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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. 

DNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how stress factors impact aging. Deer mice (Peromyscus) are long-living rodents that have emerged as an informative model to study aging, adaptation to extreme environments, and monogamous behavior. In the present study, we have undertaken an exhaustive, genome-wide analysis of DNA methylation inPeromyscus, spanning different species, stocks, sexes, tissues, and age cohorts. We describe DNA methylation-based estimators of age for different species of deer mice based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for deer mice was trained on 3 tissues (tail, liver, and brain). Two human-Peromyscusclocks accurately measure age and relative age, respectively. We present CpGs and enriched pathways that relate to different conditions such as chronological age, high altitude, and monogamous behavior. Overall, this study provides a first step towards studying the epigenetic correlates of monogamous behavior and adaptation to high altitude inPeromyscus. The human-Peromyscusepigenetic clocks are expected to provide a significant boost to the attractiveness ofPeromyscusas a biological model.

 

People’s social interactions could influence their risk of developing various diseases, including cancer, according to population-level studies. In particular, studies have identified a so-called widowhood effect where a person’s risk of disease increases following the loss of a spouse. However, the cause of the widowhood effect remains debatable, as it can be difficult to separate the impact of lifestyle changes from biological changes in the individual following bereavement. It is not possible to use laboratory mice to identify a causal biological mechanism, because they do not form long-term relationships with a single partner (pair bonds). However, several species of deer mouse form pair bonds, and suffer from anxiety and stress if these bonds are broken. Naderi et al. used these mice to study the widowhood effect on the risk of developing cancer. First, Naderi et al. grew human lung cancer cells in blood serum taken from mice that were either in a pair bond or had been separated from their partner. The cancer cells grown in the blood of mice with disrupted pair bonds changed size and shape, indicating that these mice were more likely to develop cancer. This effect was not observed when the cells were grown in the blood of bonded deer mice or of another deer mouse species that does not form pair bonds. Naderi et al. also found that the activity of genes involved in the cancer cells’ ability to spread and to stick together was different in pair-bonded mice and in pair-separated mice. Next, Naderi et al. implanted lung cancer cells into the deer mice to study their effects on live animals. When cancer cells from the deer mice were transplanted into laboratory mice with a weakened immune system, the cells taken from pair-bonded deer mice were less likely to grow than the cells from deer mice with disrupted pair bonds. This suggests that the protective effects of pair bonding persist even after removal from the original mouse. These results provide evidence for a biological mechanism of the widowhood effect, where social experiences can alter gene activity relating to cancer growth. In the future, it will be important to determine whether the same applies to humans, and to find out if there are ways to mimic the effects of long-term bonds to improve cancer prognoses.