Cyclopropane xenolipids resemble monounsaturated fatty acids and modulate peroxisome proliferator-activated receptors

Cyclopropane fatty acids (CpFAs) are members of the mammalian lipidome, originating from the diet and gut microbial metabolism. Despite being fully saturated, conformational modeling of CpFAs from C12 to C24 in length revealed that they are bent lipids sharing structural similarities with monounsaturated fatty acids (MUFAs). We therefore hypothesized that CpFAs might share some bioactivities with MUFAs. We modeled and docked a total of 429 known and theoretical CpFAs, MUFAs and saturated lipids into peroxisome proliferator activated receptor (PPAR) α, δ, and γ nuclear receptor structures. CpFAs showed unique spatial binding patterns, especially with PPARδ. In vitro, several CpFAs bound PPARα and δ with potencies comparable to dietary MUFAs, while in 3T3-L1 preadipocytes they upregulated the PPARδ/γ target gene Angptl4, indicating downstream functional engagement. These findings suggest that CpFAs share some structural and functional aspects with MUFAs, and represent an underrecognized class of metabolically relevant food- and gut-derived lipids.