Lactate induces FGF21 expression in adipocytes through a p38-MAPK pathway

Area of Science:

• Metabolic regulation
• Cellular signaling
• Endocrinology

Background:

• Fibroblast growth factor 21 (FGF21) is a key metabolic regulator primarily known for its role in the liver.
• FGF21 also influences metabolic processes in adipose and muscle tissues.
• Its role in response to specific metabolites in adipocytes is not fully understood.

Purpose of the Study:

• To investigate the rapid regulation of FGF21 expression and secretion in adipocytes by lactate.
• To elucidate the signaling pathways involved in lactate-induced FGF21 production.
• To determine if other metabolites also trigger FGF21 release from adipose tissue.

Main Methods:

• In vitro studies using adipocytes exposed to lactate.
• Pharmacological inhibition of signaling pathways, including p38-MAPK.
• Analysis of Fgf21 gene expression and protein secretion.
• Use of knockout mice models to study in vivo mechanisms.
• Exposure of adipocytes to other metabolites like pyruvate and ketone bodies.

Main Results:

• Lactate rapidly increased FGF21 expression and secretion in adipocytes.
• Lactate-induced FGF21 regulation occurs independently of NADH/NAD levels.
• Activation of the p38-MAPK signaling pathway is essential for this response.
• Pyruvate and ketone bodies also stimulated FGF21 release, indicating a broader metabolite response.
• FGF21 release by adipocytes serves as a stress response to excess intermediate metabolites.

Conclusions:

• Lactate is a potent inducer of FGF21 in adipose tissue through a p38-MAPK dependent pathway.
• Adipose-derived FGF21 acts as a metabolic sensor, responding to various intermediate metabolites.
• This mechanism highlights a physiological role for FGF21 in metabolic adaptation to environmental cues.