Objective Obesity is influenced by genetic and environmental factors. Despite the success of human genome‐wide association studies, the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify the genetic loci underlying obesity and related morphometric and metabolic traits. Methods This study measured obesity‐relevant traits, including body weight, body length, BMI, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat genome‐wide association study to date. Genetic loci were identified using a linear mixed model to account for the complex family relationships of the HS and using covariates to account for differences among the three phenotyping centers. Results This study identified 32 independent loci, several of which contained only a single gene (e.g., Epha5, Nrg1, Klhl14) or obvious candidate genes (e.g., Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity‐related traits, and there was extensive pleiotropy at individual loci. Conclusions This study demonstrates the utility of HS rats for investigating the genetics of obesity‐related traits across institutions and identify several candidate genes for future functional testing.

Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.

Obesity is a global health crisis that is influenced by both genetic and environmental factors.Rodent model organisms can be used to understand the biological and genetic basis of obesity and related morphological traits. A major advantage of model organisms is that they can be studied under uniform environmental conditions, thus reducing the complex role of environment and gene by environment interactions. Furthermore, fat pads and other tissues can be dissected and weighed, so that their role in determining body weight can be precisely defined. Highly recombinant populations allow for genetic fine-mapping of complex traits, greatly reducing the number of plausible candidate genes. We performed the largest rat GWAS ever undertaken, using 3,173 male and female adult N/NIH heterogeneous stock (HS) rats, which were created by mixing 8 inbred strains. We identified 31 independent loci for body weight, body length, body mass index, fat pad weight (retroperitoneal, epididymal, and parametrial), and fasting glucose.We observed strong evidence of pleotropic effects across multiple phenotypes. Three loci contained only a single gene (Epha5, Nrg1 and Klhl14), whereas others were larger and contained many genes. We replicated a locus containing Prlhr, and a second locus containing Adcy3, which we had previously identified in a smaller HS rat study. Finally, by subsampling our dataset, we showed an exponential growth of significant loci as sample size increased towards 3,173. Our results demonstrate the potential for rodent studies to add to our understanding of the molecular genetic factors that contribute to obesity-relevant traits and emphasize the importance of sample size.

Many personality traits are influenced by genetic factors. Rodents models provide an efficient system for analyzing genetic contribution to these traits. Using 1,246 adolescent heterogeneous stock (HS) male and female rats, we conducted a genome-wide association study (GWAS) of behaviors measured in an open field, including locomotion, novel object interaction, and social interaction. We identified 30 genome-wide significant quantitative trait loci (QTL). Using multiple criteria, including the presence of high impact genomic variants and co-localization of cis-eQTL, we identified 17 candidate genes (Adarb2, Ankrd26, Cacna1c, Cacng4, Clock, Ctu2, Cyp26b1, Dnah9, Gda, Grxcr1, Eva1a, Fam114a1, Kcnj9, Mlf2, Rab27b, Sec11a, and Ube2h) for these traits. Many of these genes have been implicated by human GWAS of various psychiatric or drug abuse related traits. In addition, there are other candidate genes that likely represent novel findings that can be the catalyst for future molecular and genetic insights into human psychiatric diseases. Together, these findings provide strong support for the use of the HS population to study psychiatric disorders.

In this study, we investigated whether intravenously self-administered nicotine with menthol and audiovisual cue modulates nicotine-metabolizing CYP2A6, oxidative stress modulators, and cytokines/chemokines in plasma extracellular vesicles (EVs) in rats. We assigned rats to self-administered nicotine with: (a) audiovisual cue (AV), (b) menthol, and (c) menthol and AV cue. We found increased levels of CD9 in plasma EVs after self-administered nicotine with menthol and AV cue. Moreover, expression of CYP2A6 in plasma EVs was significantly increased after self-administered nicotine in response to menthol and AV cue. However, despite an upward trend on SOD1 and catalase, increase was not found to be statistically significant, while total antioxidant capacity was found to be significantly increased in plasma and plasma EVs obtained after self-administered nicotine with menthol and AV cue. Among cytokine and chemokine profiling, we found a significant increase in the levels of MCP-1 after self-administered nicotine with menthol and AV cue and complete packaging of IL-1β in EVs. Taken together, the study provides evidence that nicotine in response to menthol and AV cues can package altered levels of CYP2A6, and cytokines/chemokines in plasma EVs that may contribute to cell–cell communication, nicotine metabolism, and inflammation upon cigarette smoking.