Metformin induces pyroptosis in leptin receptor-defective hepatocytes via overactivation of the AMPK axis

Metformin is the biguanide of hepatic insulin sensitizer for patients with non-alcohol fatty liver disease (NAFLD). Findings regarding its efficacy in restoring blood lipids and liver histology have been contradictory. In this study, we explore metformin’s preventive effects on NAFLD in leptin-insensitive individuals. We used liver tissue, serum exosomes and isolated hepatocytes from high-fat diet (HFD)-induced Zucker diabetic fatty (ZDF) rats and leptin receptor (Lepr) knockout rats to investigate the correlation between hepatic Lepr defective and liver damage caused by metformin. Through immunostaining, RT-PCR and glucose uptake monitoring, we showed that metformin treatment activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) and its downstream cytochrome C oxidase (CCO). This leads to overactivation of glucose catabolism-related genes, excessive energy repertoire consumption, and subsequent hepatocyte pyroptosis. Single-cell RNA sequencing further confirmed the hyper-activation of glucose catabolism after metformin treatment. Altogether, we showed that functional Lepr is necessary for metformin treatment to be effective, and that long-term metformin treatment might promote NAFLD progression in leptin-insensitive individuals. This provides important insight into the clinical application of metformin.