{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T15:29:37Z","timestamp":1789658977650,"version":"4.0.1"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Science and Technology - Science and Engineering Research Board","award":["[CRG\/2021\/004502]"],"award-info":[{"award-number":["[CRG\/2021\/004502]"]}],"id":[{"id":"https:\/\/ror.org\/03ffdsr55","id-type":"ROR","asserted-by":"crossref"}]},{"name":"DBT\/Wellcome Trust India Alliance","award":["IA\/I\/21\/1\/505613"],"award-info":[{"award-number":["IA\/I\/21\/1\/505613"]}],"id":[{"id":"https:\/\/ror.org\/04reqzt68","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NIDDK","award":["2UC4DK098085"],"award-info":[{"award-number":["2UC4DK098085"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    Obesity-associated inflammation impairs pancreatic \u03b2-cell function, yet the mechanisms by which immune cells acutely regulate insulin secretion remain poorly defined. Here, we identify myeloid Gq signaling as an immunometabolic node linking macrophage lipid sensing to impaired insulin secretion. Using chemogenetic DREADD-mediated activation of myeloid Gq, we show that acute macrophage Gq activation impairs glucose-stimulated insulin secretion (GSIS) in vivo, whereas myeloid G\u03b1q ablation enhances GSIS. Mechanistically, Gq activation rapidly induced AMPK phosphorylation and sphingolipid remodeling independently of canonical inflammatory cytokines. Macrophage-derived sphingolipids impaired \u03b2-cell insulin signaling and GSIS through CD36-PKC\u03b6, while inhibition of CD36, AMPK, or sphingolipid metabolism restored \u03b2-cell function. We further identified GPR18, a Gq-coupled endocannabinoid-responsive GPCR, as an upstream regulator. GPR18 activation with N-arachidonoyl glycine (NAGly) recapitulated this phenotype, whereas myeloid G\u03b1q deletion or\n                    <jats:italic>Gpr18\/AMPK<\/jats:italic>\n                    silencing abolished it. GPR18 signaling predominantly engaged Gq rather than Gi pathways. In human tissues,\n                    <jats:italic>GPR18<\/jats:italic>\n                    was enriched in islet macrophages, and NAGly suppressed GSIS in primary human islets. Thus, a conserved macrophage GPR18-G\u03b1q-AMPK-sphingolipid axis dynamically regulates \u03b2-cell function and represents a potential therapeutic target in obesity and type 2 diabetes.\n                  <\/jats:p>","DOI":"10.1172\/jci202344","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T16:01:29Z","timestamp":1789488089000},"source":"Crossref","is-referenced-by-count":0,"title":["Acute activation of Gq-signaling in pancreatic islet macrophages inhibits insulin secretion through AMPK-sphingolipid axis"],"prefix":"10.1172","author":[{"given":"Simran","family":"Singh","sequence":"first","affiliation":[{"name":"Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish","family":"Kumar","sequence":"additional","affiliation":[{"name":"Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudipta","family":"Paul","sequence":"additional","affiliation":[{"name":"Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mriganka","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santhosh","family":"Duraisamy","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganesh","family":"Timalsina","sequence":"additional","affiliation":[{"name":"Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raashidha","family":"Farhath","sequence":"additional","affiliation":[{"name":"Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harender","family":"Yadav","sequence":"additional","affiliation":[{"name":"Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema","family":"Kuldeep","sequence":"additional","affiliation":[{"name":"Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumita","family":"Bhaumik","sequence":"additional","affiliation":[{"name":"Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunj Kumar","family":"Prajapati","sequence":"additional","affiliation":[{"name":"Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saahiba","family":"Thaleshwari","sequence":"additional","affiliation":[{"name":"Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuj","family":"Gargya","sequence":"additional","affiliation":[{"name":"Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamojit","family":"Santra","sequence":"additional","affiliation":[{"name":"Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonal","family":"Amit","sequence":"additional","affiliation":[{"name":"Autonomous State Medical College, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashmi","family":"Parihar","sequence":"additional","affiliation":[{"name":"Central Experimental Animal Facility, Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santosh K.","family":"Misra","sequence":"additional","affiliation":[{"name":"Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamim","family":"Zafar","sequence":"additional","affiliation":[{"name":"Mehta Family Centre for Engineering in Medicine, Department of Biological S, Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz F.","family":"Barella","sequence":"additional","affiliation":[{"name":"Penguin Bio Corp., New York, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Kalwat","sequence":"additional","affiliation":[{"name":"Indiana Biosciences Research Institute, Indianapolis, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dharmaraja","family":"Allimuthu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai Prasad","family":"Pydi","sequence":"additional","affiliation":[{"name":"Molecular Metabolism & Cell Signaling Laboratory, Department of Biological , Indian Institute of Technology Kanpur, Kanpur, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,9,15]]},"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.jci.org\/articles\/view\/202344\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T16:01:30Z","timestamp":1789488090000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.jci.org\/articles\/view\/202344"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":0,"alternative-id":["10.1172\/JCI202344"],"URL":"https:\/\/doi.org\/10.1172\/jci202344","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,15]]}}}