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

Abstract

Background and purpose: Muraglitazar, a dual PPARa/g 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 PPARa/g receptors was characterized using transactivation assays. Preadipocyte differentiation, expression of genes for adipogenesis (aP2), fatty acid oxidation (ACO) and sodium reabsorption (ENaCg and Na þ , K þ -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 À1 ) 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 À1 ). 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 ENaCg and Na þ , K þ -ATPase in kidneys was upregulated 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.

Inhibitory effect of evodiamine alone and in combination with rosiglitazone on in vitro adipocyte differentiation and in vivo obesity related to diabetes

“…Earlier studies using db/db mice showed that body weight increased significantly as the result of rosi treatment at a dosage of 10 mg kg À1 per day, 49,50 thereby indicating that rosi exerts an undesirable effect on body weight. According to the results of our in vivo study, evo evidenced an apparent antiobesity effect on body weight and the ratios of EWAT and liver weight/body weight in both cases of the absence and presence of rosi.…”

A Nonthiazolidinedione Peroxisome Proliferator-Activated Receptor α/γ Dual Agonist CG301360 Alleviates Insulin Resistance and Lipid Dysregulation in db/db Mice

“…One of the side effects of TZDs is tissue damage, which often results from fluid retention and edema (Hirsch et al, 1999;Tang et al, 2003;Mittra et al, 2007). Although some TZDs induce liver failure (Watkins and Whitcomb, 1998;Hirsch et al, 1999;Al-Salman et al, 2000), CG301360 slightly but substantially decreased the level of ALT and AST in db/db mice.…”

“…In the current study, we demonstrate that this novel PPAR␣/␥ dual agonist effectively and selectively activates PPAR␣ and PPAR␥ and shows favorable effects on insulin sensitivity and lipid metabolism in db/db mice. Unlike many previous PPAR␣/␥ dual agonists (Hellmold et al, 2007;Mittra et al, 2007), CG301360 moderately activates PPAR␣ and PPAR␥. Furthermore, given that CG301360 action may not be primarily mediated through PPAR␦ propose that CG301360 might be free from PPAR␦-mediated side effects.…”

“…However, side effects of PPAR␣/␥ dual agonists still make them unsuitable for treatment of obesity and insulin resistance (Hellmold et al, 2007;Mittra et al, 2007;Tannehill-Gregg et al, 2007). In this regard, the failure of former PPAR␣/␥ dual agonists prompted us to develop novel PPAR␣/␥ dual agonists without (or with less) deleterious effects by screening different backbone structures of PPAR ligands.…”

“…However, recently identified PPAR␣/␥ dual agonists were ineffective because of undesirable side effects during preclinical or clinical trials. For example, muraglitazar, a synthetic PPAR␣/␥ dual agonist, was aborted during clinical trials because of increased mortality, fluid retention, edema, and cancer (Mittra et al, 2007;Tannehill-Gregg et al, 2007), and tesaglitazar was reported to cause fibrosarcoma in subcutaneous tissues (Hellmold et al, 2007). Furthermore, it has recently been reported that several types of TZDs induce tissue toxicity (Lloyd et al, 2002;Nissen and Wolski, 2007).…”