title: Neuropeptide exocytosis involving synaptotagmin-4 and oxytocin in hypothalamic programming of body weight and energy balance.
abstract: Hypothalamic neuropeptides play essential roles in regulating energy and body weight balance. Energy imbalance and obesity have been linked to hypothalamic signaling defects in regulating neuropeptide genes; however, it is unknown whether dysregulation of neuropeptide exocytosis could be critically involved. This study discovered that synaptotagmin-4, an atypical modulator of synaptic exocytosis, is expressed most abundantly in oxytocin neurons of the hypothalamus. Synaptotagmin-4 negatively regulates oxytocin exocytosis, and dietary obesity is associated with increased vesicle binding of synaptotagmin-4 and thus enhanced negative regulation of oxytocin release. Overexpressing synaptotagmin-4 in hypothalamic oxytocin neurons and centrally antagonizing oxytocin in mice are similarly obesogenic. Synaptotagmin-4 inhibition prevents against dietary obesity by normalizing oxytocin release and energy balance under chronic nutritional excess. In conclusion, the negative regulation of synaptotagmin-4 on oxytocin release represents a hypothalamic basis of neuropeptide exocytosis in controlling obesity and related diseases.
authors.affiliation: Department of Molecular Pharmacology and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Guo
authors.initials: G
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Bai
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.forename: Camin
authors.initials: C
authors.lastname: Dean
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wu
authors.forename: Juxue
authors.initials: J
authors.lastname: Li
authors.forename: Sara
authors.initials: S
authors.lastname: Guariglia
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Meng
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Cai
mesh_terms: D000818:Animals; D001835:Body Weight / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D005089:Exocytosis / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000096:biosynthesis; D009765:Obesity / Q000378:metabolism; D010121:Oxytocin / Q000096:biosynthesis*; D050857:Synaptotagmins / Q000096:biosynthesis*
chemical_list: D009479:Neuropeptides; C494293:Syt4 protein, mouse; D050857:Synaptotagmins; D010121:Oxytocin