Island populations repeatedly evolve extreme body sizes, but the genomic basis of this pattern remains largely unknown. To understand how organisms on islands evolve gigantism, we compared genome-wide patterns of gene expression in Gough Island mice, the largest wild house mice in the world, and mainland mice from the WSB/EiJ wild-derived inbred strain. We used RNASeq to quantify differential gene expression in three key metabolic organs: gonadal adipose depot, hypothalamus and liver. Between

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... 000 and 8,800 genes were significantly differentially expressed across the evaluated organs, representing between 20 and 50% of detected transcripts, with 20% or more of differentially expressed transcripts in each organ exhibiting expression fold changes of at least 2X. A minimum of 73 candidate genes for extreme size evolution, including Irs1 and Lrp1, were identified by considering differential expression jointly with other data sets: (i) genomic positions of published quantitative trait loci for body weight and growth rate; (ii) whole genome sequencing of 16 wild-caught Gough Island mice that revealed fixed single nucleotide differences between the strains; (iii) publicly available tissue-specific regulatory elements. Additionally, patterns of differential expression across three time points in the liver revealed that Arid5b potentially regulates hundreds of genes. Functional enrichment analyses pointed to cell cycling, mitochondrial function, signaling pathways, inflammatory response, and nutrient metabolism as potential causes of weight accumulation in Gough Island mice. Collectively, our results indicate that extensive gene regulatory evolution in metabolic organs accompanied the rapid evolution of gigantism during the short time house mice have inhabited Gough Island.