Insulin Sensitization by a Novel Partial Peroxisome Proliferator-Activated Receptor γ Agonist With Protein Tyrosine Phosphatase 1B Inhibitory Activity in Experimental Osteoporotic Rats

Abstract

Abstract. The pharmacological profile of (S)7(2{2[(E)2cyclopentylvinyl]5methyloxazol 4yl}ethoxy)2[(2E,4E)hexadienoyl]1,2,3,4tetrahydroisoquinoline3carboxylic acid (KY201), a peroxisome proliferatoractivated receptor (PPAR) g agonist, was compared with that of rosiglitazone in ovariectomized rats. The serum triglyceride and nonesterified fatty acid reducing effects of KY201 at 3 and 10 mg/kg per day for 6 weeks were similar to those of rosiglitazone despite its weaker PPARg agonistic activity. KY201 had no effects on body weight gain, blood volume, or heart and adipose weights, while rosiglitazone at 10 mg/kg per day increased them. KY201 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 KY201 was weaker than that of rosiglitazone in ST2 cells, and KY201 reduced osteoblast differentiation and increased adipocyte differentiation less potently than rosiglitazone in rat bone marrowderived mesenchymal stem cells. KY201, 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 KY201 are similar to those of rosiglitazone, but with less adverse effects, due to the combination of PPARg partial activation and PTP1B inhibition. KY201 would be useful for treatments of diabetic patients at high risk of osteoporosis, cardiovascular disease, and/or obesity.

CMHX008, a Novel Peroxisome Proliferator-Activated Receptor γ Partial Agonist, Enhances Insulin Sensitivity In Vitro and In Vivo

“…Thus, supplement of these drugs in the daily food, instead of forced administration by gavage, may possibly reflect a physiological change in feeding and weight. Secondly, weight gain of rosiglitazone treatment may depend on the dose: at a higher dose (>10 mg/kg), rosiglitazone increased body weight, but no significant change in body weight while low dose (3 mg/kg) of this drug was given [42], which is consistent with our results.…”

Transcriptome analysis of castrated Bovine reveals the characters of protein accumulation

“…The R language (v3.2.1) with edgeR package was used to identify the differential expression genes (DEGs) (Kubo et al, 2014). The fold change between the two groups was calculated as: logFC=log2 (PEG 4 hours group / control group, and PEG 12 hours group / control group).…”

“…It plays an important role in the regulation of gene expression associated with normal cell physiology as well as the pathophysiology of multiple diseases including obesity, diabetes and cancer. In this study, PPAR was considered that the most factor in PPAR signaling pathway (Kubo et al,2014). PPAR are involved in cell adhesion molecules (CAMs), Insulin signaling pathway, ECM-receptor interaction, Cytokinecytokine receptor interaction that play a role via fat metabolism, immune regulation, insulin signaling pathway.…”

Multitargeted bioactive ligands for PPARs discovered in the last decade

“…The novel agonist, KY‐201 (Figure ), was compared with the full agonist rosiglitazone in ovariectomized rats in many effects. Masahiro Kubo and others attained the result in a luciferase reporter assay that PPARγ agonism of both KY‐201 and rosiglitazone changed with their concentrations ranging from 10 −7 to 10 −5 m . The EC 50 s for them were 287 ± 88 n m and 148 ± 39 n m , respectively.…”