Cystathionine beta synthase-hydrogen sulfide system in paraventricular nucleus reduced high fatty diet induced obesity and insulin resistance by brain-adipose axis

Abstract

Hydrogen sulfide (H2S) is an essential neuromodulator, generates by cystathionine β synthase (CBS) or 3-mecaptopyruvate sulfurtransferase (3MST) in the brain. H2S can mediate paraventricular nucleus (PVN) neuron activity, and regulate neuroendocrine hormones secretion. On the other hand, CBS deficiency caused metabolic disorder and body weight reduction. However, whether CBS/H2S of PVN regulates neuroendocrine hormones to mediate energy metabolism is unknown. Here, we first identified the CBS co-localization with thyrotropin-releasing hormone (TRH) and corticotropin releasing hormone (CRH) positive neurons. In HFD induced obese rats, CBS protein of hypothalamus decreased. By contrast, overexpression CBS in PVN via lentivirus, lowered food uptake, body weight and fat mass, and reduced blood glucose, lipid disorders and insulin resistance. Intriguingly, CBS overexpression increased the pre-TRH expression, slightly elevated plasma thyroxine and thyrotropin level, but decreased the plasma ACTH and corticosterone level. Then, we found that mTOR activation contributed to pre-TRH up-regulation by CBS/H2S system. In db/db obese mice, hypothalamus CBS/H2S system also down-regulated association with reduction pre-TRH expression; in contrast, CBS overexpression in PVN slightly elevated plasma leptin. Next, leptin stimulated FOXO3a nuclear translocation, increased FOXO3a binding activity to two binding sites of CBS promoter, and then enhanced CBS protein expression. In conclusion, leptin activates neuron CBS-H2S system by FOXO3a, regulates neuroendocrine hormones to modulate the energy homeostasis, thus highlights a new brain-adipose feedback axis in energy metabolism.

Exogenous Hydrogen Sulfide Within the Nucleus Ambiguus Inhibits Gastrointestinal Motility in Rats

“…Hydrogen sulfide (H 2 S) is an essential neuromodulator in mammals (Zheng et al, 2018), which regulates numerous pathophysiological functions in the digestive, respiratory, circulatory and nervous systems (Kimura et al, 2012;Drapala et al, 2017;Yang et al, 2017;Yu et al, 2017;Zhou et al, 2018). Endogenous H 2 S levels have been detected in the brains of rats and humans (Wang, 2012;Yang and He, 2019).…”

Hydrogen Sulfide Ameliorates High Glucose-induced Inflammation Through SIRT1-mTOR/NF-κB Signaling Pathway in HT-22 cells

“…CBS is an important enzyme to catalyze H 2 S [13]. Next, we found that high glucose reduced CBS protein levels in HT-22 cells ( Figure 2B, P < 0.001).The CBS level was obviously elevated in HG + SAMe and HG + NaHS groups compared with the HG group ( Figure 2B, both P < 0.001).…”

“…While, supplementation of H 2 S donor sodium hydrosul de (NaHS) protected hyperglycemiainduced myocardial tissue damage in vivo and in vitro [12]. In the central nervous system, the production of endogenous H 2 S is mainly catalyzed by cystathionine-β-synthase (CBS) [13]. Exogenous H 2 S inhibited the expression of pro-in ammatory factors and decreased the generation of oxidative indicator reactive oxygen species in the mouse model of Alzheimer's disease [14,15].…”

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

“…The activation of mTORC1 signaling pathway is involved in the upregulation of CBS/H 2 S in pre-TRH level. Further results [74] indicated that leptin activated FOXO3a to increase CBS expression and H 2 S production in the hypothalamus, regulating neuroendocrine hormone (TRH and ACTH) to impact systemic glucose metabolism and energy homeostasis. However, the roles of H 2 S in regulating glucose metabolism control by the hypothalamus and its mechanism need to be further studied.…”

“…CBS and 3-MST are the major endogenous enzymes in the brain that produce H 2 S [69] , [70] , [71] , [72] , [73] . CBS/H 2 S pathway in the hypothalamic paraventricular nucleus (PVN) was found to improve obesity and insulin sensitivity via the brain-adipose interaction [74] . CBS was detected in thyrotropin-releasing hormone (TRH) and CRH producing neurons.…”