Effects of hydrogen sulfide on lipid metabolism in adipocytes and adipose tissues

Abstract

Hydrogen sulfide (H2S) is a gasotransmitter involved in various physiological processes. Studies indicate that H2S enhances adipogenesis and lipid accumulation in 3T3-L1 adipocytes, though the mechanism is unclear. Therapeutic applications with H2S are limited by the lack of targeted delivery routes and its rapid dispersal in vivo. While H2S shows lipogenic effects on adipocytes in vitro, its impact on adipose tissue in vivo is not well understood. This study is novel in two ways: first, we elucidate a cell signalling pathway in isolated mouse preadipocytes by which H2S increases adipogenesis, adipocyte hypertrophy, and adipocyte hyperplasia in vitro. Second, we utilize a novel H2S-slow-releasing hydrogel (SATO-IAVE2) to deliver H2S locally to subcutaneous adipose tissue, examining lipid accumulation in mice. In in vitro study, lowering endogenous H2S levels via cystathionine γ-lyase knockout (CSE KO) or a CSE inhibitor reduced lipid accumulation and adipogenesis in adipocytes. However, simultaneous treatment with exogenous H2S increased adipogenesis and lipid accumulation. Exogenous H2S enhanced lipid accumulation in primary mouse adipocytes, upregulating genes related to hyperplasia (C/EBPβ, Cdc25, Mcm3, Cdc45) and cyclin-dependent kinase 2, and activated the insulin receptor β, MAPK, and Akt pathways. Under nutrition overload conditions, H2S increased glucose consumption and exacerbated adipocyte hypertrophy. In in vivo study, we injected two doses of an H2S-releasing hydrogel SATO-IAVE2 (39 and 78 μmol/kg) and a control gel C-IAVE4, which releases oxygen instead of H2S, into the subcutaneous adipose tissue of both CSE-KO and wild-type (WT) mice. These injections were given every six days for a month. After 30 days, compared to the control, H2S- releasing hydrogel increased lipid accumulation and metabolism in both WT and CSE KO mice. In CSE KO mice, only higher dose of the H2S-releasing hydrogel increased lipid accumulation and lipid droplet size, associated with higher SREBP, PPARγ, adiponectin, and perilipin levels. In WT mice, both doses of SATO-IAVE2 increased lipid accumulation, but higher dose causing significant lipid buildup and adipocyte hypertrophy, with increased PPARγ, SREBP, and perilipin. Hormone sensitive lipase (HSL) phosphorylation increased while adiponectin expression decreased with higher dose of SATO-IAVE2 in WT mouse adipose tissue. Both in vitro and in vivo studies reach the same conclusion that H2S promotes lipid accumulation in mouse adipocytes. Lipolysis remained unaffected in vitro, while in vivo, higher H2S doses increased HSL phosphorylation in WT mice. The effect of H2S on lipolysis in vivo needs to be studied further. Our study confirms the feasibility of selectively delivering H2S via injectable SATO-IAVE2 and its effectiveness in regulating targeted tissue functions.