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Abstract Background Deregulation in lipid metabolism leads to the onset of hepatic steatosis while at subsequent stages of disease development, the induction of inflammation, marks the transition of steatosis to non-alcoholic steatohepatitis. While differential gene expression unveils individual genes that are deregulated at different stages of disease development, how the whole transcriptome is deregulated in steatosis remains unclear. Methods Using outbred deer mice fed with high fat as a model, we assessed the correlation of each transcript with every other transcript in the transcriptome. The onset of steatosis in the liver was also evaluated histologically. Results Our results indicate that transcriptional reprogramming directing immune cell engagement proceeds robustly, even in the absence of histologically detectable steatosis, following administration of high fat diet. In the liver transcriptomes of animals with steatosis, a preference for the engagement of regulators of T cell activation and myeloid leukocyte differentiation was also recorded as opposed to the steatosis-free livers at which non-specific lymphocytic activation was seen. As compared to controls, in the animals with steatosis, transcriptome was subjected to more widespread reorganization while in the animals without steatosis, reorganization was less extensive. Comparison of the steatosis and non-steatosis livers showed high retention of coordination suggesting that diet supersedes pathology in shaping the transcriptome’s profile. Conclusions This highly versatile strategy suggests that the molecular changes inducing inflammation proceed robustly even before any evidence of steatohepatitis is recorded, either histologically or by differential expression analysis. 

ABSTRACT The unfolded protein response (UPR) is involved in the pathogenesis of metabolic disorders, yet whether variations in the UPR among individuals influence the propensity for metabolic disease remains unexplored. Using outbred deer mice as a model, we show that the intensity of UPR in fibroblasts isolated early in life predicts the extent of body weight gain after high-fat diet (HFD) administration. Contrary to those with intense UPR, animals with moderate UPR in fibroblasts and therefore displaying compromised stress resolution did not gain body weight but developed inflammation, especially in the skin, after HFD administration. Fibroblasts emerged as potent modifiers of this differential responsiveness to HFD, as indicated by the comparison of the UPR profiles of fibroblasts responding to fatty acids in vitro, by correlation analyses between UPR and proinflammatory cytokine-associated transcriptomes, and by BiP (also known as HSPA5) immunolocalization in skin lesions from animals receiving HFD. These results suggest that the UPR operates as a modifier of an individual's propensity for body weight gain in a manner that, at least in part, involves the regulation of an inflammatory response by skin fibroblasts. This article has an associated First Person interview with the first author of the paper. 

Abstract Background Deer mice (genus Peromyscus ) are the most common rodents in North America. Despite the availability of reference genomes for some species, a comprehensive database of polymorphisms, especially in those maintained as living stocks and distributed to academic investigators, is missing. In the present study we surveyed two populations of P. maniculatus that are maintained at the Peromyscus Genetic Stock Center (PGSC) for polymorphisms across their 2.5 × 10 9 bp genome. Results High density of variation was identified, corresponding to one SNP every 55 bp for the high altitude stock (SM2) or 207 bp for the low altitude stock (BW) using snpEff (v4.3). Indels were detected every 1157 bp for BW or 311 bp for SM2. The average Watterson estimator for the BW and SM2 populations is 248813.70388 and 869071.7671 respectively. Some differences in the distribution of missense, nonsense and silent mutations were identified between the stocks, as well as polymorphisms in genes associated with inflammation (NFATC2), hypoxia (HIF1a) and cholesterol metabolism (INSIG1) and may possess value in modeling pathology. Conclusions This genomic resource, in combination with the availability of P. maniculatus from the PGSC, is expected to promote genetic and genomic studies with this animal model.