Gut Microbiota Modulates Fgf21 Expression and Metabolic Phenotypes Induced by Ketogenic Diet

Area of Science:

• Metabolic research
• Microbiome science
• Endocrinology

Background:

• The ketogenic diet (KD) is recognized for its efficacy in managing obesity and diabetes.
• However, the precise molecular mechanisms, particularly the role of gut microbiota, remain incompletely understood.

Purpose of the Study:

• To elucidate the role of gut microbiota and FGF21 in mediating the metabolic effects of the KD.
• To investigate the signaling pathways involved in KD-induced metabolic improvements.

Main Methods:

• Utilized antibiotic treatment to deplete gut microbiota in mice.
• Employed Fgf21-deficient mice to assess the role of FGF21.
• Analyzed serum valine levels and hepatic Fgf21 expression.

Main Results:

• Gut microbiota is essential for KD-induced weight loss and glucose metabolism improvements.
• The KD alters serum valine levels via gut microbiota, regulating hepatic Fgf21 expression through the GCN2-eIF2α-ATF5 pathway.
• Valine supplementation counteracted elevated FGF21, reducing body weight and improving glucose metabolism.

Conclusions:

• Established a regulatory network connecting the KD, gut microbiota, and FGF21 expression.
• Identified the GCN2-eIF2α-ATF5 signaling pathway as crucial for mediating KD's metabolic benefits.
• Findings provide a basis for developing targeted therapies to enhance KD efficacy.