Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production

Publication date: 6 June 2017
Source:Cell Metabolism, Volume 25, Issue 6
Author(s): Christopher Hine, Hyo-Jeong Kim, Yan Zhu, Eylul Harputlugil, Alban Longchamp, Marina Souza Matos, Preeti Ramadoss, Kevin Bauerle, Lear Brace, John M. Asara, C. Keith Ozaki, Sheue-yann Cheng, Subhankar Singha, Kyo Han Ahn, Alec Kimmelman, Ffolliott M. Fisher, Pavlos Pissios, Dominic J. Withers, Colin Selman, Rui Wang, Kelvin Yen, Valter D. Longo, Pinchas Cohen, Andrzej Bartke, John J. Kopchick, Richard Miller, Anthony N. Hollenberg, James R. Mitchell
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.

Graphical abstract

Teaser

Reduced thyroid hormone (TH) and growth hormone (GH) activity are hallmarks of genetic models of longevity in mice. Here, Hine et al. find that TH and GH negatively regulate hepatic production of the longevity-associated gas hydrogen sulfide, which feeds back to negatively regulate circulating TH and IGF-1 levels.


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