Increase in weight induced by muraglitazar, a dual PPARalpha/gamma agonist, in db/db mice: adipogenesis/or oedema?

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
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 150 Issue 4 Pg. 480-7 (Feb 2007) ISSN: 0007-1188 [Print] England
• PMID: 17211457 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Epithelial Sodium Channels
• Fatty Acids
• Hemoglobins
• Oxazoles
• PPAR alpha
• PPAR gamma
• RNA, Messenger
• Thiazolidinediones
• Rosiglitazone
• Sodium
• Sodium-Potassium-Exchanging ATPase
• Glycine
• muraglitazar

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 Channels (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)
• Rosiglitazone
• Sodium (metabolism)
• Sodium-Potassium-Exchanging ATPase (biosynthesis, metabolism)
• Thiazolidinediones (pharmacology)
• Transcriptional Activation