The relevance of hydrogen sulfide (h2s) in obesity and adipose tissue physiology
- Autores: Ferran Comas Vila
- Directores de la Tesis: José María Moreno Navarrete (dir. tes.)
- Lectura: En la Universitat de Girona ( España ) en 2021
- Idioma: español
- Tribunal Calificador de la Tesis: Marta Giralt i Oms (presid.), Marc Yeste Oliveras (secret.), Jordi Frigola Mas (voc.)
- Programa de doctorado: Programa de Doctorado en Biología Molecular, Biomedicina y Salud por la Universidad de Girona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Hydrogen sulfide (H2S), regarded as the third gasotransmitter, plays diverse physiological and pathological roles in the body along with another two gasotransmitters, including nitric oxide (NO) and carbon monoxide (CO). Endogenous H2S metabolisms (production and catabolism) take part in both normal physiology and in some human disorders. Manipulation of H2S levels by inhibiting H2S synthesis or administration of H2S-releasing molecules revealed beneficial as well as harmful effects of H2S. However, the impact of H2S in the pathophysiology of obesity and its importance in the physiology of human adipose tissue has been scarcely investigated. Here we aimed to investigate circulating H2S according to obesity, and the impact of H2S on adipocyte and adipose tissue physiology.
Circulating serum sulfide concentrations were increased in subjects with morbid obesity in proportion to fat mass and inversely associated with circulating markers of heme degradation. In addition, serum sulfide concentration decreased in morbidly obese subjects with impaired compared to those with normal fasting glucose. Longitudinally, weight gain resulted in increased serum sulfide concentration, whereas weight loss had opposite effects. These data suggested the possible role of hydrogen sulfide in the physiology of human adipose tissue. To investigate the impact of H2S on adipocyte physiology, experiments in mouse 3T3-L1 cell line, immortalized human adipose-derived mesenchymal stem cells (ASC52telo) and human preadipocytes were performed. In 3T3-L1 mouse cell line, GYY4137 slow-releasing H2S improved adipocyte differentiation in inflammatory conditions, and H2S proadipogenic effect depended on dose, donor and exposure time. In immortalized human adipose-derived mesenchymal stem cells (ASC52telo) permanent knockdown of cystathionine-β-Synthase (CBS), an important H2Ssynthesising gene in these cells, promoted a cellular senescence phenotype, characterized by increased cellular inflammation and oxidative stress, reduced cellular rejuvenation-related gene expression markers and especially increased adipogenic potential, which resulted in a nonphysiological enhanced adipocyte differentiation with excessive lipid storage. Of note, in human preadipocytes, adipocytes and adipose tissue, the relevance of H2S biosynthesis in adipogenesis was confirmed, and a new mechanism of its action through the identification of persulfidated proteins involved in adipogenesis was suggested. To sum up, H2S-synthesizing enzymes were recognized as important actors in the human adipose tissue physiology and systemic insulin sensitivity possibly, avoiding cellular senescence and inflammation, and in consequence preserving adipose tissue adipogenesis.
Altogether, this doctorate thesis provides sound and novel proofs addressing the role of H2S in the pathophysiology of obesity and its importance in the physiology of human adipose tissue, including the discovery of increased circulating serum sulfide concentrations in subjects with morbid obesity in proportion to fat mass, and unravels the importance of H2S-synthesizing enzymes and H2S as a previously unrecognized targets in the modulation of human adipocyte physiology.
