Cinnamaldehyde Contributes to Insulin Sensitivity by Activating PPARδ, PPARγ, and RXR

Cinnamon is a traditional folk herb used in Asia and has been reported to have antidiabetic effects. Our previous study showed that cinnamaldehyde (CA), a major effective compound in cinnamon, exhibited hypoglycemic and hypolipidemic effects together in db/db mice. The aim of the present study was to elucidate the molecular mechanisms of the effects of CA on the transcriptional activities of three peroxisome proliferator-activated receptors, (PPAR) alpha,delta, and gamma. We studied the effects of CA through a transient expression assay with TSA201 cells, derivatives of human embryonic kidney cell line (HEK293). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was also performed to evaluate mRNA expression levels. We show here that CA induced PPAR delta, PPAR gamma and retinoid X receptor (RXR) activation. CA may activate PPAR gamma in a different manner than pioglitazone, as CA selectively stimulated PPAR gamma S342A mutant while pioglitazone did not. In addition, CA and L-165041 had a synergistic effect on PPAR delta activation. To gather the biological evidence that CA increases PPARs transcription, we further measured the expressions of PPAR delta and PPAR gamma target genes in 3T3-L1 adipocytes. The data showed CA induced the expression of PPAR delta and PPAR gamma target genes, namely aP2 and CD36, in differentiated adipocytes. As a result, PPAR delta, PPAR gamma and their heterodimeric partner RXR appear to play a part in the CA action in the target tissues, thereby enhancing insulin sensitivity and fatty acid beta-oxidation and energy uncoupling in skeletal muscle and adipose tissue.