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<p>Increased incidence of ovarian failure and subsequent infertility has been documented in reproductive pathological conditions affecting women, particularly polycystic ovarian syndrome (PCOS). Various interventions, including short chain fatty acids, have been documented as a novel therapy against PCOS phenotypes. However, the impact of butyrate, a histone deacetylase (HDAC) inhibitor on this heterogeneous complex disease, was unknown. The present study investigated the therapeutic potential of butyrate-driven HDAC2 inhibition on ovarian failure in a rat model of PCOS. Eight-week-old female Wistar rats were divided into four groups (<i>n</i> = 5). Letrozole (1&#xa0;mg/kg, <i>p.o.</i>) was given for 21&#xa0;days to induce PCOS rat model. Thereafter, the rats were treated with 200&#xa0;mg/kg (<i>p.o.</i>) of butyrate for 6&#xa0;weeks. Rats that received letrozole showed excess (<i>p</i> &lt; 0.05) body/ovarian weight, disrupted metabolic profile (insulin resistance), hyperleptinemia, and hypoadiponectinemia, as well as increased plasma/ovarian triglyceride, lipid peroxidation, inflammatory response (NF-kB/TNF-α), and apoptotic marker (Caspase-6). These rats also revealed a significant decrease (<i>p</i> &lt; 0.05) in ovarian tissue defense mechanism (NrF2 and HIF-α) with significant increase (<i>p</i> &lt; 0.05) in plasma testosterone and anti-Mullerian hormone and decreased (<i>p</i> &lt; 0.05) levels of 17-β estradiol and sex-hormone binding globulin with multiple ovarian cysts. These systemic/ovarian changes were associated with altered mitofusin-2 (Mfn2) and HDAC2 levels. Nonetheless, treatment with butyrate, HDACi reversed these changes. The present data suggest that inhibition of HDAC2 by butyrate alleviates ovarian failure in experimental PCOS rats with evidence of normal follicles and metabolic and endocrine profile, and this beneficial effect was accomplished by improving Mfn2 level.</p>

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Butyrate ameliorates ovarian failure in experimental PCOS rat model by suppression of HDAC2

  • 期刊论文

  • 发表日期：

    2025年1月25日

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  • Kehinde S. Olaniyi,
  • Christopher O. Akintayo,
  • Tola E. Oladimeji,
  • Stephanie E. Areloegbe,
  • Olabimpe C. Badejogbin,
  • Al-Amin M. Bashir,
  • Shalom U. Agan,
  • Adedamola A. Fafure,
  • Adeshina O. Adekeye,
  • Mary B. Ajadi,
  • Olutunmise V. Owolabi,
  • Isaac O. Ajadi

摘要

Increased incidence of ovarian failure and subsequent infertility has been documented in reproductive pathological conditions affecting women, particularly polycystic ovarian syndrome (PCOS). Various interventions, including short chain fatty acids, have been documented as a novel therapy against PCOS phenotypes. However, the impact of butyrate, a histone deacetylase (HDAC) inhibitor on this heterogeneous complex disease, was unknown. The present study investigated the therapeutic potential of butyrate-driven HDAC2 inhibition on ovarian failure in a rat model of PCOS. Eight-week-old female Wistar rats were divided into four groups (n = 5). Letrozole (1 mg/kg, p.o.) was given for 21 days to induce PCOS rat model. Thereafter, the rats were treated with 200 mg/kg (p.o.) of butyrate for 6 weeks. Rats that received letrozole showed excess (p < 0.05) body/ovarian weight, disrupted metabolic profile (insulin resistance), hyperleptinemia, and hypoadiponectinemia, as well as increased plasma/ovarian triglyceride, lipid peroxidation, inflammatory response (NF-kB/TNF-α), and apoptotic marker (Caspase-6). These rats also revealed a significant decrease (p < 0.05) in ovarian tissue defense mechanism (NrF2 and HIF-α) with significant increase (p < 0.05) in plasma testosterone and anti-Mullerian hormone and decreased (p < 0.05) levels of 17-β estradiol and sex-hormone binding globulin with multiple ovarian cysts. These systemic/ovarian changes were associated with altered mitofusin-2 (Mfn2) and HDAC2 levels. Nonetheless, treatment with butyrate, HDACi reversed these changes. The present data suggest that inhibition of HDAC2 by butyrate alleviates ovarian failure in experimental PCOS rats with evidence of normal follicles and metabolic and endocrine profile, and this beneficial effect was accomplished by improving Mfn2 level.