Chchd10: A Novel Metabolic Sensor Modulating Adipose Tissue Homeostasis

Area of Science:

• Metabolic research
• Adipose tissue biology
• Obesity research

Background:

• Adipose tissue (AT) homeostasis is crucial for metabolic health, and its dysregulation in obesity leads to metabolic stress.
• Obesity is linked to metabolic disorders, highlighting the need to understand AT remodeling mechanisms.

Purpose of the Study:

• To identify novel regulators of adipose tissue remodeling during excess energy intake.
• To investigate the role of Coiled-coil-helix-coiled-coil-helix domain containing 10 (Chchd10) in diet-induced obesity and metabolic dysfunction.

Main Methods:

• Utilized mouse models fed a high-fat diet (HFD) to study adipose tissue changes.
• Analyzed gene expression, adipogenesis, and protein carbonylation in response to Chchd10 deficiency.
• Investigated the molecular pathways, including the TDP43/Raptor/p62/Keap1/NRF2 axis, involved in Chchd10-mediated AT remodeling.

Main Results:

• Chchd10 levels decrease in white adipose tissue (WAT) under HFD conditions.
• Chchd10 deficiency accelerates adipogenesis in subcutaneous AT and upregulates glutathione S-transferase A4 (GSTA4) in visceral AT, mitigating obesity and metabolic disorders.
• Chchd10 deficiency activates the TDP43/Raptor/p62/Keap1/NRF2 axis, enhancing adipogenesis and GSTA4 expression.
• The beneficial effects of Chchd10 deficiency are abolished in hypertrophic adipocytes with reduced p62 levels.

Conclusions:

• Chchd10 acts as a metabolic sensor that maintains adipose tissue homeostasis.
• Loss of Chchd10 in adipose tissue promotes adaptive remodeling to prevent obesity and related metabolic disorders.
• Impaired Chchd10-mediated AT remodeling due to p62 loss in obese conditions highlights a critical mechanism in metabolic dysfunction.