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.