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Failure of spontaneous remyelination is attributable to insufficient differentiation of oligodendrocyte precursor cells (OPCs) into mature myelin-forming oligodendrocytes in CNS demyelinated lesions. Emerging evidence suggests that peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3) is the master gatekeeper of CNS injury and repair and plays an important regulatory role in various neurodegenerative diseases. Although studies demonstrate positive effects of PPAR\u03b3 in oligodendrocyte ontogeny in vitro, the cell-intrinsic role of PPAR\u03b3 and the molecular mechanisms involved in the processes of OPC development and CNS remyelination in vivo are poorly understood.<\/jats:p>\n                  <jats:p>Here, we identify PPAR\u03b3 as an enriched transcription factor in the dysfunctional OPCs accumulated in CNS demyelinated lesions. Its expression increases during OPC differentiation and myelination and is closely related to the process of CNS demyelination\/remyelination. Administration of pharmacological agonists of PPAR\u03b3 not only promotes OPC differentiation and CNS myelination, but also causes a significant increase in remyelination in both cuprizone- and lysophosphatidylcholine-induced demyelination models. In contrast, the attenuation of PPAR\u03b3 function, either through the specific knockout of PPAR\u03b3 in oligodendrocytes in vivo or through its inhibition in vitro, leads to decreased OPC maturation, hindered myelin generation and reduced therapeutic efficacy of PPAR\u03b3 agonists. At a mechanistic level, PPAR\u03b3 induces myelin repair by directly targeting glycoprotein non-metastatic melanoma protein B (GPNMB), a novel regulator that drives OPCs to differentiate into oligodendrocytes, promotes myelinogenesis in the developing CNS of postnatal mice and enhances remyelination in mice with lysophosphatidylcholine-induced demyelination.<\/jats:p>\n                  <jats:p>In conclusion, our evidence reveals that PPAR\u03b3 is a positive regulator of endogenous OPC differentiation and CNS myelination\/remyelination and suggests that PPAR\u03b3 and\/or its downstream sensor (GPNMB) might be a candidate pharmacological target for regenerative therapy in the CNS.<\/jats:p>","DOI":"10.1093\/brain\/awae378","type":"journal-article","created":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T15:24:20Z","timestamp":1731684260000},"page":"1801-1816","source":"Crossref","is-referenced-by-count":14,"title":["Nuclear receptor PPAR\u03b3 targets GPNMB to promote oligodendrocyte development and remyelination"],"prefix":"10.1093","volume":"148","author":[{"given":"Bing","family":"Han","sequence":"first","affiliation":[{"name":"Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education; College of Life Sciences, Shaanxi Normal University , Xi\u2019an 710119 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Yue","family":"Bao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education; College of Life Sciences, Shaanxi Normal University , Xi\u2019an 710119 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-Qing","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The 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and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education; College of Life Sciences, Shaanxi Normal University , Xi\u2019an 710119 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education; College of Life Sciences, Shaanxi Normal University , Xi\u2019an 710119 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education; College of Life Sciences, Shaanxi Normal University , Xi\u2019an 710119 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