Acid Sensing Ion Channel 2 (Asic2) localization in mouse hypothalamus and importance in metabolic homeostasis

A previous study from our laboratory showed mice lacking normal levels of the degenerin channels, Acid Sensing Ion Channel 2 (Asic2) and the beta subunit of the Epithelial Na+ Channel (βENaC), are protected from high fat diet induced metabolic syndrome. To determine localization of Asic2 and βENaC in the mouse hypothalamus, we analyzed a publicly available single cell transcriptome dataset, HypoMap (PMID: 36266547), using Seurat in R Studio. Our analysis shows Asic2 is the predominant degenerin subunit expressed in hypothalamic neurons in regions that regulate feeding-satiety-energy expenditure including the ventromedial, lateral, and arcuate (ARC). These same regions contain little neuronal βENaC. Further analysis of neuronal Asic2 within the ARC showed 30-67% co-expression with key regional markers including Pomc, Agrp, Npy, leptin receptor, and insulin receptor, suggesting Asic2 is expressed in specific ARC neuronal populations. Based on these findings, we tested the hypothesis that loss of Asic2 -/- would disrupt homeostasis of feeding-satiety-energy expenditure. Compared to controls, Asic2 -/- mice showed enhanced food consumption responses to single intraperitoneal injection of ghrelin (0.5 µg/g body mass) and reduced weight loss to leptin (2.0 µg/g) in 10–14-week-old mice. Next, we examined body composition, metabolic, and behavioral responses in 16-week-old male and female Asic2 +/+ and Asic2 -/- mice raised on a normal fat diet (14% kcal from fat), and again following a 5-week 60% kcal high fat diet. Compared to controls, Asic2 -/- mice had slightly lower body and lean body masses, but similar % fat and % lean masses on both diets. Despite the lower body mass, Asic2 -/- mice had greater food intake and total motor activity under normal and high fat diet on both diets. Asic2 -/- mice also had greater O 2 uptake, CO 2 output, and total energy expenditure compared to Asic2 +/+ mice on both diets. Asic2 deletion did not protect from high fat diet induced hepatic steatosis as measured by liver mass and fat composition, liver triglyceride content, and Oil Red O staining. We found no effect of genotype on steady state plasma glucose, leptin, ghrelin, or insulin. Our findings suggest that Asic2 plays an important role in metabolic homeostasis, possibly through regulation of central pathways involved in feeding-satiety-energy expenditure. R01DK137167, P30GM149404, P20GM104357, 5T32HL105324, and P20GM121334 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.