Pck1 Deficiency Drives Mitochondrial Dysfunction and Cellular Senescence in Adipocytes

Area of Science:

• Aging biology
• Metabolic disorders
• Cellular senescence

Background:

• Cellular senescence in white adipose tissues (WAT) is an early aging sign, but mechanisms are unclear.
• Understanding WAT senescence is crucial for addressing age-related metabolic dysfunction and inflammaging.

Purpose of the Study:

• To identify key regulators of mitochondrial function and inflammaging in aging WAT.
• To elucidate the role of cytosolic phosphoenolpyruvate carboxykinase (Pck1) in WAT senescence and metabolic health.

Main Methods:

• Investigated Pck1 expression in aging gonadal and inguinal WAT.
• Utilized adipocyte-specific Pck1 deficiency models.
• Performed untargeted metabolomics and isotope-tracing analyses.
• Examined the effects of fumarate supplementation and fumarate hydratase (Fh1) overexpression.

Main Results:

• Pck1 expression decreased with age in WAT, and its deficiency accelerated inflammaging and metabolic disorders.
• Pck1 loss impaired cataplerosis, leading to fumarate accumulation in adipocytes.
• Fumarate accumulation disrupted mitochondrial homeostasis, increased oxidative stress, and activated the cGAS/STING pathway.
• Fh1 overexpression reduced fumarate and attenuated adipocyte inflammaging.

Conclusions:

• Pck1 is a critical regulator of mitochondrial metabolic homeostasis in WAT.
• Pck1 deficiency promotes adipocyte inflammaging and metabolic dysfunction via fumarate accumulation and cGAS/STING activation.
• Targeting Pck1 may offer a therapeutic strategy for age-related diseases.