2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction II

This study reports accumulation of larger lipid droplets in an adipocyte specific manner upon loss of CLPP. The mitochondria in KO BAT have mild respiratory chain deficiency but no difference in respiratory output at tissue and cellular level. Omics analysis reveals that loss of CLPP leads to tissue remodeling, and is accompanied by pertinent cytoskeletal changes. The metabolite, 2-hydroxyglutarate accumulates in KO tissue and cells and is possibly produced by the moonlighting function of PHGDH. We further identify 2-HG H3K4me3 methylation changes in epigenome being likely contributing to larger lipid droplets. The study also reports that 2HG mediated whitning is coupled to nuclear softening and changes in nuclear mechanics. Overall design: The experiment involved extraction of RNA from treated and untreated mBA cells. Preadipocytes were isolated from WT and CLPP KO animals and immortalized. This was followed by in vitro differentiation into mature adipocytes. The WT cells were either treated with the cell permeable form of the metabolite, octyl 2-hydroxyglutarate and KO cells were treated with the inhibitor of PHGDH, NCT503; and the results compared to their respective controls.