A New Retinoid-Like Compound That Activates Peroxisome Proliferator-Activated Receptors and Lowers Blood Glucose in Diabetic Mice

• Published in: Biological & pharmaceutical bulletin 2005, Vol.28(7), pp.1192-1196
• Main Authors: Deng, Tuo, Shan, Song, Li, Zhi-Bin, Wu, Zhong-Wen, Liao, Chen-Zhong, Ko, Ben, Lu, Xian-Ping, Cheng, Jing, Ning, Zhi-Qiang
• Format: Article
• Language: English
• Subjects: Alkenes - pharmacology; Animals; Base Sequence; Blood Glucose - analysis; Diabetes Mellitus, Experimental - blood; Dimerization; DNA Primers; Mice; Naphthalenes - pharmacology; peroxisome proliferator-activated receptor; Peroxisome Proliferator-Activated Receptors - agonists; retinoid X receptor; Retinoids - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; synthetic compound; type 2 diabetes
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.28.1192

Retinoid X receptor (RXR) forms heterodimers with peroxisome proliferator-activated receptors (PPARs, with subtypes of α, δ and γ), and the heterodimers can be activated by either an RXR or a PPAR subtype-specific ligand. Based on the chemical structure of the RXR natural ligand, 9-cis-retinoic acid (9-cis-RA), we designed and synthesized a retinoid-like compound, CS018. In vitro characterizations by cell-based reporter gene assays indicated that CS018 activated RXR homodimers and the heterodimers of RXR with PPARs, but not with farnesoid X-activated receptor (FXR) and liver X-activated receptor (LXR). Furthermore, RT-PCR results showed that CS018 induced the expression of the PPARγ target genes, CD36 and lipoprotein lipase (LPL). In vivo studies on the diabetic db/db mice demonstrated that CS018 dramatically lowered the animal blood glucose levels. CS018 thus may represent a new retinoid-like compound that activates RXR/PPARs and has potential therapeutic applications in type 2 diabetes and other metabolic diseases.