Dihydrocapsiate from Capsicum annuum inhibits adipogenesis and enhances glucose uptake via activation of PPARα and NRF2.

Capsinoids derived from Capsicum annuum have emerged as natural modulators of metabolic homeostasis. While capsiate is known to activate multiple nuclear receptors, its clinical utility is suspected by its inherent metabolic stability. In contrast, dihydrocapsiate (DHC) possesses a saturated side chain that confers greater metabolic stability, yet its specific pharmacological profile remains insufficiently characterized. To elucidate the DHC's metabolic effects and its underlying molecular mechanisms with a focus on glucose transport, adipocyte differentiation and nuclear receptor selectivity were investigated. In differentiated myocytes, DHC significantly upregulated glucose uptake, suggesting its potential role in improving peripheral insulin sensitivity. In adipocytes, DHC effectively antagonized rosiglitazone-induced adipogenic differentiation without modulating basal adipogenesis. These data indicate that DHC may mitigate the weight gain typically associated with PPARγ-targeted antidiabetic therapies. Transcriptional profiling revealed that DHC robustly induced NRF2 antioxidant signaling pathway and selectively activated PPARα while exerting negligible effects on PPARγ and LXR. The nuclear receptor-selective profile distinguishes DHC from the broader multi-nuclear receptor activation observed with capsiate. However, DHC was found to be similar to capsiate in enhancing AMPK phosphorylation. Owing to its enhanced metabolic stability and unique nuclear receptors' signature, DHC represents a promising natural alternative for the improved glucose uptake and selective adipogenesis. Hence it may play a significant role in management of metabolic syndrome and type2 diabetes.