Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production

Cell Metab. 2017 Jun 6;25(6):1320-1333.e5. doi: 10.1016/j.cmet.2017.05.003.


Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H2S) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic H2S production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic H2S production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the H2S-producing enzyme cystathionine γ-lyase (CGL) by TH, and substrate-level control of H2S production by GH. Mice lacking CGL failed to downregulate systemic T4 metabolism and circulating IGF-1, revealing an essential role for H2S in the regulation of key longevity-associated hormones.

Keywords: FGF21; IGF-1; IRS-1; autophagy; cystathionine γ-lyase; growth hormone; hydrogen sulfide; hypopituitary dwarfism; longevity; thyroid hormone.

MeSH terms

  • Animals
  • Cystathionine gamma-Lyase / genetics
  • Cystathionine gamma-Lyase / metabolism
  • Dextrothyroxine / metabolism
  • Female
  • Growth Hormone / genetics
  • Growth Hormone / metabolism
  • Hydrogen Sulfide / metabolism*
  • Hypothalamo-Hypophyseal System / metabolism*
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism
  • Liver / metabolism*
  • Mice
  • Mice, Knockout


  • insulin-like growth factor-1, mouse
  • Dextrothyroxine
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • Cystathionine gamma-Lyase
  • Hydrogen Sulfide