| Abstract | BACKGROUND AND PURPOSE: Muraglitazar, a dual PPARalpha/gamma agonist, caused a robust increase in body weight in db/db mice. The purpose of the study was to see if this increase in weight was due to oedema and/or adipogenesis. EXPERIMENTAL APPROACH: The affinity of muraglitazar at PPARalpha/gamma receptors was characterized using transactivation assays. Pre-adipocyte differentiation, expression of genes for adipogenesis (aP2), fatty acid oxidation (ACO) and sodium reabsorption (ENaCgamma and Na+, K+-ATPase); haemodilution parameters and serum electrolytes were measured to delineate the role of muraglitazar in causing weight gain vis a vis rosiglitazone. KEY RESULTS: Treatment with muraglitazar (10 mg kg(-1)) for 14 days significantly reduced plasma glucose and triglycerides. Reduction in plasma glucose was significantly greater than after similar treatment with rosiglitazone (10 mg kg(-1)). A marked increase in weight was also observed with muraglitazar that was significantly greater than with rosiglitazone. Muraglitazar increased aP2 mRNA and caused adipocyte differentiation in 3T3-L1 cells similar to rosiglitazone. It also caused a marked increase in ACO mRNA in the liver of the treated mice. Expression of mRNA for ENaCgamma and Na+, K+-ATPase in kidneys was up-regulated after either treatment. Increased serum electrolytes and decreased RBC count, haemoglobin and haematocrit were observed with both muraglitazar and rosiglitazone. CONCLUSIONS AND IMPLICATIONS: Although muraglitazar has a better glucose lowering profile, it also has a greater potential for weight gain than rosiglitazone. In conclusion, muraglitazar causes both robust adipogenesis and oedema in a 14-day treatment of db/db mice as observed in humans. |
| Authors | S Mittra, G Sangle, R Tandon, S Sharma, S Roy, V Khanna, A Gupta, J Sattigeri, L Sharma, P Priyadarsiny, S K Khattar, R S Bora, K S Saini, V S Bansal
(Affiliation: Ranbaxy Research Laboratories, New Drug Discovery Research, Gurgaon, Haryana, India.)
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| Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 150
Issue 4
Pg. 480-7
(Feb 2007)
ISSN: 0007-1188 England |
| PMID | 17211457
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Blood Glucose
- Epithelial Sodium Channel
- Fatty Acids
- Hemoglobins
- Oxazoles
- PPAR alpha
- PPAR gamma
- RNA, Messenger
- Thiazolidinediones
- muraglitazar
- rosiglitazone
- Glycine
- Sodium
- Sodium-Potassium-Exchanging ATPase
|
| Topics |
- 3T3-L1 Cells
- Adipocytes
(drug effects)
- Adipogenesis
(drug effects)
- Animals
- Blood Glucose
(metabolism)
- Body Weight
(drug effects)
- Cell Differentiation
(drug effects)
- Edema
(chemically induced, pathology)
- Epithelial Sodium Channel
(biosynthesis)
- Erythrocyte Count
- Fatty Acids
(metabolism)
- Glycine
(analogs & derivatives, pharmacology)
- Hemoglobins
(metabolism)
- Kidney
(drug effects, enzymology)
- Mice
- Mice, Inbred Strains
- Oxazoles
(pharmacology)
- PPAR alpha
(agonists)
- PPAR gamma
(agonists)
- RNA, Messenger
(biosynthesis)
- Sodium
(metabolism)
- Sodium-Potassium-Exchanging ATPase
(biosynthesis, metabolism)
- Thiazolidinediones
(pharmacology)
- Trans-Activation (Genetics)
|
