FGF21 is required for the metabolic benefits of IKKε/TBK1 inhibition

Area of Science:

• Metabolic disease research
• Endocrinology
• Obesity research

Background:

• Protein kinases IKKε and TBK1 are activated in obesity.
• Amlexanox, an IKKε/TBK1 inhibitor, has previously shown efficacy in weight loss and insulin resistance.
• The precise mechanisms underlying amlexanox's metabolic benefits require further elucidation.

Purpose of the Study:

• To investigate the mechanisms by which amlexanox improves metabolic health in obesity.
• To determine the roles of FGF21 and IL-6 in amlexanox-mediated effects.
• To differentiate the contributions of hepatic and adipocyte-derived factors.

Main Methods:

• Utilized mouse models of obesity.
• Administered amlexanox treatment.
• Measured food intake, energy expenditure, and tissue-specific FGF21 and IL-6 levels.
• Assessed adipose tissue beiging and hepatic glucose production.

Main Results:

• Amlexanox induced weight loss primarily through increased energy expenditure via FGF21-dependent white adipose tissue (WAT) beiging.
• Adipocyte-secreted FGF21, not hepatic FGF21, drove WAT beiging and weight loss.
• Amlexanox acutely reduced blood glucose by suppressing hepatic glucose production via IL-6/STAT3 signaling.

Conclusions:

• Amlexanox improves metabolic health by enhancing adipocyte FGF21 action, leading to increased energy expenditure and WAT beiging.
• Adipocyte-derived IL-6 plays an endocrine role in reducing hepatic glucose production through STAT3 activation.
• These dual actions of amlexanox result in a coordinated improvement of metabolic parameters in obesity.