EP300 (p300) mediated histone butyrylation is critical for adipogenesis

The master epigenetic enzyme EP300 (p300) besides having lysine acetyltransferase activity can also catalyse other acylation modifications (propionylation, butyrylation, crotonylation etc.), the physiological implications of which are yet to be established. Here we report that lysine butyrylation concomittantly increases during adipogenesis, along with increased butyryl CoA levels due to upregulated fatty acid metabolic pathways. To delineate the role of p300 catalysed butyrylation in adipogenesis, we have identified a semi-synthetic derivative (LTK-14A) of garcinol which specifically inhibited histone butyrylation without affecting acetylation. Treatment of 3T3L1 cells with LTK-14A significantly abolished adipogenesis by downregulation of genes related to adipogenesis presumably through the inhibition of H4K5 butyrylation. Administering the specific inhibitor to high fat diet fed C57BL6/J mice as well as genetically obese db/db mice led to an attenuation/decrease in their weight gain respectively. The reduced obesity could be at least partially attributed to the targeted inhibition of H4K5 butyrylation, as observed by immunofluorescence staining of the inhibitor treated mice liver sections and immunoblotting with histones extracted from epididymal fat pads. This report therefore not only for the first time causally links histone butyrylation with adipogenesis but also presents a novel small molecule modulator that could be developed for anti-obesity therapeutics. Significance StatementIn the modern era, obesity has become a highly prevalent disorder, characterized by adipose tissue hypertrophy. Excessive caloric intake with minimal energy expenditure leads to accumulation of lipids in the adipose tissue. Like in many other processes, adipogenesis is epigenetically regulated. Besides acetyltransferase activity,the epigenetic enzyme p300 also possesses acyltransferase activity such as butyrylation.Our findings not only demonsrate the physiological role of p300 catalysed butyrylation in adipogenesis but also report a selective inhibitor of butyrylation which could have high therapeutic potential.