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

Br J Pharmacol. 2007 Feb;150(4):480-7. doi: 10.1038/sj.bjp.0707000. Epub 2007 Jan 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects
  • Adipogenesis / drug effects*
  • Animals
  • Blood Glucose / metabolism
  • Body Weight / drug effects*
  • Cell Differentiation / drug effects
  • Edema / chemically induced*
  • Edema / pathology
  • Epithelial Sodium Channels / biosynthesis
  • Erythrocyte Count
  • Fatty Acids / metabolism
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • Hemoglobins / metabolism
  • Kidney / drug effects
  • Kidney / enzymology
  • Mice
  • Mice, Inbred Strains
  • Oxazoles / pharmacology*
  • PPAR alpha / agonists*
  • PPAR gamma / agonists*
  • RNA, Messenger / biosynthesis
  • Rosiglitazone
  • Sodium / metabolism
  • Sodium-Potassium-Exchanging ATPase / biosynthesis
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Thiazolidinediones / pharmacology
  • Transcriptional Activation

Substances

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