Ceramide-induced FGF13 impairs systemic metabolic health

Area of Science:

• Metabolic diseases
• Cellular biology
• Endocrinology

Background:

• Ceramide accumulation in adipocytes disrupts nutrient storage and utilization, impairing energy and glucose homeostasis.
• Obesity is linked to increased FGF13 expression in adipose tissue, correlating with type 2 diabetes indicators.

Purpose of the Study:

• To identify novel factors regulated by ceramides that impact adipocyte function.
• To investigate the role of fibroblast growth factor FGF13 in metabolic homeostasis.

Main Methods:

• Comparative transcriptomic screening to identify ceramide-regulated factors.
• Analysis of FGF13 expression in adipose tissue from mice and humans with obesity.
• Utilizing loss-of-function and gain-of-function mouse models for FGF13.
• Investigating the mechanistic effects of FGF13 on mitochondrial function, metabolic elasticity, and caveolae formation.

Main Results:

• FGF13 was identified as a ceramide-regulated factor that impairs adipocyte function.
• Obesity significantly increases FGF13 expression in adipose tissue, associated with poor glycemic control.
• FGF13 was found to be both necessary and sufficient to disrupt energy and glucose homeostasis, independent of ceramide levels.
• FGF13 inhibits mitochondrial function, metabolic flexibility, and caveolae formation, leading to reduced glucose uptake and impaired thermogenesis.

Conclusions:

• FGF13 plays a critical role in metabolic dysfunction, independent of ceramide accumulation.
• Targeting FGF13 presents a potential therapeutic avenue for metabolic diseases, including type 2 diabetes and obesity.