Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production

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

doi:10.1016/j.cmet.2017.05.003

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.

Authors

Christopher Hine¹, Hyo-Jeong Kim², Yan Zhu², Eylul Harputlugil¹, Alban Longchamp³, Marina Souza Matos², Preeti Ramadoss², Kevin Bauerle², Lear Brace¹, John M Asara⁴, C Keith Ozaki⁵, Sheue-Yann Cheng⁶, Subhankar Singha⁷, Kyo Han Ahn⁷, Alec Kimmelman⁸, Ffolliott M Fisher², Pavlos Pissios², Dominic J Withers⁹, Colin Selman¹⁰, Rui Wang¹¹, Kelvin Yen¹², Valter D Longo¹², Pinchas Cohen¹², Andrzej Bartke¹³, John J Kopchick¹⁴, Richard Miller¹⁵, Anthony N Hollenberg¹⁶, James R Mitchell¹⁷

Affiliations

¹ Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
² Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
³ Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Surgery, Heart and Vascular Center Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁵ Department of Surgery, Heart and Vascular Center Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁶ Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁷ Department of Chemistry, Center for Electro-Photo Behaviors in Advanced Molecular Systems, POSTECH, 77 Cheongam-Ro, Nam-Gu, Pohang 790-784, Republic of Korea.
⁸ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁹ Medical Research Council Clinical Science Centre, Imperial College, London W12 0NN, UK.
¹⁰ Glasgow Ageing Research Network, Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
¹¹ Department of Biology, Lakehead University, Thunder Bay, ON P7B 5E1, Canada.
¹² Department of Biological Sciences, Longevity Institute, School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
¹³ Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62794, USA.
¹⁴ Edison Biotechnology Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA.
¹⁵ Department of Pathology & Geriatrics Center, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁶ Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: thollenb@bidmc.harvard.edu.
¹⁷ Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: jmitchel@hsph.harvard.edu.

Abstract

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

Substances

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

Abstract

MeSH terms

Substances

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