Investigating Krtcap3 as a novel stress gene

Abstract

While obesity is an increasingly prevalent disease, genetic susceptibility is poorly understood and more research is sorely needed. Our lab has sought to confirm Keratinocyte-associated protein 3 ( Krtcap3) as a novel adiposity gene and characterize its role using an in vivo whole-body knock-out (KO) model on the Wistar-Kyoto (WKY) rat strain.We obtained conflicting adiposity and food intake results between two in vivo studies conducted before and after the COVID-19 pandemic, which brought along drastic environmental changes in the animal facility. Compared to pre-pandemic, in the quieter post-COVID-19 environment wild-type (WT) rats were eating more and gaining more weight, without corresponding changes in KO rats. We hypothesized that the prior environment had affected the stress levels of the rats, and that Krtcap3 may be a novel stress-related gene whose effects on adiposity are tangential.A significant environmental change was supported by altered expression of genes associated with glucocorticoid metabolism. Most interestingly, KO rats consistently have lower basal corticosterone (CORT) compared to WT rats and have a much stronger increase in CORT when their cage mate is removed for euthanasia.We have since sought to characterize the role Krtcap3 may play in the stress response. Despite the genotype differences in CORT response seen at euthanasia, there were no differences in the CORT response during a restraint test, indicating that both WT and KO are capable of responding to acute stressors. In WKY rats, there is high Krtcap3 expression in the pituitary gland and along the gastrointestinal tract, suggesting potential tissues of action for further investigation. Surprisingly, when we exposed WT and KO rats long-term to white noise and unpredictable mild stress, there was a stronger increase in the anxiety response of KO rats as compared to WT. This supports that Krtcap3 expression affects the response to stress, but suggests that the type of stress may also play a role. Taken together, these data demonstrate that Krtcap3 participates in the stress response. Though more work is needed to elucidate the finer mechanisms of the role of Krtcap3, these findings have important implications for human health, where stress is a known co-morbidity for many diseases, including obesity. R01 DK106386, T32 DA041349 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.