Cannabinoids interact with more than the classical cannabinoid receptors CB1 and CB2. One important target is PPARγ, a nuclear receptor involved in metabolism, inflammation, insulin sensitivity and several disease-related pathways.

In this study, researchers examined how multiple Cannabis sativa cannabinoids bind to and activate PPARγ. The results showed that different cannabinoids can engage the receptor through multiple binding modes, with acidic cannabinoids such as THCA and CBDA showing particularly strong activity.

The findings help clarify another molecular pathway through which cannabis compounds may influence biological processes relevant to metabolic, inflammatory and other disorders.

“Introduction: Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor with broad therapeutic relevance across various pathologies, including type 2 diabetes, obesity, cancer, and inflammatory disorders. Cannabinoids are a class of terpene-phenolic compounds from Cannabis sativa L. that have been shown to act as partial agonists of PPARγ. Among them, the acidic forms Δ⁹-tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA) display higher potency than their decarboxylated counterp arts Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). Despite experimental evidence supporting direct PPARγ-cannabinoid interaction, the molecular determinants governing ligand recognition within the binding pocket have not yet been comprehensively investigated.

Methods: A combination of molecular docking and molecular dynamics simulations was employed to characterize the binding modes of THC, CBD, THCA, and CBDA within the PPARγ ligand-binding domain. Docking calculations were performed on a curated set of 70 PPARγ crystal structures co-crystallized with structurally diverse ligands, exploiting thus the conformational variability of the binding pocket. The best-ranked solutions were subjected to 500 ns MD simulations and evaluated on the basis of ligand stability, persistence of polar and aromatic-aromatic interactions with the receptor, and energetic contributions estimated by MM/GBSA. Three candidate binding modes per ligand were selected and their trajectories extended to 1,000 ns.

Results: All four cannabinoids yielded at least one stable binding mode at the microsecond timescale. The cannabinoids THCA and CBDA displayed a greater number of stable binding modes than THC and CBD, a result consistent with the higher potency previously reported for these compounds in experimental studies. This behavior may be attributable to the formation of salt bridges with basic residues in the binding pocket.

Conclusion: Our findings provide a structural framework for understanding cannabinoid recognition by PPARγ. The ability of these compounds to adopt multiple binding modes may contribute to their partial agonist profile, opening new avenues for the rational design of selective PPARγ modulators with improved therapeutic properties.”

https://pubmed.ncbi.nlm.nih.gov/42639023

“This work provides a foundation for future studies addressing the molecular basis of cannabinoid action on PPARγ.

Moreover, these findings could serve as a starting point to explore the allosteric mechanism by which these small lipophilic molecules influence receptor structure and dynamics.

Finally, the strategy described here may also be applied to determine the binding modes of these natural compounds in other members of the nuclear receptor family, including PPARα and PPARδ, as well as to investigate the binding modes of minor cannabinoids, such as cannabichromene and cannabigerol.”

https://www.frontiersin.org/journals/bioinformatics/articles/10.3389/fbinf.2026.1893303/full

THC and cannabis extracts may have important effects on obesity-related metabolic dysfunction. In this study, both THC and cannabis extracts reduced body weight and fat mass in diet-induced obese mice while improving abnormalities in adipose-tissue signaling. Cannabis extracts produced the strongest metabolic effects, more effectively normalizing adipokine expression and restoring glucose clearance to levels seen in lean mice, an effect not achieved by THC alone. The findings suggest that chronic cannabinoid exposure—particularly whole cannabis extracts—can improve glucose homeostasis, adipose function, and metabolic regulation in obesity.

“Diet-induced obesity (DIO) is associated with dysregulated adipoinsular axis and endocannabinoid system (eCBS) function. Acute cannabis consumption stimulates appetite; however, chronic consumption is paradoxically associated with lower prevalence of human obesity and type 2 diabetes.

We investigated the impact of chronic exposure to Δ⁹ tetrahydrocannabinol (THC) and cannabis extracts on DIO and glucose homeostasis in mice.

Male mice were fed a high-fat/sucrose diet or a low-fat/no-sucrose diet for 60 days. At day 30, mice were administered THC (5 mg/kg) or cannabis extracts matched for THC content daily for 30 days. We assessed adipocyte biology, glucose tolerance, insulin sensitivity, eCBS expression, body weight, food intake and motor activity. Roles for the eCBS in cannabis-induced changes in metabolic processes, including cellular bioenergetics, were analysed in 3T3-L1 adipocytes.

THC and extracts reduced body weight and fat mass in DIO mice, and reversed DIO-associated changes in expression of adipokines that regulate the adipoinsular axis. Extracts normalized expression of adipokines more effectively than THC. Notably, extracts – but not THC – normalized glucose clearance in DIO mice to levels found in lean mice. In addition, THC and extracts promoted anti-adipogenic effects and changes in energy metabolism in 3T3-L1 cells in a concentration-dependent manner.

These studies suggest that chronic cannabinoid exposure improves metabolic function and dysregulated glucose homeostasis in DIO by a mechanism that includes restoring impaired adipoinsular axis function.

KEY POINTS: Δ⁹ Tetrahydrocannabinol (Δ⁹THC) and cannabis extracts reduce body weight and fat mass in obese mice. Cannabis extracts, but not Δ⁹THC alone, improve glucose homeostasis in obese mice. Extracts more effectively normalize expression of components of the adipoinsular axis in obese mice. Δ⁹THC and extracts promote anti-adipogenic effects in 3T3-L1 cells. Δ⁹THC and extracts alter cellular bioenergetics in 3T3-L1 cells.”

https://pubmed.ncbi.nlm.nih.gov/42113966

“In conclusion, this study demonstrates that chronic cannabinoid exposure, particularly with cannabis extract, reduces body weight, improves glucose homeostasis and normalizes adipose tissue function in a mouse model of DIO. Our findings highlight the potential therapeutic value of cannabinoids in managing obesity and related metabolic disorders, though further research is needed to fully understand the underlying mechanisms and translate these findings into clinical applications.”

https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP290431