2. Academic Validation
  3. Butyrate Prevents Obesity Accompanied by HDAC9-Mediated Browning of White Adipose Tissue

Butyrate Prevents Obesity Accompanied by HDAC9-Mediated Browning of White Adipose Tissue

  • Biomedicines. 2025 Jan 21;13(2):260. doi: 10.3390/biomedicines13020260.
Jing Yang 1 2,  Guoli Li 2,  Shan Wang 2,  Mingqian He 1 2,  Sijing Dong 2,  Ting Wang 3,  Binyin Shi 1 2,  Patrick C N Rensen 1 4,  Yanan Wang 1 2 4
Affiliations

Affiliations

  • 1 Department of Endocrinology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
  • 2 Med-X Institute, Center for Immunological and Metabolic Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
  • 3 Department of Cardiovascular Medicine, Shaanxi Provincial People's Hospital, Xi'an 710061, China.
  • 4 Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, P.O. Box 9600, 2300 Leiden, The Netherlands.
PMID: 40002674 DOI: 10.3390/biomedicines13020260
Abstract

Background/objectives: Mounting evidence indicates that the short-chain fatty acid butyrate protects against obesity and associated comorbidities, partially through the induction of adipose tissue thermogenesis. However, the effects of butyrate on white adipose tissue (WAT) browning and its molecular mechanism are still elusive. The objective of this study was to investigate butyrate-induced thermogenesis in white adipose tissue and its underlying mechanism.

Methods: We studied the effects of butyrate on diet-induced obesity in the humanized APOE*3-Leiden.CETP transgenic mouse model and explored factors related to white adipose browning. Specifically, mice were challenged with a high-fat diet supplemented with butyrate. Adiposity was measured to assess obesity development. Energy metabolism was detected using an indirect calorimetry system. RNA-seq analysis was conducted to analyze the transcription landscape of WAT and responsible targets. Furthermore, the revealed molecular mechanism was verified in vitro.

Results: Butyrate alleviated high-fat diet-induced obesity and promoted energy expenditure accompanied by brown adipose tissue activation and WAT browning. Mechanistically, RNA-seq analysis revealed that butyrate downregulated HDAC9 in WAT. Additionally, butyrate decreased HDAC9 while increasing thermogenesis in vitro. Inhibition of HDAC9 with TMP269 promoted thermogenic gene expression, mimicking the effects of butyrate.

Conclusions: Butyrate protects against diet-induced obesity accompanied by decreasing the expression of HDAC9 in white adipose tissue and inducing browning. This study reveals a new mechanism whereby butyrate activates adaptive thermogenesis and provides new insights for the development of weight-loss drugs targeting adipose HDAC9.

Keywords

HDAC9; butyrate; obesity; thermogenesis.

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    98.16%, HDACIIa Inhibitor