Biology subjects

Seshie, O.

Publications and source records attributed to Seshie, O..

4 recordsLinked to original sources

bioRxiv2023

Changes in Environmental Stress over COVID-19 Pandemic Likely Contributed to Failure to Replicate Adiposity Phenotype Associated with Krtcap3

We previously identified Keratinocyte-associated protein 3, Krtcap3, as an obesity-related gene in female rats where a whole-body Krtcap3 knock-out (KO) led to increased adiposity compared to wild-type (WT) controls when fed a high-fat diet (HFD). We sought to replicate this work to better understand the function of Krtcap3 but were unable to reproduce the adiposity phenotype. In the current work, WT female rats ate more compared to WT in the prior study, with corresponding increases in body weight and fat mass, while there were no changes in these measures in KO females between the studies. The prior study was conducted before the COVID-19 pandemic, while the current study started after initial lock-down orders and was completed during the pandemic with a generally less stressful environment. We hypothesize that the environmental changes impacted stress levels and may explain the failure to replicate our results. Analysis of corticosterone (CORT) at euthanasia showed a significant study by genotype interaction where WT had significantly higher CORT relative to KO in Study 1, with no differences in Study 2. These data suggest that decreasing Krtcap3 expression may alter the environmental stress response to influence adiposity. We also found that KO rats in both studies, but not WT, experienced a dramatic increase in CORT after their cage mate was removed, suggesting a separate connection to social behavioral stress. Future work is necessary to confirm and elucidate the finer mechanisms of these relationships, but these data indicate the possibility of Krtcap3 as a novel stress gene.

molecular biology↗

bioRxiv2022

Sex and genetic specific effects on behavioral, but not metabolic, responses to a high fat diet in heterogeneous stock rats

Obesity is a growing epidemic associated with a range of comorbidities, including anxiety and depression. Genetics and environmental factors such as diet contribute to both adiposity and anxiety/depression. Heterogeneous stock (HS) rats are an outbred colony and useful for genetic mapping of complex traits. We have previously shown that HS male rats exhibit worsened metabolic and behavioral health in response to high fat diet (HFD). This study aims to determine if females have similar response to diet and if response to diet interacts with genetic background. We measured multiple metabolic (body weight, fat pad weight, glucose tolerance, fasting glucose and insulin) and behavioral (elevated plus maze, open field test, and forced swim test) outcomes in a large cohort of male and female rats on either HFD or low fat diet (LFD). We estimated overall heritability as well as heritability of response to diet for each outcome. Both sexes showed worsened metabolic measures when fed HFD compared to LFD. In contrast, only males exhibited altered behavioral responses to HFD relative to LFD, with no effect in females. Most metabolic and behavioral measures showed overall heritability in both sexes. In contrast, although there was some evidence for gene by diet (GxD) interactions for behavioral measures in males, GxD interactions were generally not found for the metabolic measures. These data demonstrate an important role of diet, sex and genetics in metabolic and behavioral phenotypes in HS rats, with a potential role of gene by diet interactions for behavioral outcomes only in males.

genetics↗

bioRxiv2022

Genetic mapping of multiple metabolic traits identifies novel genes for adiposity, lipids and insulin secretory capacity in outbred rats

Despite the successes of human genome-wide association studies, the causal genes underlying most metabolic traits remain unclear. We used outbred heterogeneous stock (HS) rats, coupled with expression data and mediation analysis, to identify quantitative trait loci (QTLs) and candidate gene mediators for adiposity, glucose tolerance, serum lipids and other metabolic traits. Physiological traits were measured in 1519 male HS rats, with liver and adipose transcriptomes measured in over 410 rats. Genotypes were imputed from low coverage whole genome sequence. Linear mixed models were used to detect physiological and expression QTLs (pQTLs and eQTLs, respectively), employing both SNP- and haplotype-based models for pQTL mapping. Genes with cis-eQTLs that overlapped pQTLs were assessed as causal candidates through mediation analysis. We identified 15 SNP-based pQTLs and 19 haplotype-based pQTLs, of which 11 were in common. Using mediation, we identified the following genes as candidate mediators of pQTLs: Grk5 for a fat pad weight pQTL on Chr1, Krtcap3 for fat pad weight and serum lipids pQTLs on Chr6, Ilrun for a fat pad weight pQTL on Chr20 and Rfx6 for a whole pancreatic insulin content pQTL on Chr20. Furthermore, we verified Grk5 and Ktrcap3 using gene knock-down/out models, thereby shedding light on novel regulators of obesity.

genetics↗

bioRxiv2022

Keratinocyte-Associated Protein 3 is a novel gene for adiposity with differential effects in males and females

ObjectiveDespite the obesity crisis in the United States, the underlying genetics are poorly understood. Our lab previously identified Keratinocyte-associated protein 3, Krtcap3, as a candidate gene for adiposity where increased expression of Krtcap3 correlated with decreased fat mass. Here we seek to confirm that Krtcap3 expression affects adiposity traits. MethodsWe developed an in vivo whole-body Krtcap3 knock-out (KO) rat model. Wild-type (WT) and KO rats were placed onto a high-fat or low-fat diet at six weeks of age and were maintained on diet for 13 weeks, followed by assessments of metabolic health. We hypothesized that Krtcap3-KO rats will have increased adiposity and a worsened metabolic phenotype relative to WT. ResultsWe found that KO male and female rats have significantly increased body weight versus WT. KO females ate more, had more fat mass, but were also more insulin sensitive than WT. Alternatively, KO males weighed more and were more insulin resistant than WT, with no differences in eating or fat mass. ConclusionsThis study validates Krtcap3 in body weight regulation and demonstrates sex-specific effects on food intake, adiposity, and insulin sensitivity. Future studies will investigate how Krtcap3 is acting and seek to better understand these sex differences. Study Importance QuestionsWhat is already known about this subject? O_LIOver 900 low-risk, common genetic variants for BMI have been identified, but these still only explain a fraction of the heritability and many of the underlying causal genes remain unknown C_LIO_LIKrtcap3 has been identified as a candidate gene for obesity in both rats and humans, but no verification or functional studies have been done C_LI What are the new findings in your manuscript? O_LIIdentified Krtcap3 as a novel gene that impacts feeding behavior and adiposity in female rats C_LIO_LIDetermined that Krtcap3 impacts insulin sensitivity differentially in male and female rats C_LI How might your results change the direction of research or the focus of clinical practice? O_LIThis work may lead to identification of new pathways that contribute to obesity without metabolic complications, which will advance understanding of the biology of obesity and potentially identify novel drug targets C_LIO_LIThis work highlights the need to investigate sex differences in the genetics of obesity C_LI

genetics↗