Histone Demethylase LSD1 Promotes Adipocyte Differentiation through Repressing Wnt Signaling

Abstract

Adipose tissue plays important roles in animals. White fat stores energy in lipids, while brown fat is responsible for nonshivering thermogenesis through UCP1-mediated energy dissipation. Although epigenetic mechanisms modulate differentiation in multiple lineages, the epigenetic regulation of brown adipocyte differentiation is poorly understood. By screening a collection of epigenetic compounds, we found that Lysine-Specific Demethylase 1 (LSD1) inhibitors repress brown adipocyte differentiation. RNAi-mediated Lsd1 knockdown causes a similar effect, which can be rescued by expression of wild-type but not catalytic-inactive LSD1. Mechanistically, LSD1 promotes brown adipogenesis by demethylating H3K4 on promoter regions of Wnt signaling components and repressing the Wnt pathway. Furthermore, deletion of Lsd1 in mice leads to inhibition of brown adipogenesis, validating the pivotal role of LSD1 in brown fat development in vivo. Our work identifies LSD1 as a key epigenetic regulator in brown adipogenesis. The link between LSD1 and the Wnt pathway provides potential opportunities to modulate brown fat differentiation.

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

“…Overexpression of LSD1 in BMSCs blocked Wnt signaling pathway by demethylating H3K4 and epigenetically silencing pro‐osteogenic Wnt‐gene promoters (Fig. ) . In addition, knockdown of LSD1 or its partner REST corepressor 2 (rcor2) blocked adipogenesis and increased expression of inflammatory cytokines and chemokines in 3T3‐L1 preadipocytes .…”

“…LSD1 has also been identified as a key epigenetic regulator in brown adipogenesis, and inhibition or depletion of LSD1 repressed brown adipocyte tissue differentiation in vitro and in vivo . Knockdown of LSD1 decreased differentiation of 3T3‐L1 preadipocytes.…”

“…Upregulation of LSD1 protein along with downregulation of JMJD2B expression by a plant extract, triptolide, has also been shown to cause cell‐cycle arrest and apoptosis of RPMI8226 MM cells . Several studies reported that LSD1 inhibits osteogenic and supports adipogenic differentiation . LSD1 inhibitors, pargyline and CBB1007, have been shown to enhance alkaline phosphatase activity and extracellular matrix mineralization by hASCs without apparent cellular toxicity .…”

Lysine‐specific demethylase‐2 is distinctively involved in brown and beige adipogenic differentiation

“…LSD1 forms a complex with PRDM16 and C‐terminal binding proteins 1 and 2 to repress WAT‐specific gene expression in BAT (17). In addition, LSD1 promotes both white and brown adipocyte differentiation by suppressing Wnt signaling in mesenchymal stem cells (36). In this study, we found that LSD2 positively regulates BAT‐associated genes while repressing myogenic genes depending on the derivation of cells.…”

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

“…Mechanistically, KDM1A demethylates H3K4me1/me2 at promoter regions of Wnt-pathway target genes, activating their expression and promoting brown adipogenesis [37].…”