Activation of Endogenous H₂S Biosynthesis or Supplementation with Exogenous H₂S Enhances Adipose Tissue Adipogenesis and Preserves Adipocyte Physiology in Humans

Abstract

Aims: To investigate the impact of exogenous hydrogen sulfide (H 2 S) and its endogenous biosynthesis on human adipocytes and adipose tissue in the context of obesity and insulin resistance. Results: Experiments in human adipose tissue explants and in isolated preadipocytes demonstrated that exogenous H 2 S or the activation of endogenous H 2 S biosynthesis resulted in increased adipogenesis, insulin action, sirtuin deacetylase, and PPARc transcriptional activity, whereas chemical inhibition and gene knockdown of each enzyme generating H 2 S (CTH, CBS, MPST) led to altered adipocyte differentiation, cellular senescence, and increased inflammation. In agreement with these experimental data, visceral and subcutaneous adipose tissue expression of H 2 S-synthesising enzymes was significantly reduced in morbidly obese subjects in association with attenuated adipogenesis and increased markers of adipose tissue inflammation and senescence. Interestingly, weight-loss interventions (including bariatric surgery or diet/exercise) improved the expression of H 2 S biosynthesis-related genes. In human preadipocytes, the expression of CTH, CBS, and MPST genes and H 2 S production were dramatically increased during adipocyte differentiation. More importantly, the adipocyte proteome exhibiting persulfidation was characterized, disclosing that different proteins involved in fatty acid and lipid metabolism, the citrate cycle, insulin signaling, several adipokines, and PPAR, experienced the most dramatic persulfidation (85-98%). Innovation: No previous studies investigated the impact of H 2 S on human adipose tissue. This study suggests that the potentiation of adipose tissue H 2 S biosynthesis is a possible therapeutic approach to improve adipose tissue dysfunction in patients with obesity and insulin resistance. Conclusion: Altogether, these data supported the relevance of H 2 S biosynthesis in the modulation of human adipocyte physiology. Antioxid. Redox Signal. 00, 000-000.

The Impact of H2S on Obesity-Associated Metabolic Disturbances

“…Supporting the importance of H 2 S and persulfidation in the physiology of adipose tissue (Figure 2), Comas et al recently demonstrated that proteins required for an appro-priate adipogenesis and adipose tissue functionality present higher persulfidation levels in adipocytes in comparison to preadipocytes, sustaining the idea that persulfidation preserves the function of adipogenesis-related proteins [70].…”

“…Recently Comas et al, showed that in ex vivo adipose tissue explants the stimulation of H 2 S synthesis via L-cysteine and pyridoxal 5 -phosphate (PLP) enhanced the expression of adipogenic genes in association with the insulin sensitivity, indicating a beneficial role of adipose tissue H 2 S in insulin pathway. In different human cohorts, insulin sensitivity was positively associated mainly with subcutaneous CTH and CBS, and weight loss resulted in increased CTH, CBS, and MPST mRNA, in parallel with improved insulin sensitivity [70]. In line with this, it is known that subcutaneous adipose tissue, VAT, is associated with insulin resistance, whereas SAT is associated with a decreased risk of insulin resistance [123].…”

“…On the other hand, adipose tissue acts as an endocrine organ and produces numerous bioactive factors such as adipokines that communicate with other organs and modulate a range of metabolic pathways [116]. As explained, previous studies indicate that H 2 S plays an important role in adipose tissue, and all three enzymes are expressed in human adipose tissue [70].…”

“…The overexpression of the H 2 S generation enzyme CTH and the administration of the H 2 S donor sodium hydrosulfide (NaHS) to 3T3-L1 cells in an environment of high glucose restored adiponectin secretion and decreased the secretion of proinflammatory cytokines [79]. Recently, Comas et al first reported the relevance of H 2 S and human adipose tissue physiology in the context of obesity [70]. Experiments in human adipose tissue explants and in isolated preadipocytes demonstrated that exogenous H 2 S or the activation of endogenous H 2 S biosynthesis resulted in increased adipogenesis, insulin action, sirtuin deacetylase, and PPARγ transcriptional activity, whereas inhibition through chemical compound or gene knockdown of one of the H 2 S-generating enzymes (CTH, CBS, MPST) led to altered adipocyte differentiation, cellular senescence, and increased inflammation.…”

“…In morbidly obese subjects, reduced gene expression of H 2 S-synthesising enzymes in visceral and subcutaneous adipose tissue depots was reported, whereas weight loss interventions improved the expression of these enzymes. In human preadipocytes, the expression of CTH, CBS, and MPST genes and hydrogen sulfide production were dramatically increased during adipocyte differentiation [70]. In addition, a recent study demonstrated the relevance of selenium-binding-protein 1 (SELENBP1) in 3T3-L1 adipocyte differentiation through the modulation of cellular H 2 S levels and the expression of H 2 S-producing enzymes [80].…”