Novel regulation of melanogenesis by adiponectin via the AMPK/CRTC pathway

Abstract

Several studies observed that adiponectin, an important adipokine that improves glucose metabolism by regulating AMP-activated protein kinase (AMPK) signaling, is dermatologically beneficial. In our recent microarray data, we found that adiponectin expression was lower in lesional skin than in non-lesional skin of melasma patients. Given that AMPK is a key adiponectin signaling mediator, we investigated the role of adiponectin and AICAR, a cell-permeable AMPK activator, in melanogenesis. We herein showed that adiponectin and AICAR downregulated MITF, tyrosinase, TRP-1, and DCT expression and reduced melanin content in normal human and mouse melanocytes. The depigmenting effect of adiponectin was mediated via AMPK activation, which induced the inhibitory phosphorylation of CREB-regulated transcription co-activators (CRTCs) and subsequent suppression of the novel CRTC/CREB pathway in melanocytes. These findings suggest that adiponectin and its analogs are useful as a clinical strategy for treating hyperpigmentation disorders.

Globular adiponectin acts as a melanogenic signal in human epidermal melanocytes

“…In particular, full-length adiponectin was reported to suppress melanogenesis. 17 However, in this study, we demonstrated that, unlike fulllength adiponectin, which has an antimelanogenic effect, globular adiponectin, a truncated form of full-length adiponectin, possessed melanogenic activity and that its effects were mediated by activating AMPK-mediated signalling. In addition, it was recently reported that the skin of patients with diabetes had a lower melanin content.…”

“…In recent studies, effects of adiponectin on skin cells (keratinocytes, fibroblasts and melanocytes) have been reported. In particular, full‐length adiponectin was reported to suppress melanogenesis . However, in this study, we demonstrated that, unlike full‐length adiponectin, which has an antimelanogenic effect, globular adiponectin, a truncated form of full‐length adiponectin, possessed melanogenic activity and that its effects were mediated by activating AMPK‐mediated signalling.…”

“…Moreover, a recent study reported that full-length adiponectin inhibits melanogenesis. 17 Adiponectin exists as a full-length 30-kDa protein, which circulates in trimeric, hexameric and higher-order complexes. 18 A fragment containing the globular domain of adiponectin (gAd) has been shown to display metabolic effects in various tissues.…”

“…These results suggest that adiponectin released by adipocytes in subcutaneous adipose tissue can influence the adjacent skin (epidermis and dermis). Moreover, a recent study reported that full‐length adiponectin inhibits melanogenesis …”

Transcriptional co-activator regulates melanocyte differentiation and oncogenesis by integrating cAMP and MAPK/ERK pathways

“…In keeping with their considerable sequence homology, CRTCs have been found to exert overlapping effects on CREB target gene expression; yet knockout studies also reveal distinct phenotypes for each family member [25][26][27][28] . In melanocytes, CRTCs have been proposed as targets for treatment of hyperpigmentary disorders by virtue of their ability to mediate effects of CREB on MITF expression [29][30][31][32] .…”