title: 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.
authors.affiliation: Laboratory of Lipid & Glucose Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ming
authors.affiliation: College of Pharmacy, Chongqing Medical University, Chongqing, China.
authors.forename: Xiangnan
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Endocrine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Song
authors.affiliation: Laboratory of Lipid & Glucose Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health and Management, Chongqing Medical University, Chongqing, China.
authors.forename: Jibin
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Lipid & Glucose Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Endocrine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Rufei
authors.initials: R
authors.lastname: Gao
authors.affiliation: Laboratory of Lipid & Glucose Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Yuyao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: College of Bioengineering, Chongqing University, Chongqing, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Mei
authors.affiliation: College of Bioengineering, Chongqing University, Chongqing, China.
authors.forename: Tingwang
authors.initials: T
authors.lastname: Guo
authors.affiliation: College of Bioengineering, Chongqing University, Chongqing, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xiao
authors.affiliation: College of Bioengineering, Chongqing University, Chongqing, China.
authors.forename: Bochu
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Chaodong
authors.initials: C
authors.lastname: Wu
authors.affiliation: Laboratory of Lipid & Glucose Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Endocrine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Xiaoqiu
authors.initials: X
authors.lastname: Xiao
mesh_terms: D041721:3T3-L1 Cells; D052436:Adipose Tissue, White / Q000187:drug effects / Q000473:pathology; D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002454:Cell Differentiation; D016764:Cell Polarity; D059305:Diet, High-Fat / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical; D050171:Dyslipidemias / Q000188:drug therapy / Q000209:etiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007333:Insulin Resistance; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C000602141:3-tert-butoxycarbonylmethyl-5-(4-(2-(N-methyl-N-(2-pyridyl)amino)ethoxy)benzyl)thiazolidine-2,4-dione; D000631:Aminopyridines; D000893:Anti-Inflammatory Agents; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone