Adiponectin, an AMPK activator, increases the phosphorylation of CRTC2 and CRTC3, down-regulates the expression of MITF-M, and decreases melanin contents in Mel-Ab cultures, and its mRNA levels are lower in the lesional skin of melasma patients compared with non-lesional skin 45. This evidence concerns the gene CRTC3 and freckles.