FGF21 Lowers Plasma Triglycerides by Accelerating Lipoprotein Catabolism in White and Brown Adipose Tissues

Area of Science:

• Metabolic research
• Endocrinology
• Lipid metabolism

Background:

• Fibroblast Growth Factor 21 (FGF21) is known to reduce plasma triglycerides (TGs) in various models.
• The precise mechanisms by which FGF21 exerts its triglyceride-lowering effects remain incompletely understood.

Purpose of the Study:

• To investigate the role of FGF21 in the production and clearance of triglyceride-rich lipoproteins (TRLs).
• To elucidate the molecular mechanisms underlying FGF21's effects on TRL metabolism in mice.

Main Methods:

• Administration of pharmacological doses of FGF21 to mice.
• Measurement of plasma non-esterified fatty acids (NEFAs), liver TG content, and VLDL-TG secretion.
• Metabolic turnover studies to assess TRL catabolism in white adipose tissue (WAT) and brown adipose tissue (BAT).
• Utilized CD36-deficient and lipoprotein lipase-deficient mice to examine FGF21-dependent pathways.

Main Results:

• FGF21 treatment acutely decreased plasma NEFAs, hepatic TG content, and very-low-density lipoprotein (VLDL)-TG secretion.
• Metabolic studies demonstrated FGF21 enhances TRL catabolism in both WAT and BAT.
• These FGF21 effects were significantly reduced in mice lacking CD36 or adipose lipoprotein lipase (LPL).
• Insulin resistance altered FGF21's tissue-specific responses, favoring BAT over WAT.

Conclusions:

• FGF21 lowers plasma TGs via a dual mechanism: reducing NEFA levels to decrease hepatic VLDL lipidation and enhancing CD36 and LPL-dependent TRL disposal in adipose tissues.
• Tissue-specific responses to FGF21 can be modulated by metabolic state, such as insulin resistance.