{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T19:15:31Z","timestamp":1788981331474,"version":"build-2803163510"},"reference-count":32,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2019,9,5]],"date-time":"2019-09-05T00:00:00Z","timestamp":1567641600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2019,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      To evaluate a novel tetrahydroisoquinoline derivative YR4\u201042 as a selective peroxisome proliferator\u2010activated receptor \u03b3 (PPAR\u03b3) modulator (SPPARM) and explore its anti\u2010diabetic effects\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      Using two standard full PPAR\u03b3 agonists rosiglitazone and pioglitazone as controls, the PPAR\u03b3 binding affinity and transactivation action of YR4\u201042 were evaluated using biochemical and cell\u2010based reporter gene assays. The capacity of YR4\u201042 to recruit coactivators of PPAR\u03b3 was also assessed. The effects of YR4\u201042 on adipogenesis and glucose consumption and PPAR\u03b3 Ser273 phosphorylation were investigated in 3T3\u2010L1 adipocytes. The effects of YR4\u201042 and pioglitazone, serving as positive control, on glucose and lipids metabolism were investigated in high\u2010fat diet\u2010induced obese (DIO) C57BL\/6J mice. The expression of PPAR\u03b3 target genes involved in glucose and lipid metabolism was also assessed\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vitro<\/jats:italic>\n                      biochemical and cell\u2010based functional assays showed that YR4\u201042 has much weaker binding affinity, transactivation, and recruitment to PPAR\u03b3 of the coactivators thyroid hormone receptor\u2010associated protein complex 220\u2009kDa component (TRAP220) and PPAR\u03b3 coactivator 1\u2010\u03b1 (PGC1\u03b1) compared to full agonists. In 3 T3\u2010L1 adipocytes, YR4\u201042 significantly improved glucose consumption without a lipogenesis effect, while blocking tumour necrosis factor \u03b1\u2010mediated phosphorylation of PPAR\u03b3 at Ser273, thereby upregulating the expression of the PPAR\u03b3 Ser273 phosphorylation\u2010dependent genes. Furthermore, in DIO mice, oral administration of YR4\u201042 ameliorated the hyperglycaemia, with a similar insulin sensitization effect to that of pioglitazone. Importantly, YR4\u201042 also improved hyperlipidaemia\u2010associated hepatic steatosis without weight gain, which avoids a major side effect of pioglitazone. Thus, YR4\u201042 appeared to selectively modulate PPAR\u03b3 responses. This finding was supported by the gene expression analysis, which showed that YR4\u201042 selectively targets PPAR\u03b3\u2010regulated genes mapped to glucose and lipid metabolism in DIO mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We conclude that YR4\u201042 is a novel anti\u2010diabetic drug candidate with significant advantages compared to standard PPAR\u03b3 agonists. YR4\u201042 should be further investigated in preclinical and clinical studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.13843","type":"journal-article","created":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T05:20:12Z","timestamp":1564550412000},"page":"2553-2563","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["A novel specific peroxisome proliferator\u2010activated receptor \u03b3 (PPAR\u03b3) modulator YR4\u201042 ameliorates hyperglycaemia and dyslipidaemia and hepatic steatosis in diet\u2010induced obese mice"],"prefix":"10.1111","volume":"21","author":[{"given":"Yi","family":"Huan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key laboratory of Polymorphic Drugs of Beijing Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 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