Liver-expressed antimicrobial peptide 2 (LEAP2) is a newly discovered antagonist of the growth hormone secretagogue receptor (GHSR) and is considered the first endogenous peptide that can antagonize the metabolic actions of ghrelin. The effects of ghrelin administration on feeding behavior, body weight, and energy metabolism involve the activation of orexigenic neurons in the arcuate nucleus (ARC) of the hypothalamus. It is unclear, however, if LEAP2 applied directly to the ARC of the hypothalamus affects these metabolic processes. Here, we show that overexpression of LEAP2 in the ARC through adeno-associated virus (AAV) reduced food intake and body weight in wild-type (WT) mice fed chow and a high-fat diet (HFD) and improved metabolic disorders. LEAP2 overexpression in the ARC overrides both central and peripheral ghrelin action on a chow diet. Interestingly, this AAV-LEAP2 treatment increased proopiomelanocortin (POMC) expression while agouti-related peptide (AGRP)/neuropeptide Y (NPY) and GHSR levels remained unchanged in the hypothalamus. Additionally, intracerebroventricular (i.c.v.) administration of LEAP2 decreased food intake, increased POMC neuronal activity, and repeated LEAP2 administration to mice induced body weight loss. Using chemogenetic manipulations, we found that inhibition of POMC neurons abolished the anorexigenic effect of LEAP2. These results demonstrate that central delivery of LEAP2 leads to appetite-suppressing and body weight reduction, which might require activation of POMC neurons in the ARC.
The therapeutic effects of volatile anesthetics on mental diseases, particularly schizophrenia, have gained considerable interest. Although isoflurane is a commonly used volatile anesthetic, there’s no more evidence that it could work on treating schizophrenia. Here, we discovered that inhaling isoflurane at low concentrations might reverse the behavioral phenotypes of schizophrenia caused by MK801, such as hyperlocomotion, pre-pulse inhibition impairment, and working memory loss. Isoflurane also helped recovering adult neurogenesis and synaptic plasticity impairments in the dentate gyrus (DG) induced by MK801. To better understand the mechanism, we discovered that isoflurane could reverse the reduction of parvalbumin (PV)-positive GABAergic interneuron (PVI) number and the aberration of NRG1-ErbB4 signaling in the DG; however, isoflurane could not reverse the schizophrenia-related phenotypes caused by PVI ablation, indicating that PVI are necessary for the therapeutic effect of isoflurane. Interestingly, isoflurane could reverse phenotypes caused by blocking PVIs GABA release in the DG, indicating the therapeutic impact is independent of PVI GABA release. Our research revealed that isoflurane might be used to treat schizophrenia, possibly through PVI in the DG.
AimsDopamine D1 receptor (D1R) hypofunction is associated with negative and cognitive symptoms in schizophrenia; therefore, the mechanism of D1R function modulation needs further investigation. Gm527 is the rodent homologous of the schizophrenia‐related gene C14orf28, encoding a predicated D1R‐interacting protein. However, the role of Gm527‐D1R interaction in schizophrenia needs to be clarified.MethodsGm527‐floxed mice were generated and crossed with D1‐Cre mice (D1:Gm527−/−) to knockout Gm527 in D1R‐positive neurons. Then behavioral tests were performed to explore the schizophrenia‐related phenotypes. Immunofluorescence, fluorescence in situ hybridization, electrophysiological recording, quantitative real‐time PCR, and western blotting were conducted to investigate the mechanisms.ResultsWorking memory, long‐term memories, and adult neurogenesis in the DG were enhanced in D1:Gm527−/− mice. LTP was also increased in the DG in D1:Gm527−/− mice, resulting from the Gm527 knockout‐induced D1R expression enhancement on the plasma membrane and subsequently cAMP signaling and NMDA receptor pathways activation. The requirement of Gm527 knockout in the DG was confirmed by reversing Gm527 expression or knockdown Gm527 in the DG D1R‐positive neurons through AAV‐CAG‐FLEX‐Gm527‐GFP or AAV‐CMV‐FLEX‐EGFP‐Gm527‐RNAi injection.ConclusionsThe DG Gm527 knockout induces D1R hyperfunction in improving schizophrenia cognitive symptoms.
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