1964-P: Slug Epigenetically Represses Adipose Thermogenic Programs

Thermogenic fat, such as brown adipose tissue (BAT) and beige fat, gains increasing attention due to its ability to protect against obesity and type 2 diabetes. Brown adipocytes and beige adipocytes contain dense mitochondria that burn glucose and free fatty acids to produce heat, and mitochondrial Ucp1 mediates heat production. Coactivator PGC1α is a master regulator of mitochondrial biogenesis and Ucp1 expression, and profoundly influences the energy expenditure capability of thermogenic fat. We attempted to delineate transcriptional regulators that govern thermogenic fat activity through PGC1α, and identified transcriptional repressor Slug. Both human and mouse PGC1α promoters contain multiple Slug binding motifs. Slug potently suppressed the activity of PGC1α promoter luciferase reporters but not mutant PGC1α promoters lacking Slug motifs. Consistently, Slug physically bound to the PGC1α promoter and decreased the levels of PGC1α promoter H3K9 acetylation, a transcriptionally-active epigenetic mark, presumably by recruiting HDAC1/2 to the promoter. In line with this notion, treatment with HDAC1/2 inhibitor trichostatin A abrogated the ability of Slug to suppress PGC1α promoter luciferase reporters. Remarkably, deletion of Slug substantially increased expression of PGC1α and Ucp1 in both BAT and inguinal fat in mice, and increased H3K9 acetylation levels on the PGC1α promoter in BAT. Slug-deficient BAT had increased O2 consumption rates and thermogenesis capability. Slug knockout mice were resistant to high fat diet-induced obesity, insulin resistance, glucose intolerance, and fatty liver disease. Likewise, adipocyte-specific deletion of Slug also ameliorated HFD-induced glucose intolerance. Unlike global Slug knockout mice, adipocyte-specific Slug knockout mice displayed mild metabolic phenotypes. In conclusion, our data suggest that Slug regulates thermogenic fat energy expenditure at least in part by epigenetically suppressing the PGCα-mitochondria axis. Disclosure Q. Kang: None. L. Jiang: None. L. Rui: None.