Peroxisome proliferator-activated receptors gamma and alpha agonists stimulate cardiac glucose uptake via activation of AMP-activated protein kinase.

Myocardial energy and glucose homeostasis are crucial for normal cardiac structure and function. Peroxisome proliferator-activated receptors (PPARs) play an important role in controlling transcriptional expression of key enzymes that are involved in glucose metabolism, and they have been demonstrated to significantly reduce tissue injury in cardiovascular diseases. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a sensor that maintains intracellular energy homeostasis and mediates a number of physiological signals. It has been reported that AMPK promotes glucose uptake. We hypothesize that PPAR gamma and alpha agonists may play a role in the regulation of glucose metabolism through AMPK. We tested this hypothesis by using isolated papillary muscles of rat hearts treated with PPAR gamma and alpha agonists, troglitazone and GW7647, respectively. Our results demonstrated that both troglitazone and GW7647 significantly stimulated 2-deoxyglucose uptake of cardiac muscles. Interestingly, both agonists stimulated phosphorylation of AMPK and its downstream protein target acetyl-CoA carboxylase. Endothelial nitric oxide synthase (eNOS) was also activated by both agonists. In addition, AMPK activator 5-amino-4-imidazole-1-beta-D-carboxamide ribofuranoside increased glucose uptake, while AMPK inhibitor compound C and NOS inhibitor, N(omega)-nitro-L-arginine, significantly blocked troglitazone- and GW7647-stimulated glucose uptake in cardiac muscles. There was also a reduction of glucose uptake with a marked decrease in AMPK and eNOS phosphorylation. In conclusion, both PPAR gamma and alpha activation play a role in the regulation of glucose uptake in cardiac muscles and this regulation is mediated by the AMPK and eNOS signaling pathways. (c) 2010 Elsevier Inc. All rights reserved.