nach oben

Diabetologia

Erschienen in:

01.02.2013 | Article

Identification of the antibiotic ionomycin as an unexpected peroxisome proliferator-activated receptor γ (PPARγ) ligand with a unique binding mode and effective glucose-lowering activity in a mouse model of diabetes

verfasst von: W. Zheng, X. Feng, L. Qiu, Z. Pan, R. Wang, S. Lin, D. Hou, L. Jin, Y. Li

Erschienen in: Diabetologia | Ausgabe 2/2013

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

Existing thiazolidinedione (TZD) drugs for diabetes have severe side effects. The aim of this study is to develop alternative peroxisome proliferator-activated receptor γ (PPARγ) ligands that retain the benefits in improving insulin resistance but with reduced side effects.

Methods

We used AlphaScreen assay to screen for new PPARγ ligands from compound libraries. In vitro biochemical binding affinity assay and in vivo cell-based reporter assay were used to validate ionomycin as a partial ligand of PPARγ. A mouse model of diabetes was used to assess the effects of ionomycin in improving insulin sensitivity. Crystal structure of PPARγ complexed with ionomycin revealed the unique binding mode of ionomycin, which elucidated the molecular mechanisms allowing the discrimination of ionomycin from TZDs.

Results

We found that the antibiotic ionomycin is a novel modulating ligand for PPARγ. Both the transactivation and binding activity of PPARγ by ionomycin can be blocked by PPARγ specific antagonist GW9662. Ionomycin interacts with the PPARγ ligand-binding domain in a unique binding mode with properties and epitopes distinct from those of TZD drugs. Ionomycin treatment effectively improved hyperglycaemia and insulin resistance, but had reduced side effects compared with TZDs in the mouse model of diabetes. In addition, ionomycin effectively blocked the phosphorylation of PPARγ at Ser273 by cyclin-dependent kinase 5 both in vitro and in vivo.

Conclusions/interpretation

Our studies suggest that ionomycin may represent a unique template for designing novel PPARγ ligands with advantages over current TZD drugs.

Nur mit Berechtigung zugänglich

Michalik L, Auwerx J, Berger JP et al (2006) International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol Rev 58:726–741PubMedCrossRef

Jin L, Li Y (2010) Structural and functional insights into nuclear receptor signaling. Adv Drug Deliv Rev 62:1218–1226PubMedCrossRef

Tontonoz P, Spiegelman BM (2008) Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem 77:289–312PubMedCrossRef

Kuda O, Jelenik T, Jilkova Z et al (2009) n-3 fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet. Diabetologia 52:941–951PubMedCrossRef

Lennon R, Welsh GI, Singh A et al (2009) Rosiglitazone enhances glucose uptake in glomerular podocytes using the glucose transporter GLUT1. Diabetologia 52:1944–1952PubMedCrossRef

Serrano-Marco L, Barroso E, El Kochairi I et al (2012) The peroxisome proliferator-activated receptor (PPAR) β/δ agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells. Diabetologia 55:743–751PubMedCrossRef

Lehrke M, Lazar MA (2005) The many faces of PPARgamma. Cell 123:993–999PubMedCrossRef

Wang YX (2010) PPARs: diverse regulators in energy metabolism and metabolic diseases. Cell Res 20:124–137PubMedCrossRef

Weismann D, Erion DM, Ignatova-Todorava I et al (2011) Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in a rat model of insulin resistance. Diabetologia 54:935–944PubMedCrossRef

10.

Yki-Jarvinen H (2004) Thiazolidinediones. N Engl J Med 351:1106–1118PubMedCrossRef

11.

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

12.

Zanchi A, Maillard M, Jornayvaz FR et al (2010) Effects of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals. Diabetologia 53:1568–1575PubMedCrossRef

13.

Evans RM, Barish GD, Wang YX (2004) PPARs and the complex journey to obesity. Nat Med 10:355–361PubMedCrossRef

14.

Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W (2006) From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res 45:120–159PubMedCrossRef

15.

Moras D, Gronemeyer H (1998) The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol 10:384–391PubMedCrossRef

16.

Allen T, Zhang F, Moodie SA et al (2006) Halofenate is a selective peroxisome proliferator-activated receptor gamma modulator with antidiabetic activity. Diabetes 55:2523–2533PubMedCrossRef

17.

Zhang F, Lavan BE, Gregoire FM (2007) Selective modulators of PPAR-γ activity: molecular aspects related to obesity and side-effects. PPAR Res 2007:32696PubMedCrossRef

18.

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

19.

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

20.

Houtkooper RH, Auwerx J (2010) Obesity: new life for antidiabetic drugs. Nature 466:443–444PubMedCrossRef

21.

Li P, Fan W, Xu J et al (2011) Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity. Cell 147:815–826PubMedCrossRef

22.

Otwinowski Z, Minor W (1997) Processing of x-ray diffraction data collected in oscillation mode. Method Enzymol 276:307–326CrossRef

23.

Emsley P, Cowtan K (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60:2126–2132PubMedCrossRef

24.

Li Y, Suino K, Daugherty J, Xu HE (2005) Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor. Mol Cell 19:367–380PubMedCrossRef

25.

Li Y, Choi M, Cavey G et al (2005) Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. Mol Cell 17:491–502PubMedCrossRef

26.

Jin L, Lin S, Rong H et al (2011) Structural basis for iloprost as a dual peroxisome proliferator-activated receptor alpha/delta agonist. J Biol Chem 286:31473–31479PubMedCrossRef

27.

Lin S, Han Y, Shi Y et al (2012) Revealing a steroid receptor ligand as a unique PPARgamma agonist. Cell Res 22:746–756PubMedCrossRef

28.

Leesnitzer LM, Parks DJ, Bledsoe RK et al (2002) Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry 41:6640–6650PubMedCrossRef

29.

Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79:1147–1156PubMedCrossRef

30.

Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM (1994) mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 8:1224–1234PubMedCrossRef

31.

Gampe RT Jr, Montana VG, Lambert MH et al (2000) Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell 5:545–555PubMedCrossRef

32.

Chandra V, Huang P, Hamuro Y et al (2008) Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA. Nature 456:350–356PubMedCrossRef

33.

Nolte RT, Wisely GB, Westin S et al (1998) Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 395:137–143PubMedCrossRef

34.

Liu C, Hermann TE (1978) Characterization of ionomycin as a calcium ionophore. J Biol Chem 253:5892–5894PubMed

35.

Oberfield JL, Collins JL, Holmes CP et al (1999) A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation. Proc Natl Acad Sci USA 96:6102–6106PubMedCrossRef

36.

Itoh T, Fairall L, Amin K et al (2008) Structural basis for the activation of PPARgamma by oxidized fatty acids. Nat Struct Mol Biol 15:924–931PubMedCrossRef

37.

Li Y, Zhang J, Schopfer FJ et al (2008) Molecular recognition of nitrated fatty acids by PPAR gamma. Nat Struct Mol Biol 15:865–867PubMedCrossRef

38.

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

Titel: Identification of the antibiotic ionomycin as an unexpected peroxisome proliferator-activated receptor γ (PPARγ) ligand with a unique binding mode and effective glucose-lowering activity in a mouse model of diabetes
verfasst von: W. Zheng
X. Feng
L. Qiu
Z. Pan
R. Wang
S. Lin
D. Hou
L. Jin
Y. Li
Publikationsdatum: 01.02.2013
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 2/2013
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-012-2777-9

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Identification of the antibiotic ionomycin as an unexpected peroxisome proliferator-activated receptor γ (PPARγ) ligand with a unique binding mode and effective glucose-lowering activity in a mouse model of diabetes

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Blutdrucksenkung könnte Uterusmyome verhindern

„Jeder Fall von plötzlichem Tod muss obduziert werden!“

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

Schlechtere Vorhofflimmern-Prognose bei kleinem linken Ventrikel

Update Innere Medizin

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2013

Improved lifestyle and decreased diabetes risk over 13 years: long-term follow-up of the randomised Finnish Diabetes Prevention Study (DPS)

Functional relevance of genes implicated by obesity genome-wide association study signals for human adipocyte biology

Prediction and classification of cardiovascular disease risk in older adults with diabetes

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

Pharmacological reduction of NEFA restores the efficacy of incretin-based therapies through GLP-1 receptor signalling in the beta cell in mouse models of diabetes

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Blutdrucksenkung könnte Uterusmyome verhindern

„Jeder Fall von plötzlichem Tod muss obduziert werden!“

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

Schlechtere Vorhofflimmern-Prognose bei kleinem linken Ventrikel

Update Innere Medizin