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


METHODS
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.


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
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.
Mittra
S
S
Ranbaxy Research Laboratories, New Drug Discovery Research, Gurgaon, Haryana, India.
Sangle
G
G
Tandon
R
R
Sharma
S
S
Roy
S
S
Khanna
V
V
Gupta
A
A
Sattigeri
J
J
Sharma
L
L
Priyadarsiny
P
P
Khattar
S K
SK
Bora
R S
RS
Saini
K S
KS
Bansal
V S
VS
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D004487:Edema / Q000139:chemically induced* / Q000473:pathology; D053503:Epithelial Sodium Channels / Q000096:biosynthesis; D004906:Erythrocyte Count; D005227:Fatty Acids / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006454:Hemoglobins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008815:Mice, Inbred Strains; D010080:Oxazoles / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D012333:RNA, Messenger / Q000096:biosynthesis; D000077154:Rosiglitazone; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000096:biosynthesis / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D015533:Transcriptional Activation
D001786:Blood Glucose; D053503:Epithelial Sodium Channels; D005227:Fatty Acids; D006454:Hemoglobins; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D005998:Glycine; C500085:muraglitazar