Effect of a novel non-thiazolidinedione peroxisome proliferator-activated receptor alpha/gamma agonist on glucose uptake.
OBJECTIVE
The effect of the benzopyran derivative T33, a novel non-thiazolidinedione agent, was studied on peroxisome proliferator-activated receptors (PPARs), insulin signalling and glucose uptake in adipocytes and skeletal muscle. We hypothesised that T33 could activate PPARgamma and exert a beneficial effect on insulin action on glucose uptake and lipid metabolism.


METHODS
Using a cell-based reporter gene assay, T33 was identified as a PPARalpha/gamma dual agonist, which activated human PPARgamma and PPARalpha with EC50 values of 19 and 148 nmol/l, respectively. The effect of T33 on glucose metabolism was studied in cultured 3T3-L1 adipocytes and L6 myotubes. In vivo effects of T33 on skeletal muscle were determined in ob/ob mice treated with 8 mg/kg T33. The effect of T33 on metabolic abnormalities was observed in diet-induced obese mice.


RESULTS
Exposure of 3T3-L1 adipocytes to T33 for 4 days increased basal and insulin-stimulated glucose uptake, with no effect noted in L6 myotubes. Treatment of ob/ob mice for 20 days with T33 normalised basal and insulin-stimulated glucose uptake and increased phosphorylation of Akt and p38 mitogen-activated protein kinase in skeletal muscle. In contrast, phosphorylation of AMP-activated protein kinase was unaltered. Moreover, T33 improved insulin sensitivity and lipid metabolism in diet-induced obese mice.


CONCLUSIONS
T33 is non-thiazolidinedione PPARalpha/gamma dual agonist which directly increases basal and insulin-stimulated glucose uptake in adipocytes and secondarily improves insulin action on insulin signalling and glucose metabolism in skeletal muscle from diabetic ob/ob mice.
Hu
X
X
Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Zu Chong Zhi Road 555, Shanghai 201203, China.
Feng
Y
Y
Liu
X
X
Zhao
X-F
XF
Yu
J-H
JH
Yang
Y-S
YS
Sydow-Bäckman
M
M
Hörling
J
J
Zierath
J R
JR
Leng
Y
Y
D016475:3T3 Cells; D000230:Adenocarcinoma; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D003374:Coumarins / Q000494:pharmacology*; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D003374:Coumarins; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; C523632:methyl 7-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)coumarin-7-carboxylate; D000077154:Rosiglitazone; D005947:Glucose