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Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production.

Christopher Hine1, Hyo-Jeong Kim2, Yan Zhu2

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Cell Metabolism
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Summary

Hydrogen sulfide (H2S) production increases with reduced growth hormone (GH) and thyroid hormone (TH) signaling, linking H2S to longevity and metabolic health. This molecule is essential for regulating key hormones associated with a longer lifespan.

Keywords:
FGF21IGF-1IRS-1autophagycystathionine γ-lyasegrowth hormonehydrogen sulfidehypopituitary dwarfismlongevitythyroid hormone

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Area of Science:

  • Endocrinology
  • Metabolism
  • Aging Research

Background:

  • Decreased growth hormone (GH) and thyroid hormone (TH) signaling are linked to longevity and improved metabolic health.
  • Dietary restriction (DR) also confers similar benefits, with increased hydrogen sulfide (H2S) playing a key role.
  • Understanding the interplay between GH, TH, H2S, and DR is crucial for longevity research.

Purpose of the Study:

  • To investigate the role of hepatic hydrogen sulfide (H2S) production in long-lived mouse models with altered GH and TH signaling.
  • To elucidate the mechanisms by which GH and TH regulate H2S production.
  • To determine the function of H2S in mediating the effects of reduced GH/TH signaling on longevity-associated hormones.

Main Methods:

  • Measured hepatic H2S production in long-lived mouse strains with reduced GH and/or TH action.
  • Utilized in vitro cell-autonomous assays upon serum withdrawal to assess H2S regulation.
  • Investigated the transcriptional and substrate-level control mechanisms of H2S production by GH and TH, focusing on cystathionine γ-lyase (CGL).
  • Analyzed systemic T4 metabolism and circulating IGF-1 levels in CGL-deficient mice.

Main Results:

  • Increased hepatic H2S production was observed in long-lived mouse strains with reduced GH and/or TH signaling.
  • TH directly represses CGL transcription, while GH exerts substrate-level control over H2S production; these effects are additive.
  • Mice lacking CGL were unable to downregulate systemic T4 metabolism and circulating IGF-1.

Conclusions:

  • Reduced GH and TH signaling enhances hepatic H2S production through distinct, additive mechanisms.
  • Hydrogen sulfide (H2S) is essential for mediating the downregulation of T4 metabolism and IGF-1, key hormones linked to longevity.
  • This study reveals a novel role for H2S in the endocrine regulation of aging and metabolic fitness.