Inhibition of the 3-mercaptopyruvate sulfurtransferase-hydrogen sulfide system promotes cellular lipid accumulation

H₂S is generated in the adipose tissue by cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase (3-MST). H₂S plays multiple roles in the regulation of various metabolic processes, including insulin resistance. H₂S biosynthesis also occurs in adipocytes. Aging is known to be associated with a decline in H₂S. Therefore, the question arises whether endogenous H₂S deficiency may affect the process of adipocyte maturation and lipid accumulation. Among the three H₂S-generating enzymes, the role of 3-MST is the least understood in adipocytes. Here we tested the effect of the 3-MST inhibitor 2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one (HMPSNE) and the H₂S donor (GYY4137) on the differentiation and adipogenesis of the adipocyte-like cells 3T3-L1 in vitro. 3T3-L1 cells were differentiated into mature adipocytes in the presence of GYY4137 or HMPSNE. HMPSNE significantly enhanced lipid accumulation into the maturing adipocytes. On the other hand, suppressed lipid accumulation was observed in cells treated with the H₂S donor. 3-MST inhibition increased, while H₂S donation suppressed the expression of various H₂S-producing enzymes during adipocyte differentiation. 3-MST knockdown also facilitated adipocytic differentiation and lipid uptake. The underlying mechanisms may involve impairment of oxidative phosphorylation and fatty acid oxidation as well as the activation of various differentiation-associated transcription factors. Thus, the 3-MST/H₂S system plays a tonic role in suppressing lipid accumulation and limiting the differentiation of adipocytes. Stimulation of 3-MST activity or supplementation of H₂S-which has been recently linked to various experimental therapeutic approaches during aging-may be a potential experimental approach to counteract adipogenesis.