Cyclopropane FAs (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 Show more
Cyclopropane FAs (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 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 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, whereas in 3T3-L1 preadipocytes, they upregulated the pan-PPAR target gene Angptl4, indicating downstream functional engagement. These findings suggest that CpFAs share some structural and functional aspects with MUFAs and represent an under-recognized class of metabolically relevant food- and gut-derived lipids. Show less
In a screen for genes that affect the metabolic response to high-fat diet (HFD), we selected one line of N-ethyl-N-nitrosourea (ENU)-mutagenized mice, Jll, with dominantly inherited resistance to diet Show more
In a screen for genes that affect the metabolic response to high-fat diet (HFD), we selected one line of N-ethyl-N-nitrosourea (ENU)-mutagenized mice, Jll, with dominantly inherited resistance to diet-induced obesity (DIO). Mutant animals had dramatically reduced body weight and fat mass, and low basal insulin and glucose levels relative to unaffected controls. Both white adipose tissue (WAT) and brown adipose tissue (BAT) depots were smaller in mutant animals. Mutant animals fed a HFD gained only slightly more weight than animals fed regular chow, and were protected from hepatic lipid accumulation. The phenotype was genetically linked to a 5.7-Mb interval on chromosome 12, and sequencing of the entire interval identified a single coding mutation, predicted to cause a methionine-to-isoleucine substitution at position 279 of the Adcy3 protein (Adcy3M279I, henceforth referred to as Adcy3Jll). The mutant protein is hyperactive, possibly constitutively so, producing elevated levels of cyclic AMP in a cell-based assay. These mice demonstrate that increased Adcy3 activity robustly protect animals from diet-induced metabolic derangements. Show less