Beta-Caryophyllene (BCP) Modulating the Endocannabinoid System and PPARγ to Combat Metabolic Dysregulation: A Narrative Review.

Abstract

Metabolic diseases are characterized by disruptions in normal metabolic processes and are often caused by genetic, environmental, or lifestyle-related factors. These conditions, including obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome, and dyslipidemia, are associated with impaired regulation of glucose and lipid metabolism, chronic inflammation, and insulin resistance. Several studies have also shown that metabolic diseases cause the body to experience a state of dysregulation, characterized by impaired insulin signaling, chronic low-grade inflammation, mitochondrial dysfunction, and abnormal lipid and glucose homeostasis. This review summarizes current research on therapeutic strategies for modulating the molecular pathways involved in metabolic diseases. The primary focus is on the use of beta (β)-caryophyllene (BCP), which has demonstrated therapeutic potential in treatment through various molecular mechanisms involving activation of the endocannabinoid system and PPAR-γ receptors, either directly or indirectly. Crucially, BCP exerts its lipid-lowering and insulin-sensitizing effects by activating the AMPK/SIRT1 signaling pathways and inhibiting HMG-CoA reductase. Evidence from animal studies suggests that BCP reduces oxidative stress and systemic inflammation by lowering the levels of pro-inflammatory cytokines such as TNF-α and IL-6, while improving the expression of adiponectin and leptin. Unlike previous literature that predominantly focuses on isolated cellular pathways, the novelty of this review lies in its comprehensive integration of BCP's pharmacodynamics with its pharmacokinetic (ADME) limitations. By explicitly addressing translational hurdles-such as BCP's extensive first-pass metabolism and the need for advanced self-emulsifying delivery systems (SEDDS)-this work provides a uniquely balanced perspective. A comprehensive synthesis of BCP's molecular mechanisms in metabolic diseases is crucial for exploring its potential as a safer, effective complementary therapy. Given its unique mechanism of action and safety profile, BCP is a promising candidate for further clinical investigation. This review highlights the importance of exploring BCP as a complementary approach for managing metabolic health.