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

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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.