The Ketone Body β-Hydroxybutyrate Alleviates Metabolic Syndrome Through Epigenetic Chromatin Remodeling

Introduction: Elevated blood pressure (BP), body weight, and blood glucose are features of metabolic syndrome (MetS). Regular exercise is one of the lifestyle modifications recommended to lower MetS. Exercise generates ketone bodies, but the mechanisms by which ketone bodies regulate MetS are unknown. We previously reported that ketone body β-hydroxybutyrate (βOHB) lowers BP. It has recently been found that βOHB remodels chromatin by histone β-hydroxybutyrylation (β-OHBylation). Using the assay for transposase-accessible chromatin with sequencing (ATAC-seq) and chromatin immunoprecipitation assays, we found that renal histone β-OHBylation enhances chromatin accessibility for transcription of fatty acid oxidation genes. We, therefore, hypothesized that supplementation of βOHB lowers MetS by remodeling the chromatin to upregulate fatty acid oxidation. Methods: The inbred low-capacity runner (LCR/Tol) rat was developed and used as a model for MetS. Five-month-old male and female LCR/Tol rats were divided into 2 groups (n=5/group/sex) and supplemented with or without 20% (v/v) 1,3-butanediol, a precursor to βOHB, in drinking water. BP was measured weekly by radiotelemetry for 10 weeks. Tissues and blood were collected for analyses following euthanasia. βOHB level was quantified by a colorimetric assay. Histone β-OHBylation was examined by western blotting. The liver function was examined by measuring serum levels of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase. Urinary total protein excretion level was measured for evaluating kidney function. Real-time PCR was performed for measuring the relative expression of fatty acid oxidation genes. Results: MetS was significantly attenuated in both female and male LCR/Tol rats supplemented with 1,3-butanediol compared to controls. Significant reductions were noted in body weight (females: 232g vs. 248g, p<0.05; males: 410g vs. 455g, p<0.05); blood glucose (females: 79.6mg/dl vs. 100.8mg/dl, p<0.05; males: 91.17mg/dl vs. 140.4 mg/dl, p<0.05), and BP (females: systolic BP 116mmHg vs. 120mmHg, p<0.05; males: systolic BP 128mmHg vs. 132mmHg, p<0.01; diastolic BP 92mmHg vs. 95mmHg, p<0.01; and mean arterial BP 108mmHg vs. 112mmHg, p<0.01.) Rats treated with 1,3-butanediol showed a >2-fold increase in serum βOHB (females: 1.9mM vs. 0.7mM, p<0.05; males: 3.3mM vs. 1.4mM, p<0.01) and higher renal histone β-OHBylation (both females and males: p<0.01) compared to their controls. Serum βOHB was positively correlated to renal β-OHBylation (r=0.86, p<0.01) in both females and males, implying that systemic βOHB was responsible for β-OHBylation. The relative expression of the transcriptional target gene 3-Hydroxy-3-Methylglutaryl-Coenzyme A Synthase 2 ( Hmgcs2 ) was upregulated in both sexes (p<0.01). In addition, two other target genes of chromatin remodeling by histone β-OHBylation, Cytochrome P450, family 2, subfamily d, polypeptide 4 ( Cyp2d4 ) and Acetyl-Coenzyme A acyltransferase 1B ( Acaa1b ) were expressed significantly higher in female and male rats compared to controls (p<0.01; p<0.05, respectively). There were no differences in liver injury markers and urinary protein excretion in either female or male rats, indicating no liver and kidney damage. Conclusions: This is the first study to demonstrate that enhanced systemic βOHB attenuates MetS by histone β-OHBylation-mediated chromatin remodeling to upregulate the transcription of Hmgcs2, Cyp2d4, and Acaa1b and promote oxidation of fatty acids. Our findings provide a strong foundation for exploring 1,3-butanediol as a potential epigenetic approach for individuals who are physically unable to achieve the MetS lowering benefits of exercise. Bina Joe gratefully acknowledges funding support from the National Institutes of Health (R01HL171401-01). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.