Combined effects of genetic background and diet on mouse metabolism and gene expression

In humans, dietary patterns impact weight and metabolism differentially across individuals. To uncover genetic determinants for differential dietary effects, we subjected four genetically diverse mouse strains to humanized diets (American, Mediterranean, vegetarian, and vegan) with similar macronutrient composition, and performed body weight, metabolic parameter, and RNA-seq analysis. We observed pronounced diet- and strain-dependent effects on weight, and triglyceride and insulin levels. Differences in fat mass, adipose tissue and skeletal muscle glucose uptake, and gene expression changes in most tissues were strain-dependent. In visceral adipose tissue ~400 genes responded to diet in a strain-dependent manner, many of them in metabolite transport and lipid metabolism pathways and several previously identified to modify diet effects in humans. Thus, genetic background profoundly impacts metabolism, and dietary patterns modify effects. This study paves the way for future mechanistic investigations into strain-diet interactions in mice and translation to precision nutrition in humans. Overall design: We obtained four strains of 12 week old male mice (A/J, DBA/2J, C57BL/6J, SJL) and fed them mouse versions of four populat human diets (American, Mediterranean, vegetarian, vegan) for 6 weeks. Using two mice of each strain and diet combination at 18 weeks of age, we harvested metabolic tissues (liver, quadriceps muscle, brown adipose (BAT), subcutaneous adipose (SAT), and visceral adipose (VAT)) and isolated mature RNA species.We sequenced them using the NovaSeq6000 S4 (150bp PE) with the TruSeq Stranded mRNA Library Prep Kit. We obtained > 50M total reads per sample, >25M read1 and read2. Processed data QC using fastQC, adapters removed with trimGalore, alignment to GRCm39 using hisat2 with relaxed mismatch penality for non-C57BL/6J mice. Reads quantified using ht-seq with fractional alignment.