Changes in Environmental Stress over COVID-19 Pandemic Likely Contributed to Failure to Replicate Adiposity Phenotype Associated withKrtcap3

Abstract

AbstractWe previously identifiedKeratinocyte-associated protein 3, Krtcap3,as an obesity-related gene in female rats where a whole-bodyKrtcap3knock-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 ofKrtcap3but 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 decreasingKrtcap3expression 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 ofKrtcap3as a novel stress gene.