The effect of exogenous addition of metformin hydrochloride on lipid synthesis in Mucor circinelloides WJ11

As a well-established oleaginous model fungus, Mucor circinelloides has been extensively employed in lipid metabolism research due to its high lipid accumulation capacity and genetic tractability. Metformin hydrochloride, a biguanide drug, exerts significant effects on glucose and lipid metabolism in animal model, however, its effect on lipid metabolism in oleaginous microorganism is unclear. This investigation elucidates the regulatory effects of metformin hydrochloride on lipid biosynthesis in the model oleaginous fungus M. circinelloides. The findings revealed that metformin hydrochloride suppresses fatty acid biosynthesis in M. circinelloides. Addition of 4 g/L metformin hydrochloride to the growth medium of the fungus reduced the total fatty acid content from 29.57 % to 23.27 %, representing a decrease of 21.30 %. Furthermore, metformin hydrochloride significantly upregulated the transcriptional levels of AMPK subunits (such as Snf-α1, Snf-γ1, and Snf-γ3) while suppressing the expression of key genes involved in lipid synthesis, including acl, acc1, and acc2. Our enzymatic assays revealed that metformin hydrochloride treatment markedly inhibited ACC and 6PGDH activities, thereby restricting the availability of both acetyl-CoA precursors and NADPH reducing equivalents required for lipid biosynthesis. This study provided evidence supporting the relationship between metformin hydrochloride and lipid synthesis and validated metformin hydrochloride as a targeted drug for inhibiting lipid synthesis in M. circinelloides.