A nutrient-responsive AMPK/TBK1 circuit restricts adipocyte catabolism

Area of Science:

• Metabolic regulation
• Cellular signaling
• Obesity research

Background:

• Metabolic adaptation to caloric changes conserves energy by suppressing catabolism through poorly understood feedback mechanisms.
• TANK binding kinase 1 (TBK1) acts as a brake on AMP-activated protein kinase (AMPK) signaling in adipocytes, responding to nutrients and inflammation.

Purpose of the Study:

• To elucidate the role of the AMPK/TBK1 axis in metabolic adaptation and energy expenditure.
• To investigate the therapeutic potential of targeting TBK1 and AMPK in obesity.

Main Methods:

• Investigated the AMPK/TBK1 signaling axis in adipocytes using genetic manipulation (adipocyte-specific TBK1 deletion) and pharmacological interventions (amlexanox, AICAR).
• Assessed metabolic parameters, including energy expenditure, mitochondrial function, glucose tolerance, insulin sensitivity, and gene expression in lean and obese mouse models.

Main Results:

• Fasting and AMPK activation induce Tbk1 transcription, which limits AMPK activity, conserving energy.
• Obesity disrupts the AMPK/TBK1 axis, increasing basal TBK1 and reducing energy expenditure during fasting.
• TBK1 deletion or inhibition in adipocytes enhances fasting-induced AMPK activation, mitochondrial function, and lipolysis.
• Combined amlexanox and AICAR treatment improved weight loss, glucose/insulin homeostasis, and reduced inflammation and fibrosis.

Conclusions:

• A nutrient-sensitive AMPK/TBK1 feedback loop regulates adipocyte catabolism.
• Targeting TBK1 and AMPK may counteract metabolic adaptation and improve the efficacy of obesity treatments.