AMPK is not required for the effect of metformin on the inhibition of BMP6-induced hepcidin gene expression in hepatocytes

The biguanide metformin is used for its antidiabetic effect for many years but how metformin acts remains poorly understood and controversial. AMP-activated protein kinase (AMPK), a protein kinase that plays a key role in maintaining energy homeostasis, is assumed to be one of the prime targets of metformin. However, since our demonstration that AMPK is not required for the beneficial effects of metformin on the control of glycemia, the list of AMPK-independent actions of metformin is rapidly increasing. Given the conflicting results on the effects of metformin we sought, using our genetic mouse models deficient in the catalytic subunits of AMPK, to determine whether this kinase is involved in the effects of metformin on the expression of the iron-regulatory hormone hepcidin, as recently proposed. Here we demonstrate, using different approaches, either isolated hepatocytes that lack AMPK, or direct AMPK activators, that, AMPK activation is not necessary for metformin to inhibit BMP6-induced hepcidin gene expression. These results may shed new lights on the increasingly recognized AMPK-independent metformin’s molecular action, an important area of current research.