Metformin also activates AMPK signaling to reduce age-related hepatic lipid accumulation, remodel extracellular matrix in adipose tissue and decrease insulin resistance in obesity by inhibiting the downstream transforming growth factor-β1 (TGFβ1)/Smad3 signaling and the upstream Rho-kinase 1 (ROCK1), which has been shown to accelerate obesity-induced steatosis in mice [32,33]. The gene discussed is SMAD3; the disease is obesity due to melanocortin 4 receptor deficiency.