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GLP-1 and incretin mimetics, such as exenatide, have been shown to attenuate hepatocyte steatosis in vivo and in vitro, but the specific underlying mechanism is unclear. SIRT1, an NAD(+)-dependent protein deacetylase, has been considered as a crucial regulator in hepatic lipid homeostasis by accumulated studies. Here, we speculate that SIRT1 might mediate the effect of the GLP-1 receptor agonist exenatide (exendin-4) on ameliorating hepatic steatosis. After 8 weeks of exenatide treatment in male SIRT1(+/-) mice challenged with a high-fat diet and their wild-type (WT) littermates, we found that lipid deposition and inflammation in the liver, which were improved dramatically in the WT group, diminished in SIRT1(+/-) mice. In addition, the protein expression of SIRT1 and phosphorylated AMPK was upregulated, whereas lipogenic-related protein, including SREBP-1c and PNPLA3, was downregulated in the WT group after exenatide treatment. However, none of these changes were observed in SIRT1(+/-) mice. In HepG2 cells, exendin-4-reversed lipid deposition induced by palmitate was hampered when SIRT1 was silenced by SIRT1 RNA interference. Our data demonstrate that SIRT1 mediates the effect of exenatide on ameliorating hepatic steatosis, suggesting the GLP-1 receptor agonist could serve as a potential drug for nonalcoholic fatty liver disease (NAFLD), especially in type 2 diabetes combined with NAFLD, and SIRT1 could be a therapeutic target of NAFLD.

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Proopiomelanocortin (POMC)-derived peptides and their receptors have been identified in many peripheral organs including the skin in which they exert a diversity of biological actions. We investigated the expression and potential role of the POMC system in human dermal papilla cells (DPCs), a specialized cutaneous mesenchymal cell type regulating hair follicle activity. In culture, these cells expressed POMC and displayed immunoreactivity for ACTH, alphaMSH, and beta-endorphin. Among the prohormone convertases (PCs) tested, only PC2, its chaperone 7B2, and furin convertase but not PC1 and paired basic amino acid cleaving enzyme 4 gene were detected. Human DPCs in vitro expressed both the melanocortin-1 receptor (MC-1R) and MC-4R, and immunoreactivity for these receptors was also present in cells of the human dermal papilla in situ. In contrast to the dermal papilla of agouti mice, agouti signaling protein, a natural and highly selective MC-1R and MC-4R antagonist, was undetectable in human DPCs. The MC-Rs detected in human DPCs were functionally active because alphaMSH increased intracellular cAMP and calcium. Preincubation of the cells with a synthetic peptide corresponding to the C-terminal domain of agouti signaling protein abrogated cAMP induction by alphaMSH. Furthermore, alphaMSH was capable of antagonizing the expression of intercellular adhesion molecule-1 induced by the proinflammatory cytokine interferon-gamma. Our data suggest a regulatory function of alphaMSH within the dermal papilla whose disruption may lead to deregulation of immune and inflammatory responses of the hair follicle, thereby possibly contributing to the development of inflammatory forms of alopecia.