The Many Facets of PPAR-γ Agonism in Obesity and Associated Comorbidities: Benefits, Risks, Challenges, and Future Directions

Obesity is strongly associated with cardiometabolic disorders and certain malignancies, emphasizing the key role of adipose tissue in human health. While incretin mimetics have shown effectiveness in glycemic control and weight loss, a holistic strategy for combating obesity and associated comorbidities remains elusive. This review explores peroxisome proliferator-activated receptor gamma (PPAR-γ) agonism as a potential therapeutic approach, highlighting its benefits, addressing its limitations, and outlining future directions for developing more effective treatment strategies.

Both natural and synthetic PPAR-γ agonists hold significant therapeutic potential as insulin sensitizers, while also demonstrating anti-inflammatory properties and playing a critical role in regulating lipid metabolism. However, the clinical use of natural agonists is limited by poor bioavailability, while synthetic agents like thiazolidinediones are associated with adverse effects, including fluid retention, weight gain, and bone loss. Current research is focused on developing modified, tissue-specific PPAR-γ agonists, as well as dual PPAR-α/PPAR-γ agonists, with improved safety profiles to mitigate these side effects. Nanotechnology-based drug delivery systems also hold promise for enhancing bioavailability and therapeutic efficacy. Furthermore, the transformative potential of machine learning and artificial intelligence offers opportunities to accelerate advancements in this field.

PPAR-γ agonists exhibit significant potential in addressing metabolic syndrome, cardiovascular disease, and cancer. However, their clinical use is restricted by safety concerns and suboptimal pharmacokinetics. Innovations in modified PPAR-γ agonists, nanotechnology-based delivery systems, and computational tools hold promise for creating safer and more effective therapeutic options for obesity and its associated disorders.