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

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

  • J Med Chem. 2022 Sep 22;65(18):12273-12291. doi: 10.1021/acs.jmedchem.2c00943.
Aditya Bhattacharya 1,  Sourav Chatterjee 1,  Utsa Bhaduri 2,  Akash Kumar Singh 1,  Madavan Vasudevan 3,  Koneni V Sashidhara 4,  Rajdeep Guha 5,  Aamir Nazir 6,  Srikanta Kumar Rath 6,  Nagashayana Natesh 7,  Tapas K Kundu 1 8
Affiliations

Affiliations

  • 1 Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India.
  • 2 Chromatin Biology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India.
  • 3 Theomics International Pvt Ltd, Bangalore 560038, India.
  • 4 Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
  • 5 Division of Laboratory Animal Facility, CSIR-Central Drug Research Institute, Lucknow 226031, India.
  • 6 Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226031, India.
  • 7 Central Government Health Scheme Wellness Centre Number 8, Domlur, Bangalore 560071, India.
  • 8 Division of Neuroscience and Aging Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
PMID: 36074919 DOI: 10.1021/acs.jmedchem.2c00943
Abstract

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.

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