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Original Article | Open Access

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

Yi Houa,c, Xuemei Caoa,c, Xiangnan Hub, Xinyu Lia, Xiaoqin Shia,c, Hongying Wanga,c, Chuan Penga,c, Jiayu Lia,c, Jibin Lid, Qifu Lic, Chaodong Wuf, Xiaoqiu Xiaoa,c,e( )
Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
College of Pharmacy, Chongqing Medical University, China
The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
Department of Nutrition and Food Hygiene, School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China
Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, 400016, China
Department of Nutrition and Food Science, Texas A&M University, College Station, TX, 77843, USA

Peer review under responsibility of Chongqing Medical University.

Show Author Information

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.

Keywords

Type 2 diabetes mellitusOsteoblastsPeroxisome proliferator-activated receptor γThiazolidinedionesTR-FRET

References

1

Jaacks LM, Siegel KR, Gujral UP, Narayan KM. Type 2 diabetes: a 21st century epidemic. Best Pract Res Clin Endocrinol Metab. 2016;30(3):331–343.
Crossref Google Scholar
2

Zimmet P, Alberti KG, Magliano DJ, Bennett PH. Diabetes mellitus statistics on prevalence and mortality: facts and fallacies. Nat Rev Endocrinol. 2016;12(10):616–622.
Crossref Google Scholar
3

Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998;47(4):507–514.
Crossref Google Scholar
4

Kong AP, Yamasaki A, Ozaki R, et al. A randomized-controlled trial to investigate the effects of rivoglitazone, a novel PPAR gamma agonist on glucose-lipid control in type 2 diabetes. Diabetes Obes Metab. 2011;13(9):806–813.
Crossref Google Scholar
5

Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–2471.
Crossref Google Scholar
6

Hiatt WR, Kaul S, Smith RJ. The cardiovascular safety of diabetes drugs — insights from the rosiglitazone experience. N Engl J Med. 2013;369(14):1285–1287.
Crossref Google Scholar
7

Consoli A, Formoso G. Do thiazolidinediones still have a role in treatment of type 2 diabetes mellitus? Diabetes Obes Metab. 2013;15(11):967–977.
Crossref Google Scholar
8

Lecka-Czernik B. Diabetes, bone and glucose-lowering agents: basic biology. Diabetologia. 2017;60(7):1163–1169.
Crossref Google Scholar
9

Billington EO, Grey A, Bolland MJ. The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis. Diabetologia. 2015;58(10):2238–2246.
Crossref Google Scholar
10

Napoli N, Chandran M, Pierroz DD, Abrahamsen B, Schwartz AV, Ferrari SL. Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol. 2017;13(4):208–219.
Crossref Google Scholar
11

Watkins MP, Norris JY, Grimston SK, et al. Bisphosphonates improve trabecular bone mass and normalize cortical thickness in ovariectomized, osteoblast Connexin43 deficient mice. Bone. 2012;51(4):787–794.
Crossref Google Scholar
12

Scotti E, Tontonoz P. Peroxisome proliferator-activated receptor gamma dances with different partners in macrophage and adipocytes. Mol Cell Biol. 2010;30(9):2076–2077.
Crossref Google Scholar
13

Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem. 2008;77:289–312.
Crossref Google Scholar
14

Cao J, Ou G, Yang N, et al. Impact of targeted PPARgamma disruption on bone remodeling. Mol Cell Endocrinol. 2015;410:27–34.
Crossref Google Scholar
15

Cock TA, Houten SM, Auwerx J. Peroxisome proliferator-activated receptor-gamma: too much of a good thing causes harm. EMBO Rep. 2004;5(2):142–147.
Crossref Google Scholar
16

Choi SS, Kim ES, Jung JE, et al. PPARgamma antagonist gleevec improves insulin sensitivity and promotes the browning of white adipose tissue. Diabetes. 2016;65(4):829–839.
Crossref Google Scholar
17

Weidner C, de Groot JC, Prasad A, et al. Amorfrutins are potent antidiabetic dietary natural products. Proc Natl Acad Sci USA. 2012;109(19):7257–7262.
Crossref Google Scholar
18

Higgins LS, Depaoli AM. Selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulation as a strategy for safer therapeutic PPARgamma activation. Am J Clin Nutr. 2010;91(1):267S-272S.
Crossref Google Scholar
19

Choi JH, Banks AS, Estall JL, et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature. 2010;466(7305):451–456.
Crossref Google Scholar
20

DePaoli AM, Higgins LS, Henry RR, Mantzoros C, Dunn FL. Can a selective PPARgamma modulator improve glycemic control in patients with type 2 diabetes with fewer side effects compared with pioglitazone? Diabetes Care. 2014;37(7):1918–1923.
Crossref Google Scholar
21

Dunn FL, Higgins LS, Fredrickson J, DePaoli AM. Selective modulation of PPARgamma activity can lower plasma glucose without typical thiazolidinedione side-effects in patients with Type 2 diabetes. J Diabet Complicat. 2011;25(3):151–158.
Crossref Google Scholar
22

Zheng W, Qiu L, Wang R, et al. Selective targeting of PPARgamma by the natural product chelerythrine with a unique binding mode and improved antidiabetic potency. Sci Rep. 2015;5:12222.
Crossref Google Scholar
23
Ming Y Hu X Song Y CMHX008, a novel peroxisome proliferator-activated receptor gamma partial agonist, enhances insulin sensitivity in vitro and in vivoPLoS One201497e10210210.1371/journal.pone.0102102

Ming Y, Hu X, Song Y, et al. CMHX008, a novel peroxisome proliferator-activated receptor gamma partial agonist, enhances insulin sensitivity in vitro and in vivo. PLoS One. 2014;9(7):e102102.
Crossref Google Scholar
24

Song Y, Li J, Zhao Y, et al. Severe maternal hyperglycemia exacerbates the development of insulin resistance and fatty liver in the offspring on high fat diet. Exp Diabetes Res. 2012;2012:254976.
Crossref Google Scholar
25

Liu Z, Lim CY, Su MY, et al. Neonatal overnutrition in mice exacerbates high-fat diet-induced metabolic perturbations. J Endocrinol. 2013;219(2):131–143.
Crossref Google Scholar
26

Yuasa M, Yamada T, Taniyama T, et al. Dexamethasone enhances osteogenic differentiation of bone marrow- and muscle-derived stromal cells and augments ectopic bone formation induced by bone morphogenetic protein-2. PLoS One. 2015;10(2). e0116462.
Crossref Google Scholar
27

Banks AS, McAllister FE, Camporez JP, et al. An ERK/Cdk5 axis controls the diabetogenic actions of PPARgamma. Nature. 2015;517(7534):391–395.
Crossref Google Scholar
28

Stechschulte LA, Czernik PJ, Rotter ZC, et al. PPARG post-translational modifications regulate bone formation and bone resorption. EBioMedicine. 2016;10:174–184.
Crossref Google Scholar
29

Atanasov AG, Wang JN, Gu SP, et al. Honokiol: a non-adipogenic PPARγ agonist from nature. Biochim Biophys Acta Gen Subj. 2013;1830(10):4813–4819.
Crossref Google Scholar
30

Liu C, Feng T, Zhu N, et al. Identification of a novel selective agonist of PPARgamma with no promotion of adipogenesis and less inhibition of osteoblastogenesis. Sci Rep. 2015;5:9530.
Crossref Google Scholar
31

Amato AA, Rajagopalan S, Lin JZ, et al. GQ-16, a novel peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, promotes insulin sensitization without weight gain. J Biol Chem. 2012;287(33):28169–28179.
Crossref Google Scholar
32

Chen Z, Vigueira PA, Chambers KT, et al. Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor gamma-sparing thiazolidinedione. J Biol Chem. 2012;287(28):23537–23548.
Crossref Google Scholar
33

Zhang X, Liu H, Sun B, et al. Novel podophyllotoxin derivatives as partial PPARgamma agonists and their effects on insulin resistance and type 2 diabetes. Sci Rep. 2016;6:37323.
Crossref Google Scholar
34

Atanasov AG, Blunder M, Fakhrudin N, et al. Polyacetylenes from notopterygium incisum–new selective partial agonists of peroxisome proliferator-activated receptor-gamma. PLoS One. 2013;8(4):e61755.
Crossref Google Scholar
35

Coelho MS, de Lima CL, Royer C, et al. GQ-16, a TZD-derived partial PPARgamma agonist, induces the expression of thermogenesis-related genes in Brown fat and visceral white fat and decreases visceral adiposity in obese and hyperglycemic mice. PLoS One. 2016;11(5). e0154310.
Crossref Google Scholar
36

Liu L, Wan J, Lang H, et al. Dihydromyricetin delays the onset of hyperglycemia and ameliorates insulin resistance without excessive weight gain in Zucker diabetic fatty rats. Mol Cell Endocrinol. 2017;439:105–115.
Crossref Google Scholar
37

Schwartz AV, Chen H, Ambrosius WT, et al. Effects of TZD use and discontinuation on fracture rates in ACCORD bone study. J Clin Endocrinol Metab. 2015;100(11):4059–4066.
Crossref Google Scholar
38

Kolli V, Stechschulte LA, Dowling AR, Rahman S, Czernik PJ, Lecka-Czernik B. Partial agonist, telmisartan, maintains PPARgamma serine 112 phosphorylation, and does not affect osteoblast differentiation and bone mass. PLoS One. 2014;9(5):e96323.
Crossref Google Scholar
39

Marciano DP, Kuruvilla DS, Boregowda SV, et al. Pharmacological repression of PPARγ promotes osteogenesis. Nat Commun. 2015;6:7443.
Crossref Google Scholar
40

Silva JC, Cesar FA, de Oliveira EM, et al. New PPARgamma partial agonist improves obesity-induced metabolic alterations and atherosclerosis in LDLr(-/-) mice. Pharmacol Res. 2016;104:49–60.
Crossref Google Scholar
41

Fukunaga T, Zou W, Rohatgi N, Colca JR, Teitelbaum SL. An insulin-sensitizing thiazolidinedione, which minimally activates PPARγ, does not cause bone loss. J Bone Miner Res. 2015;30(3):481–488.
Crossref Google Scholar
42

Neglia C, Argentiero A, Chitano G, et al. Diabetes and obesity as independent risk factors for osteoporosis: updated results from the ROIS/EMEROS registry in a population of five thousand post-menopausal women living in a region chnaracterized by heavy environmental pressure. Int J Environ Res Publ Health. 2016;13(11).
Crossref Google Scholar
43

Wan Y. PPARγ in bone homeostasis. Trends Endocrinol Metab. 2010;21(12):722–728.
Crossref Google Scholar
Genes & Diseases
Volume 5 Issue 3,
September 2018
Pages 290-299
DOI: 10.1016/j.gendis.2018.05.004
Cite this article:
Hou Y, Cao X, Hu X, et al. CMHX008, a PPARγ partial agonist, enhances insulin sensitivity with minor influences on bone loss. Genes & Diseases, 2018, 5(3): 290-299. https://doi.org/10.1016/j.gendis.2018.05.004

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Received: 27 April 2018
Accepted: 31 May 2018
Published: 06 June 2018
© 2018, Chongqing Medical University.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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