Butyrylation Meets Adipogenesis-Probed by a p300-Catalyzed Acylation-Specific Small Molecule Inhibitor: Implication in Anti-obesity Therapy

The enzyme p300, besides having acetyltransferase activity,
can
also catalyze other acylation modifications, whose physiological implications
are still being investigated. Here, we report that the level of histone
butyrylation increases globally as well as locally in the promoters
of pro-adipogenic genes during adipogenesis. To delineate the role
of p300-catalyzed butyrylation from acetylation in adipogenesis, we
identified a semisynthetic derivative (LTK-14A) of garcinol, which
specifically inhibited histone butyrylation without affecting acetylation.
Treatment of 3T3L1 cells with LTK-14A abolished adipogenesis with
downregulation of pro-adipogenic genes along with inhibition of H4K5
butyrylation. Administering LTK-14A to high-fat diet-fed and genetically
obese db/db mice led to attenuation/decrease in their weight gain.
The reduced obesity could be partially attributed to the inhibition
of H4K5 butyrylation in adipocytes and liver. This report therefore
not only, for the first time, causally links histone butyrylation
with adipogenesis but also presents a probable candidate for anti-obesity
therapeutics.