Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) as a Target for Concurrent Management of Diabetes and Obesity-Related Cancer

Abstract

Background: Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear receptor superfamily of ligand-inducible transcription factors that regulate adipogenesis, lipid metabolism, cell proliferation, inflammation and insulin sensitization. Abnormalities in PPARγ signaling have been associated with obesity, diabetes and cancer. The use of agonists to manage these diseases has been limited by their side effects. Accordingly, dual or pan agonists targeting the PPARα or PPARα and PPARδ, respectively, in addition to the PPARγ have been developed to overcome these side effects. This review details the shared PPARγ-dependent mechanisms between obesity-related cancers and diabetes and their potential therapeutic values.

Method: We performed a systematic literature search through pubmed, Scopus and google scholar for articles on PPARγ-dependent signaling in diabetes or cancer.

Results: There is growing co-occurrence of obesity-related cancers and diabetes, necessitating the use of effective therapies with the least amount of side effects for concurrent management of these diseases, by targeting potentially shared PPARγ-dependent mechanisms including abnormalities of the wnt/β-catenin, lysosomal acid lipase, inflammatory and cell cycle pathways, and the plasminogen activator system. Taking advantage of the multiple docking sites of the PPARγ and the pleiotropic nature of its signaling, structure-activity relationship and molecular docking studies have provided insights into designer PPARγ agonists or dual PPARα/γ agonists that modulate PPARγ signaling and negate side effects of full PPARγ agonists.

Conclusion: Effective therapies, possibly devoid of side effects, for concurrent management of obesity-related cancers and diabetes can be developed through diligent structure-activity and molecular docking studies.

Keywords: Cancer; Wnt/β-catenin signaling; diabetes; inflammation; lysosomal acid lipase; peroxisome proliferator activated receptor gamma; plasminogen activator inhibitor-1; thiazolidinedione.