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.
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: Richard W Nesto; David Bell; Robert O Bonow; Vivian Fonseca; Scott M Grundy; Edward S Horton; Martin Le Winter; Daniel Porte; Clay F Semenkovich; Sidney Smith; Lawrence H Young; Richard Kahn Journal: Circulation Date: 2003-12-09 Impact factor: 29.690
Authors: Thomas Harrity; Dennis Farrelly; Aaron Tieman; Cuixia Chu; Lori Kunselman; Liqun Gu; Randolph Ponticiello; Michael Cap; Fucheng Qu; Chunning Shao; Wei Wang; Hao Zhang; William Fenderson; Sean Chen; Pratik Devasthale; Yoon Jeon; Ramakrishna Seethala; Wen-Pin Yang; Jimmy Ren; Min Zhou; Denis Ryono; Scott Biller; Kasim A Mookhtiar; John Wetterau; Richard Gregg; Peter T Cheng; Narayanan Hariharan Journal: Diabetes Date: 2006-01 Impact factor: 9.461
Authors: Bronwyn D Hegarty; Stuart M Furler; Nicholas D Oakes; Edward W Kraegen; Gregory J Cooney Journal: Endocrinology Date: 2004-04-01 Impact factor: 4.736
Authors: M Revermann; A Mieth; L Popescu; A Paulke; M Wurglics; M Pellowska; A S Fischer; R Steri; T J Maier; R T Schermuly; G Geisslinger; M Schubert-Zsilavecz; R P Brandes; D Steinhilber Journal: Br J Pharmacol Date: 2011-08 Impact factor: 8.739