Nat. Cell. Biol. 17, 57–67 (2015)
Brown adipose tissue (BAT) differs from white adipose tissue (WAT) in cellular morphology, gene expression and metabolic function. BAT contains multiple small lipid droplets and expresses uncoupling protein 1 (UCP1), which disrupts the respiratory chain to release heat, whereas WAT contain large lipid droplets whose primary function is to store energy. As promoting increased thermogenesis to burn excess calories has been thought of as a potential therapeutic treatment to combat obesity and type 2 diabetes, researchers have searched for strategies that increase the amount of BAT. Considering that thermogenic stimuli such as cold exposure or β-adrenergic stimulation promote the appearance of brown adipocytes in white depots in both mice and humans, Moisan et al. envisioned that small molecules might perform the same task to convert WAT into BAT. They applied an annotated collection of small molecules in human pluripotent stem cell–derived adipocytes (PSC-WAs) using UCP1 expression as a readout of BAT identity. Some of the most effective candidates were inhibitors of Janus kinase (JAK)-STAT signaling that promoted changes in morphology consistent with brown-like adipocytes. Although these adipocytes were genetically similar to WAT, they exhibited BAT features, such as increased mitochondrial content, oxygen consumption and lipid catabolism. To determine the mechanism of these changes, Moisan et al. performed RNA-seq analysis of JAK-inhibited adipocytes and detected changes in interferon (IFN)-responsive and Sonic Hedgehog (SHH) target genes. IFN-γ treatment of PSC-WA promoted a WAT phenotype that was blocked by the JAK inhibitors, whereas treatment with the SHH inhibitor cyclopamine blocked the JAK inhibitors' effects. Although JAK inhibition can also alter immune response, these findings may inspire development of a modified JAK inhibitor that is effective on adipocytes for treatment of obesity and type II diabetes while sparing immune function.
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Miura, G. BATting the WAT. Nat Chem Biol 11, 97 (2015). https://doi.org/10.1038/nchembio.1744