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Journal of Pharmacological Sciences 2014

Insulin sensitization by a novel partial peroxisome proliferator-activated receptor γ agonist with protein tyrosine phosphatase 1B inhibitory activity in experimental osteoporotic rats.

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Masahiro Kubo
Masaki Fukui
Yuma Ito
Tatsuya Kitao
Hiroaki Shirahase
Eiichi Hinoi
Yukio Yoneda

Sleutelwoorden

Abstract

The pharmacological profile of (S)-7-(2-{2-[(E)-2-cyclopentylvinyl]-5-methyloxazol-4-yl}-ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (KY-201), a peroxisome proliferator-activated receptor (PPAR) γ agonist, was compared with that of rosiglitazone in ovariectomized rats. The serum triglyceride and non-esterified fatty acid reducing effects of KY-201 at 3 and 10 mg/kg per day for 6 weeks were similar to those of rosiglitazone despite its weaker PPARγ agonistic activity. KY-201 had no effects on body weight gain, blood volume, or heart and adipose weights, while rosiglitazone at 10 mg/kg per day increased them. KY-201 had few effects on bone mineral density (BMD) or fat in marrow (FM), whereas rosiglitazone strongly decreased BMD and increased FM. The PPARγ agonistic activity of KY-201 was weaker than that of rosiglitazone in ST-2 cells, and KY-201 reduced osteoblast differentiation and increased adipocyte differentiation less potently than rosiglitazone in rat bone marrow-derived mesenchymal stem cells. KY-201, but not rosiglitazone inhibited protein tyrosine phosphatase 1B (PTP1B) and increased phosphorylation of the insulin receptor in HepG2 cells. These results suggest that the hypolipidemic effects of KY-201 are similar to those of rosiglitazone, but with less adverse effects, due to the combination of PPARγ partial activation and PTP1B inhibition. KY-201 would be useful for treatments of diabetic patients at high risk of osteoporosis, cardiovascular disease, and/or obesity.

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