Neural adaption in midbrain GABAergic cells contributes to high-fat-diet induced obesity
Overeating disorders significantly contribute to worldwide incidences of obesity. Available treatments are limited. Here, we discovered that long-term chemogenetic activation of ventrolateral periaqueductal gray (vlPAG) GABAergic cells rescue obesity of high-fat diet induced obesity (DIO) mice. This was associated with the recovery of enhanced mIPSCs, decreased food intake, increased energy expenditure, and inguinal white adipose tissue (iWAT) browning. In vivo calcium imaging confirmed vlPAG GABAergic suppression for DIO mice, with corresponding reduction in intrinsic excitability. Single-nucleus RNA sequencing identified transcriptional expression changes in GABAergic cell subtypes in DIO mice, highlighting Cacna2d1 as of potential importance. Overexpressing Cacna2d1 in vlPAG GABAergic cells of DIO mice rescued enhanced mIPSCs and calcium response, reversed obesity, and therefore presented here as a potential target for obesity treatment. Overall design: To explore changes in the gene expression profile of vlPAG GABAergic cells in DIO mice, we collected the vlPAG from mice fed with either 7 weeks of HFD or normal chow and performed single cell nucleus sequencingSingle-nuclei suspensions were loaded to 10X Chromium to capture 8000 single cells using a 10X Genomics Chromium Single-Cell 3' kit (V3) according to the manufacturer's instructions.