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

Background and purpose:

Muraglitazar, a dual PPARα/γ 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 PPARα/γ receptors was characterized using transactivation assays. Pre‐adipocyte differentiation, expression of genes for adipogenesis (aP2), fatty acid oxidation (ACO) and sodium reabsorption (ENaCγ 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 ENaCγ 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.

DOI: 10.1038/sj.bjp.0707000

View this article

• Full article (html)
• Enhanced article (html)
• PDF
• References