Cystathionine γ‐lyase deficiency aggravates obesity‐related insulin resistance via FoxO1‐dependent hepatic gluconeogenesis

Abstract

Hepatic gluconeogenesis makes a significant contribution to the pathogenesis of obesity and its related insulin resistance. Cystathionine γ‐lyase (CSE; also cystathionase), a principal hydrogen sulfide (H2S)‐synthesizing enzyme in the liver, is involved in glucose and lipid metabolism disorders. However, the roles and precise mechanisms of CSE/H2S in obesity and its related insulin resistance remain obscure. Here we show that CSE knockout exacerbated high‐fat diet—induced mouse obesity as well as its related insulin resistance. Further study elucidated that the inhibition of insulin and AMPK signaling pathways by CSE deficiency resulted in nuclear accumulation of Forkhead box protein O1 and subsequently promoted hepatic gluconeogenesis. These phenomena can be reversed by NaHS supplementation. However, in wild‐type mice, NaHS treatment ameliorates high fat diet—induced obesity and metabolism disorders, indicating that maintaining an appropriate level of H2S is critical for its mutual change of positive and negative effects of obesity‐associated insulin resistance. Our study reveals a double‐edged sword effect and a novel mechanism for CSE/H2S in obesity associated with insulin resistance and provides evidence for CSE/H2S as a promising therapeutic potential target for obesity‐related insulin resistance.—Guo, W., Li, D., You, Y., Li, W., Hu, B., Zhang, S., Miao, L., Xian, M., Zhu, Y., Shen, X. Cystathionine γ‐lyase deficiency aggravates obesity‐related insulin resistance via FoxO1‐dependent hepatic gluconeogenesis. FASEB J. 33, 4212–4224 (2019). http://www.fasebj.org

Hydrogen sulfide regulates insulin secretion and insulin resistance in diabetes mellitus, a new promising target for diabetes mellitus treatment? A review

“…Guo et al indicated that CSE knockout promoted HFD-induced mouse obesity and insulin resistance and increased hepatic gluconeogenesis. A low dose of NaHS treatment (25 μmol/kg/d, intraperitoneally for 12 weeks) improved HFD-induced obesity and insulin resistance but a high dose of NaHS treatment (50 μmol/kg/d, intraperitoneally for 12 weeks) promoted HFD–induced obesity and insulin resistance [35] . Treatment with H 2 S gas buffer, or the H 2 S donor GYY4137 improved insulin resistance in HFD-induced obese mice [43] .…”

“… Action Cells/Model H 2 S gas/donor application (concentration) Effects Refs. Glucose uptake In vitro study HepG2 cells/primary mouse hepatocytes NaHS (10, 30 and 100 μM)/– Inhibited [32] Glycogen storage In vitro study HepG2 cells NaHS (10, 30 and 100 μM) Inhibited [32] In vivo study Liver from mice under nonfastingor 6-h fasting condition – Inhibited [32] Gluconeogenesis In vitro study HepG2 cells/primary mouse hepatocytes NaHS (10, 30 and100 μM)/– Promoted [32] Primary mouse hepatocytes NaHS (30 μM) Promoted [33] HepG2 cells/primary mouse hepatocytes NaHS (50 μM)/– Promoted [34] HepG2 cells/primary mouse hepatocytes NaHS (100 μM)/– Inhibited [35] In vivo study Pyruvate tolerance test on overnight-fasted mice NaHS (39 and 63 μM/kg) Promoted [33] Pyruvate tolerance test on high fat diet-fed mice NaHS (50 μM/kg/day) Inhibited [35] Mitochondrial function Biogenesis Primary moue hepatocytes NaHS (30 μM) Promoted [38] Bioenergetics HepG2 cells NaHS (0.01 and 0.1 μM) Promoted …”

“…In contrast, another view is that H 2 S inhibits hepatic gluconeogenesis. Guo et al [35] reported that CSE deficiency promoted hepatic gluconeogenesis. Knockdown of CSE in HepG2 cells increased glucose production under insulin stimulation, while NaHS (100 μM) attenuated CSE knockdown-induced glucose production.…”

Pharmacological modulation of the hydrogen sulfide (H2S) system by dietaryH2S‐donors: A novel promising strategy in the prevention and treatment of type 2 diabetes mellitus

“…In contrast, other data report that H 2 S suppresses hepatic gluconeogenesis, thus supporting its potential usefulness in the pharmacotherapy of T2DM. In particular, Guo and colleagues (Guo et al, 2019) showed that global CSE deficiency aggravates obesity‐induced insulin resistance by promoting hepatic gluconeogenesis in mice, probably by inhibition of the AMPK signaling pathway and increase in nuclear accumulation of forkhead boxprotein O1 (FoxO1). Accordingly, daily treatment with NaHS for 12 weeks (25 μmol/kg/day, i.p) reversed these effects, partially restoring physiological H 2 S concentrations in the liver.…”

“…This finding further supports the hormetic theory of H 2 S, which states that low levels of H 2 S are beneficial while high levels may be detrimental for health (Hua, Zhou, & Gong, 2013). Furthermore, silencing of CSE in hepatic cells (HepG2) significantly reduced the inhibitory effect promoted by insulin on gluconeogenesis, while NaHS (100 μM) fully restored the control of insulin on hepatic glucose production in these cells (Guo et al, 2019). Noteworthy, decreased CSE activity has been also recorded both in livers of diabetic rats and peripheral blood mononuclear cells of diabetic patients (Manna et al, 2014).…”