Phloretin and phloridzin improve insulin sensitivity and enhance glucose uptake by subverting PPARγ/Cdk5 interaction in differentiated adipocytes

Abstract Activators of peroxisome proliferator-activated receptor-γ (PPARγ agonists) are therapeutically promising candidates against insulin resistance and hyperglycemia. Synthetic PPARγ agonists are known to effectively enhance insulin sensitivity, but these are also associated with adverse side-effects and rising cost of treatment. Therefore, natural PPARγ targeting ligands are desirable alternatives for the management of insulin resistance associated with type 2 diabetes. Phloretin (PT) and Phloridzin (PZ) are predominant apple phenolics, which are recognized for their various pharmacological functions. The present study assessed the potential of PT and PZ in modulating insulin sensitivity and glucose uptake by inhibiting Cdk5 activation and corresponding PPARγ phosphorylation in differentiated 3T3L1 cells. In silico docking and subsequent validation using 3T3L1 cells revealed that PT and PZ not only block the ser273 site of PPARγ, but also inhibit the activation of Cdk5 itself, thereby indicating their potent PPARγ regulatory attributes. Corroborating this, application of PT and PZ significantly enhanced the accumulation of cellular triglycerides as well as expression of insulin-sensitizing genes in adipocytes ultimately resulting in improved glucose uptake. Taken together, the present study reports that PT and PZ inhibit Cdk5 activation, which could be directly influencing the apparent PPARγ inhibition at ser273, ultimately resulting in improved insulin sensitivity and glucose uptake.