{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE315nnn/GSE315247/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE315247"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Immune checkpoint ENPP1 dampens brown adipocyte derived extracellular cGAMP to protect against systemic metabolic dysfunction","description":"Chronic systemic inflammation has been long recognized as a mediator of metabolic disorders such as obesity and type 2 diabetes. The double stranded DNA (dsDNA)-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is one of the recently recognized immune pathways involved in metabolic diseases. However, the contributions of autocrine vs. paracrine cGAMP signaling in these disorders are unknown. Variants in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), the dominant extracellular hydrolase of cGAMP, have been linked to obesity and type 2 diabetes. However, ENPP1 has multiple biochemical functions, and therefore the contribution of cGAMP degradation by ENPP1 in these disorders are also unknown. Here, we utilized mice specifically lacking ENPP1’s cGAMP hydrolysis activity (Enpp1H362A) to delineate these questions. We showed that when fed a high-fat diet (HFD), Enpp1H362A mice had more severe weight gain, insulin resistance, and impaired glucose uptake in brown adipose tissue (BAT) compared to wildtype. In these mice, HFD increased cGAMP production and export, resulting in high overall cGAMP levels in BAT. cGAMP directly suppressed glucose uptake and altered transcriptional programs in brown adipocytes in a STING-dependent manner. Additionally, BAT from Enpp1H362A mice were more heavily infiltrated with macrophages. Macrophages from Enpp1H362A BAT showed increased interferon-stimulated gene activation and polarization from anti-inflammatory to proinflammatory. Our results highlight the importance of ENPP1 as an immunometabolic regulator of BAT function while providing potential therapeutic targets for metabolic disease.","dates":{"publication":"2026/08/17"},"accession":"GSE315247","cross_references":{"GSM":["GSM9423591","GSM9423592","GSM9423593","GSM9423585","GSM9423586","GSM9423587","GSM9423588","GSM9423589","GSM9423590"],"GPL":["28457"],"GSE":["315247"],"taxon":["Mus musculus"]}}