Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production

Abstract

Summary 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.

Empowering thyroid hormone research in human subjects using OMICs technologies

“…β-oxidation and oxidative stress, the complement system and the coagulation cascade. Further, cysteine and its putative degradation intermediate 4-amino-2-hydroxybutyrate were among the strongest predictors providing a link to the very recent discovery of a direct TH effect on cystathionine generation (Hine et al 2017). The appearance of threonate replicates animal studies but has an uncertain biological meaning (Constantinou et al 2011, Montoya et al 2013.…”

Diallyl trisulfide, a H2S donor, inhibits cell growth of human papillary thyroid carcinoma KTC‐1 cells through a positive feedback loop between H2S and cystathionine‐gamma‐lyase

“…Intracellular H 2 S level was examined using P3 fluorescent probe, which was a kind gift from Subhankar Singha's laboratory (Hine et al, ). Briefly, when cells adhered to the surface of culture plate firmly, KTC‐1 cells were pretreated with 10 μM of P3 probe for 30 min followed by H 2 S donors treatment.…”

Regulators of the transsulfuration pathway

“…In the long‐lived Ames dwarf mice, which have reduced growth hormone (GH) and thyroid‐stimulating hormone signalling, as well as in mice lacking GH receptors, CSE and CBS levels are elevated and H 2 S production is increased. GH and TH negatively regulate hepatic H 2 S production through distinct mechanisms involving the hypothalamic–pituitary axis (Hine et al ., ).…”