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.

Figure 1

(a) Relative quantitation of aP2 mRNA expression by rosiglitazone and muraglitazar as determined by semiquantitative RT-PCR. Confluent 3T3-L1 cells were incubated for 5 days with various concentrations of PPAR-γ ligands, rosiglitazone, muraglitazar or 0.1% DMSO (as vehicle control) and RNA was isolated as described under ‘Methods'. aP2 mRNA levels were normalized by endogenous 18S control. Data shown are means±s.d. of duplicate determinations. A representative bar graph is shown. In (b) mRNA expression of ACO after 14 days treatment with muraglitazar (10 mg kg⁻¹) and rosiglitazone (10 mg kg⁻¹); n=2.

Figure 2

mRNA expression of ENaCγ in db/db mice and C57BL/6 mice after 14 days treatment with muraglitazar (10 mg kg⁻¹) and rosiglitazone (10 mg kg⁻¹). ^**P<0.01 vs control; n=4.

Figure 3

Dose-dependent effect of muraglitazar on random glucose (a) and triglyceride levels (c). Effect of rosiglitazone and muraglitazar on random glucose (b) and triglyceride levels (d) after 14 days treatment in db/db mice. ^*P<0.05,^**P<0.01 vs control; ^##P<0.01 vs rosiglitazone group; n=12 per group.

Figure 4

Weight gain in db/db mice. (a) Effect of rosiglitazone (10 mg kg⁻¹) and muraglitazar (10 mg kg⁻¹) on body weight change after a 14-day treatment. (b) Dose–response for muraglitazar on body weight change in db/db mice after a 14-day treatment. ^*P<0.5; ^**P<0.01 vs control; ^##P<0.01 vs rosiglitazone group; n=8 per group.

Figure 5

Effect of rosiglitazone (10 mg kg⁻¹), muraglitazar (10 mg kg⁻¹) and fenofibrate (100 mg kg⁻¹) on liver weight (shown as % body weight) after 14-day treatment in db/db mice. ^*P<0.05 vs control; n=6 per group.

Figure 6

Haemodilution parameters after 14 days treatment with muraglitazar (10 mg kg⁻¹) and rosiglitazone (10 mg kg⁻¹). Mean (±s.e.m.) values for RBC count (a), haemoglobin (Hb, b) and % haematocrit (%HCT, c) are shown. ^*P<0.05 vs control; n=8 per group.