Butyrylation Meets Adipogenesis-Probed by a p300-Catalyzed Acylation-Specific Small Molecule Inhibitor: Implication in Anti-obesity Therapy.
Aditya BhattacharyaSourav ChatterjeeUtsa BhaduriAkash Kumar SinghMadavan VasudevanKoneni V SashidharaRajdeep GuhaAamir NazirSrikanta Kumar RathNagashayana NateshTapas K KunduPublished in: Journal of medicinal chemistry (2022)
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.
Keyphrases
- high fat diet induced
- insulin resistance
- high fat diet
- weight gain
- adipose tissue
- small molecule
- metabolic syndrome
- dna methylation
- type diabetes
- skeletal muscle
- weight loss
- body mass index
- genome wide
- induced apoptosis
- birth weight
- room temperature
- cell proliferation
- signaling pathway
- anti inflammatory
- bone marrow
- oxidative stress
- stem cells
- single molecule
- cell therapy
- obese patients
- transcription factor
- combination therapy
- genome wide identification
- mass spectrometry