DIDO is necessary for the adipogenesis that promotes diet-induced obesity

• 成果类型: Article
• 署名作者: Garcia-Lopez, Maria angeles; Mora, Alfonso; Corrales, Patricia; Pons, Tirso; de Diego, Ainhoa Sanchez; Gutierrez, Amaia Talavera; van Wely, Karel H. M.; Medina-Gomez, Gema; Sabio, Guadalupe; Martinez-A, Carlos; Fischer, Thierry
• 署名单位: Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro Nacional de Biotecnologia (CNB); Autonomous University of Madrid; Centro Nacional de Investigaciones Cardiovasculares (CNIC); Universidad Rey Juan Carlos
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11199
• DOI: 10.1073/pnas.2300096121
• 发表日期: 2024-01-16
• 关键词: insulin; differentiation; expression; alpha; disruption; leptin; lipase; mice

摘要

The prevalence of overweight and obesity continues to rise in the population worldwide. Because it is an important predisposing factor for cancer, cardiovascular diseases, diabetes mellitus, and COVID- 19, obesity reduces life expectancy. Adipose tissue (AT), the main fat storage organ with endocrine capacity, plays fundamental roles in systemic metabo-lism and obesity- related diseases. Dysfunctional AT can induce excess or reduced body fat (lipodystrophy). Dido1 is a marker gene for stemness; gene- targeting experiments compromised several functions ranging from cell division to embryonic stem cell differ-entiation, both in vivo and in vitro. We report that mutant mice lacking the DIDO N terminus show a lean phenotype. This consists of reduced AT and hypolipidemia, even when mice are fed a high- nutrient diet. DIDO mutation caused hypothermia due to lipoatrophy of white adipose tissue (WAT) and dermal fat thinning. Deep sequencing of the epididymal white fat (Epi WAT) transcriptome supported Dido1 control of the cellu-lar lipid metabolic process. We found that, by controlling the expression of transcription factors such as C/EBP alpha or PPAR gamma, Dido1 is necessary for adipocyte differentiation, and that restoring their expression reestablished adipogenesis capacity in Dido1 mutants. Our model differs from other lipodystrophic mice and could constitute a new system for the development of therapeutic intervention in obesity.