GYY4137 Promotes Mice Feeding Behavior via Arcuate Nucleus Sulfur-Sulfhydrylation and AMPK Activation.

Jun Zhou,Ao-Qi Song,Li-Yun Dang,Jun-Juan Fan,Bo Gao,Kun Dong,Xiao-Hui Lv,Wen-Ning Wu

doi:10.3389/fphar.2018.00966

Abstract

Hydrogen sulfide (H2S) is an endogenous gaseous molecule and plays important biological and neurochemical roles in many processes such as the neural activity and immunity. The arcuate nucleus (ARC) of hypothalamus is a control center for appetite and energy metabolism. AMPK is a gage kinase in the monitoring of energy status and regulation of energy metabolism, and it can be activated by H2S via CaMKKβ/AMPK pathway. But the role of H2S in ARC and appetite has not been reported. Here we studied the orexigenic effect of H2S and the mechanisms by means of GYY4137, a water soluble and slow-releasing donor of H2S, and protein sulfur-sulfhydrylation analysis. We demonstrated that GYY4137-derived H2S increased food intake of mice, augmented the production of neuropeptide Y (NPY), and elevated the protein sulfur-sulfhydrylation level and the activation of AMPK and CaMKKβ in ARC. Blocking sulfur-sulfhydrylation with DTT eliminated GYY4137-induced activation of AMPK and CaMKKβ. DTT and preventing AMPK activation in ARC with Compound C and Ara-A could both attenuate the orexigenic effect of GYY4137. These findings suggest that H2S enhances appetite through protein sulfur-sulfhydrylation and the activation of AMPK and NPY function in ARC.

Highlights

Hydrogen sulfide (H2S) is produced endogenously in mammals by metabolism of sulfurcontaining amino acids under the catalysis of special enzymes (Predmore et al, 2012; Sheibani et al, 2017) and has been regarded as the third bio-active gas or gaseous signaling molecule by accumulated evidence (Gadalla and Snyder, 2010; Predmore et al, 2012; Yu et al, 2017)
We found that this effect of H2S is mediated by the sulfur-sulfhydrylation of arcuate nucleus (ARC) proteins, including AMPK and CaMKKβ, which subsequently increases the activation of AMPK and neuropeptide Y (NPY) function in ARC and food intake of mice
Arcuate nucleus is the regulation center of appetite and food intake and our previous study found that the percentage of NPYpositive neurons was about 57 ± 6.4 % in ARC neurons (Wu et al, 2013), we wanted to know if ARC neurons and NPY function are activated in the orexigenic effect induced by GYY4137

Summary

Introduction

Hydrogen sulfide (H2S) is produced endogenously in mammals by metabolism of sulfurcontaining amino acids under the catalysis of special enzymes (Predmore et al, 2012; Sheibani et al, 2017) and has been regarded as the third bio-active gas or gaseous signaling molecule by accumulated evidence (Gadalla and Snyder, 2010; Predmore et al, 2012; Yu et al, 2017). The arcuate nucleus (ARC) of hypothalamus is an important control center for appetite and energy metabolism (Joly-Amado et al, 2014; Reis et al, 2015). Adenosine 5 -monophosphate (AMP)-activated protein kinase (AMPK) is an important modulator and gage molecule in energy metabolism and food intake (Oh et al, 2016; Dong et al, 2017). By sensing the available level of energetic substrates, AMPK determines the activation or suppression of orexigenic neurons such as neuropeptide Y (NPY) neurons and controls the production of NPY in ARC, the appetite regulation center in hypothalamus, and regulates feeding behavior (Blankenship et al, 2016; Carneiro et al, 2016). Ca2+/calmodulin-dependent protein kinase β (CaMKKβ) is a vital upstream activator of AMPK (Anderson et al, 2008), and it has been reported that AMPK-mediated feedback phosphorylation of CaMKKβ regulates the CaMKKβ/AMPK signaling cascade and may be physiologically important for intracellular maintenance of Ca2+-dependent AMPK activation by CaMKKβ (Nakanishi et al, 2017)

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