Piperine inhibits adipocyte differentiation via dynamic regulation of histone modifications

Abstract

Previously, we reported that piperine, one of the major pungent components in black pepper, attenuates adipogenesis by repressing PPARγ activity in 3T3‐L1 preadipocytes. However, the epigenetic mechanisms underlying this activity remain unexplored. Here, gene set enrichment analysis using microarray data indicated that there was significant downregulation of adipogenesis‐associated and PPARγ target genes and upregulation of genes bound with H3K27me3 in response to piperine. As shown by Gene Ontology analysis, the upregulated genes are related to lipid oxidation and polycomb repressive complex 2 (PRC2). Chromatin immunoprecipitation assays revealed that PPARγ (and its coactivators), H3K4me3, and H3K9ac were less enriched at the PPAR response element of three adipogenic genes, whereas increased accumulation of H3K9me2, H3K27me3, and Ezh2 was found, which likely led to the reduced gene expression. Further analysis using three lipolytic genes revealed the opposite enrichment pattern of H3K4me3 and H3K27me3 at the Ezh2 binding site. Treatment with GSK343, an Ezh2 inhibitor, elevated lipolytic gene expression by decreasing the enrichment of H3K27me3 during adipogenesis, which confirms that Ezh2 plays a repressive role in lipolysis. Overall, these results suggest that piperine regulates the expression of adipogenic and lipolytic genes by dynamic regulation of histone modifications, leading to the repression of adipocyte differentiation.

Anti-Adipogenic Effects of Unripe Green Banana Flour Extracts (Musa abb cv. Kluai “namwa”) in 3T3-L1 Adipocytes

“…From in vitro study, gallic acid was shown to inhibit pre-adipocyte proliferation (Hsu et al, 2006) and adipocyte differentiation (Pandey et al, 2014). A recent study by Park et al, 2019 reported that piperine markedly reduced intracellular lipid accumulation through inhibiting the expression of transcription factors, PPARγ, SREBP-1c, and C/EBPβ in 3T3-L1 cells. In addition, among various components, malic acid, which was found in all extractants, has been reported lipolytic activity via stimulating glycerol release in 3T3-L1 adipocytes (Duangjai et al, 2018).…”

Trained immunity in monocyte/macrophage: Novel mechanism of phytochemicals in the treatment of atherosclerotic cardiovascular disease

“…In terms of pharmaceuticals, piperine decreases depressive disorders, prevents hepatotoxicity, and reduces obesity and diabetes ( Nogara et al, 2016 ). According to studies, piperine suppresses the development of adipocytes by dynamically controlling histone modifications and regulating the expression of genes involved in adipogenesis and lipolysis ( Park et al, 2019 ). In THP-1-differentiated human macrophages, piperine was likewise observed to increase ABCA1 protein expression.…”

The PPARα and PPARγ Epigenetic Landscape in Cancer and Immune and Metabolic Disorders

“…Histone modifications have been investigated in a genome-wide analysis in mouse and human adipocytes during adipogenesis, demonstrating enrichment of the H3K4me2/me3 and H3K27ac active histone marks in the promoters of Pparg 1 and 2 [ 157 ]. Interestingly, a recent study showed that Pparg is repressed by the action of piperine, a major component of black pepper, resulting in the inhibition of various adipogenic genes [ 158 ]. In contrast, Pparg expression and lipogenesis are enhanced upon H3K4 methylation by the methyltransferases mixed-lineage leukemia proteins 3 and 4 (MLL3 and MLL4), which form a complex with ASC-2 and are recruited by C/EBPβ to the Pparg locus [ 159 ].…”