CMHX008, a PPARγ partial agonist, enhances insulin sensitivity with minor influences on bone loss

Abstract

Traditional thiazolidinediones (TZDs), such as rosiglitazone, are peroxisome proliferator-activated receptor γ (PPARγ) potent agonists that can be used to treat type 2 diabetes but carry unwanted effects, including increased risk for fracture. The present work aimed to compare the insulin-sensitizing efficacies and bone-loss side effects of CMHX008, a novel TZDs-like PPARγ partial agonist, with those of rosiglitazone. A TR-FRET PPARγ competitive binding assay was used to compare the binding affinity between CMHX008 and rosiglitazone. Mice were administered vehicle, CMHX008 or rosiglitazone for 16 weeks. Mesenchymal stem cells (MSCs) were used to examine differences in differentiation into osteoblasts after compounds treatment. TR-FRET showed lower affinity to PPARγ by CMHX008 compared with rosiglitazone. Mice treated with CMHX008 showed insulin sensitization similar to that of mice treated with rosiglitazone, which was related to the significant inhibition of PPARγ Ser273 phosphorylation and improved insulin sensitivity by facilitating the phosphorylation of insulin receptor and Akt in adipose tissues. Micro-CT and histomorphometric analyses demonstrated that the degree of trabecular bone loss after treatment with CMHX008 was weaker than that observed with rosiglitazone, as evidenced by consistent changes in BV/TV, Tb.N, Tb.Th, Tb.Sp, and the mineral apposition rate. MSCs treated with CMHX008 showed higher ALP activity and mRNA levels of bone formation markers than did cells treated with rosiglitazone in the osteoblast differentiation test. Thus, CMHX008 showed insulin-sensitizing effects similar to those of rosiglitazone with a lower risk of bone loss, suggesting that PPARγ sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.

Silencing Smad7 potentiates BMP2-induced chondrogenic differentiation and inhibits endochondral ossification in human synovial-derived mesenchymal stromal cells

“…The rate of p-nitrophenol liberation is proportional to ALP activity and can be measured photometrically. The ALP activity was measured by a microplate reader (Thermo Scientific™, USA) at an absorbance of 405 nm [39]. In addition, the protein concentration of the cell lysate was determined by a BCA Protein Assay Kit (Beyotime), and ALP activity was normalized to total protein per well.…”

“…Then, the cells were cultured in chondrogenic medium for 1 week, and this medium was composed of DMEM with ITS (Sigma-Aldrich), 50 μg/mL ascorbate (Sigma-Aldrich), 100 nM dexamethasone (Sigma-Aldrich), and 10 ng/mL transforming growth factor-β3 (Sigma-Aldrich). Then, the cells were cultured in hypertrophic medium for another week, and this medium contained ITS supplement, 50 μg/mL ascorbate, 1 nmol/L dexamethasone, and 100 ng/mL triiodothyronine (T3, Sigma-Aldrich) [39].…”

Peroxisome Proliferator-Activated Receptors and Caloric Restriction—Common Pathways Affecting Metabolism, Health, and Longevity

“…Synthetic agonists of PPARγ can be divided into two groups: classical full agonists, which are represented by the thiazolidinediones (TZDs) [ 121 ] such as troglitazone, rosiglitazone, and pioglitazone, and partial agonists, which were developed to reduce the side effects of full agonists, including weight gain and bone loss [ 122 , 123 ]. PPARα/γ dual agonists exert positive influences on both lipid and glucose metabolism.…”

<p>Anti-Diabetic Effect of Telmisartan Through its Partial PPARγ-Agonistic Activity</p>

“…40,41 CMHX008, a partial PPARγ modulator, showed comparable insulin-sensitizing effects with lower adipogenic capacity and lower risk of bone loss compared to rosiglitazone, and it could be an effective agent for the management of DM and other metabolic disorders. 42,43 GQ-16 and L312, PPARγ partial agonists, also showed a promising anti-diabetic effect with an improved side effect profile. 44,45 There are several partial PPARγ agonists under investigation, with an insulin sensitization action and fewer adverse effects, including a reduced tendency to cause weight gain, adipose tissue gain, and fluid retention.…”