Aims/hypothesis
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 PPARγ and exert a beneficial effect on insulin action on glucose uptake and lipid metabolism.
Materials and methods
Using a cell-based reporter gene assay, T33 was identified as a PPARα/γ dual agonist, which activated human PPARγ and PPARα
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/interpretation
T33 is non-thiazolidinedione PPARα/γ 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.
Keywords Adipose tissue - Diet-induced obesity - Glucose uptake - Insulin sensitivity - Insulin signalling - Peroxisome proliferator-activated receptors - Skeletal muscle - Thiazolidinediones