Background/objectives: Both genetic and dietary factors contribute to the metabolic syndrome (MetS) in humans and animal models. Characterizing their individual roles as well as relationships among these factors is critical for understanding MetS pathogenesis and developing effective therapies. By studying phenotypic responsiveness to high-risk versus control diet in two inbred mouse strains and their derivatives, we estimated the relative contributions of diet and genetic background to MetS, characterized strain-specific combinations of MetS conditions, and tested genetic and phenotypic complexity on a single substituted chromosome.

Methods: Ten measures of metabolic health were assessed in susceptible C57BL/6 J and resistant A/J male mice fed either a control or a high-fat, high-sucrose (HFHS) diet, permitting estimates of the relative influences of strain, diet and strain-diet interactions for each trait. The same traits were measured in a panel of C57BL/6 J (B6)-Chr(A/J) chromosome substitution strains (CSSs) fed the HFHS diet, followed by characterization of interstrain relationships, covariation among metabolic traits and quantitative trait loci (QTLs) on Chromosome 10.

Results: We identified significant genetic contributions to nine of ten metabolic traits and significant dietary influence on eight. Significant strain-diet interaction effects were detected for four traits. Although a range of HFHS-induced phenotypes were observed among the CSSs, significant associations were detected among all traits but one. Strains were grouped into three clusters based on overall phenotype and specific CSSs were identified with distinct and reproducible trait combinations. Finally, several Chr10 regions were shown to control the severity of MetS conditions.

Conclusions: Generally strong genetic and dietary effects validate these CSSs as a multifactorial model of MetS. Although traits tended to segregate together, considerable phenotypic heterogeneity suggests that underlying genetic factors influence their co-occurrence and severity. Identification of multiple QTLs within and among strains highlights both the complexity of genetically regulated, diet-induced MetS and the ability of CSSs to prioritize candidate loci for mechanistic studies.