{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:08:03Z","timestamp":1779253683541,"version":"3.51.4"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","award":["23 3033 PJ, 20090 PJ"],"award-info":[{"award-number":["23 3033 PJ, 20090 PJ"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2022\u201300562"],"award-info":[{"award-number":["2022\u201300562"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Obesity arises from the interplay between genetic predisposition, metabolic signaling, and neural circuits that regulate feeding and energy expenditure. Large-scale association studies repeatedly implicate regulators of Ras\/Rap GTPase signaling in adiposity and metabolic risk, but the mechanisms linking these intracellular switch modules to neural control of energy balance remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used a translational approach centered on Drosophila RasGAP1, the closest ortholog of mammalian RASA2\/3. Pan-neuronal RasGAP1 knockdown was assessed for effects on locomotor behavior, feeding interactions, systemic metabolic markers, expression of the leptin analog unpaired 1 (upd1), and protein-interaction networks. We then extended these findings to humans using protein-network and phenome-wide association analyses focused on RASA2\/3-related pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Pan-neuronal RasGAP1 knockdown shifted behavior toward an obesity-like phenotype, combining reduced locomotor output with increased feeding interactions. This was accompanied by elevated lipid storage, increased circulating sugars, and reduced expression of upd1. Protein-interactome mapping positioned RasGAP1 within a connected signaling neighborhood linking Ras signaling with cytokine pathways relevant to feeding control. In humans, protein-network and phenome-wide association analyses converged on a KRAS-centered pathway in which RASA2\/3, KRAS, and LEP were consistently associated with fat mass, BMI, and lipid dysregulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings support RasGAP1\/RASA2\/3 as a candidate conserved neuro-metabolic regulator. More broadly, they provide hypothesis-generating evidence that RasGAP dysfunction may bias neural and metabolic control systems toward adiposity-linked phenotypes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1773383","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T04:33:02Z","timestamp":1779251582000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The RASA2\/RASA3 ortholog RasGAP1 modulates obesity-linked phenotypes and is associated with leptin-analog signaling in Drosophila"],"prefix":"10.3389","volume":"17","author":[{"given":"Thiago C.","family":"Moulin","sequence":"first","affiliation":[{"name":"Department of Surgical Sciences, Uppsala University","place":["Uppsala, Sweden"]},{"name":"Department of Pharmaceutical Biosciences, Uppsala University","place":["Uppsala, Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael 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