Synthetic and natural Peroxisome Proliferator-Activated Receptor (PPAR) agonists as candidates for the therapy of the metabolic syndrome

ABSTRACT

Introduction: Peroxisome proliferator-activated receptors (PPARs) are the molecular targets of hypolipidemic and insulin-sensitizing drugs and implicated in a multitude of processes that fine-tune the functions of all organs in vertebrates. As transcription factors they sense endogenous and exogenous lipid signaling molecules and convert these signals into intricate gene responses that impact health and disease. The PPARs act as modulators of cellular, organ, and systemic processes, such as lipid and carbohydrate metabolism, making them valuable for understanding body homeostasis influenced by nutrition and exercise.

Areas covered: This review concentrates on synthetic and natural PPAR ligands and how they have helped reveal many aspects of the transcriptional control of complex processes important in health.

Expert opinion: The three PPARs have complementary roles in the fine-tuning of most fundamental body functions, especially energy metabolism. Understanding their inter-relatedness using ligands that simultaneously modulate the activity of more than one of these receptors is a major goal. This approach may provide essential knowledge for the development of dual or pan-PPAR agonists or antagonists as potential new health-promoting agents and for nutritional approaches to prevent metabolic diseases.

KEYWORDS:

• Agonists
• insulin resistance
• lipid metabolism
• metabolic syndrome
• PPARs
• type 2 diabetes
• phytochemicals

Article highlights

• PPARs are transcription factors activated by fatty acids and fatty acid derivatives with a broad range of cellular (proliferation, differentiation) and metabolic regulatory functions.

• PPARs convert lipid signaling into appropriate gene responses, influencing cellular and whole-organism energy homeostasis.

• Ligands specific to each of the three PPARs have contributed to unveiling their respective functions.

• Dual and pan agonists help explore the complementary roles of PPARs.

• Natural plant-derived molecules represent a rich source of PPAR ligands and possible lead compounds for the development of therapeutic agents.

• Dual and pan agonists are promising leads for the development of safer drugs.

• PPARs are key mediators of the health effects of nutrition and exercise.

This box summarizes key points contained in the article.

Acknowledgments

The authors would like to acknowledge the language editing services of San Francisco Edit, Mill Valley, California. They would like to thank Rachel Tee for her help during the preparation of the manuscript.

Declaration of interest

W. Wahli is a consultant for Zydus Cadila Healthcare Limited, Ahmedabad, India. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was funded by Lee Kong Chian School of Medicine, Nanyang Technological University (Start-Up Grant) and the Ministry of Education, Singapore [2015-T1-001-034].