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

Abstract

The peroxisome proliferator-activated receptor γ (PPARγ) plays an important role in adipocyte differentiation and insulin sensitivity. Its ligand rosiglitazone has anti-diabetic effect but is frequently accompanied with some severe unwanted effects. The aim of the current study was to compare the anti-diabetic effect of CMHX008, a novel thiazolidinedione-derivative, with rosiglitazone. A luciferase assay was used to evaluate in vitro PPARγ activation. 3T3-L1 cells were used to examine adipocyte differentiation. High fat diet (HFD) mice were used to examine in vivo insulin sensitivity. The mRNA levels were evaluated by real-time RT-PCR. Serum biochemical and hormonal variables were assessed using a clinical chemistry analyser. CMHX008 displayed a moderate PPARγ agonist activity, and promoted 3T3-L1 preadipocyte differentiation with lower activity than rosiglitazone. CMHX008 regulated the expression of PPARγ target genes in a different manner from rosiglitazone. CMHX008 increased the expression and secretion of adiponectin with the similar efficacy as rosiglitazone, but only 25% as potent as rosiglitazone for the induction of adipocyte fatty acid binding protein. Treatment of CMHX008 and rosiglitazone protected mice from high fat diet (HFD)-induced glucose intolerance, hyperinsulinemia and inflammation. CMHX008 reduced the mRNA expression of M1 macrophage markers, and significantly increased the expressions of M2 markers. In conclusion, CMHX008 shared the comparable insulin-sensitizing effects as rosiglitazone with lower adipogenic capacity and might potentially be developed into an effective agent for the treatment of diabetes and metabolic disorders.

The prevention and treatment of hypoadiponectinemia-associated human diseases by up-regulation of plasma adiponectin

“…CMHX008, a 706 synthetic PPARγ agonist and derivative of rosiglitazone, significantly 707 promoted adipocyte differentiation. CMHX008 was also shown to 708 enhance the expression and secretion of adiponectin with a similar effi-709 cacy as rosiglitazone, suggesting that CMHX008 possesses similar 710insulin-sensitizing effects[116]. CMHX008 also up-regulated the 711 expression of glucose transporter 4 (Glut4) in 3T3-L1 cells, which 712 showed the efficacy of CMHX008 to stimulate glucose uptake by cells 713[116].…”

“…CMHX008 was also shown to 708 enhance the expression and secretion of adiponectin with a similar effi-709 cacy as rosiglitazone, suggesting that CMHX008 possesses similar 710insulin-sensitizing effects[116]. CMHX008 also up-regulated the 711 expression of glucose transporter 4 (Glut4) in 3T3-L1 cells, which 712 showed the efficacy of CMHX008 to stimulate glucose uptake by cells 713[116]. Similar to CMHX008, the PPARγ ligands, such as artepillin C,714 cilostazol and magnolol, promoted adipocyte differentiation, enhanced 715 adiponectin expression and improved insulin sensitivity through 716 PPARγ activation [21,22,146,197].…”

“…Thus, adiponectin is thought to improve in-112 sulin sensitivity by stimulating glucose utilization and fatty acid oxida-113 tion. Previous studies suggest that this function is achieved through 114 the phosphorylation and activation of AMP-activated protein kinase 115 (AMPK), which is the downstream of adiponectin receptor 1 (AdipoR1) 116 in both skeletal muscle and liver tissue [185,209]. AdipoR2 is expressed 117 predominantly in the liver and can activate peroxisome proliferator- 118 activated receptor-alpha (PPARα) to stimulate fatty acid oxidation 119 and insulin sensitivity when bound to adiponectin [31,32].…”

A step ahead of PPARγ full agonists to PPARγ partial agonists: Therapeutic perspectives in the management of diabetic insulin resistance

“…In addition, CMHX008 had a lower adipogenic capacity compared to rosiglitazone. This study suggested that CMHX008 could be an effective agent for the treatment of diabetes mellitus and metabolic disorders (Ming et al, 2014). However, further studies are needed to better clarify the pharmacological profile of CMHX008.…”

“…2 depicts the structural similarity of GQ-16 with rosiglitazone . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 A recent study by Ming et al (2014) compared the anti-diabetic effect of CMHX008, a nove...…”