ESPE Yearbook of Paediatric Endocrinology

J Steroid Biochem Mol Biol. 2020; 200:105684.https://pubmed.ncbi.nlm.nih.gov/32360359/

In this mouse cell model, the authors show that metformin appears to directly inhibit signaling of MC2R (the ACTH receptor) and also MC3R.

Metformin is used to treat type 2 diabetes and obesity, and may reduce the androgen excess in women with polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH). The mechanisms of its action are manifold. Metformin inhibits the cellular stress response at the level of the mitochondrial OXPHOS system and through AMPK-dependent and independent mechanisms. It also decreases pituitary ACTH secretion and reduces the ACTH-stimulated adrenal secretion. The authors previously reported that metformin inhibits complex I and the activities of the steroidogenic enzymes 3β-hydroxysteroid dehydrogenase (HSD3B2) and CYP17/17,20-lyse, enzymes essential for androgen production (1). MC2R is expressed primarily in the adrenal cortex and controls steroidogenesis and adrenal growth. MC3R and MC4R play essential roles in energy homeostasis and are expressed in brain and spinal cord. MC3R is important in regulating energy homeostasis and feeding, especially under stressful conditions.

The studies were performed in an adrenal OS3 cell model. Mouse adrenal OS3 cells, which do not express MC2R, were co-transfected to expressing human MC2R and luciferase (a fluorescent marker) and then stimulated with ACTH. In these cells, metformin inhibited ACTH-induced MC2R activation. A 3-fold increase in MC2R mRNA expression with ACTH stimulation, which was abolished to basal levels by metformin. By contrast, there was no effect of metformin on MRAP expression. This shows that metformin directly blocks ACTH stimulated MC2R expression. No significant effect of metformin was found on MC1R and MC4R activity. Metformin did not shift the α-MSH stimulated MC3R CRC, but produced 40% inhibition of the maximal response (Rmax), suggesting non-competitive inhibition. MC3R is involved in energy balance and seems to act as a rheostat when the metabolism is challenged.

The findings suggest that inhibition of MC2R and MC3R are mechanisms whereby metformin acts to produce weight loss and attenuate the androgen excess in PCOS and CAH.

Reference: 1. Hirsch A, Hahn D, Kempná P, Hofer G, Nuoffer JM, Mullis PE, Flück CE. Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain. Endocrinology. 2012; 153(9): 4354–66.