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Adv."],"published-print":{"date-parts":[[2026,1,23]]},"abstract":"<jats:p>\n                    GPR75, a G protein\u2013coupled receptor implicated in human obesity through loss-of-function variants, has emerged as a promising regulator of energy and metabolic homeostasis. To dissect its tissue-specific functions, we generated a humanized floxed\n                    <jats:italic toggle=\"yes\">Gpr75<\/jats:italic>\n                    mouse model with conditional deletions in the brain and adipose tissue. Mice with brain-specific Gpr75 deletion using Nestin-Cre were resistant to diet-induced obesity, primarily through suppressed food intake and modest increases in energy expenditure. In contrast, adipocyte-specific deletion of Gpr75 had minimal effects on systemic metabolism but modestly enhanced mitochondrial oxygen consumption in brown adipose tissue under cold exposure. Gpr75 expression was up-regulated in key brain regions and down-regulated in white adipose tissue under high-fat diet conditions, supporting a predominant central role in metabolic adaptation. Histological and transcriptomic analyses further revealed depot-specific effects on adipocyte morphology and hepatic lipid accumulation in global knockouts. These findings position GPR75 as a critical regulator of central energy balance and provide a mechanistic framework for developing brain-targeted therapies against obesity.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.ady7993","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T18:58:41Z","timestamp":1769194721000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["Neuronal GPR75 deficiency protects against diet-induced obesity in a humanized mouse model"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2588-6648","authenticated-orcid":true,"given":"Xue-Nan","family":"Sun","sequence":"first","affiliation":[{"name":"Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, 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