Keratinocyte-associated Protein 3May Participate in the Stress Response to Impact Adiposity.

Although obesity rates have been steadily climbing the last few decades, the genetics underlying the disease are poorly understood. Previous work in our lab identified Keratinocyte-associated protein 3(Krtcap3) as a candidate gene for adiposity. To characterize the role of Krtcap3in adiposity, we developed an in vivowhole-body knock-out (KO) rat model of Krtcap3,hypothesizing that KO rats would have greater adiposity compared to wild-type (WT) rats. In our first in vivostudy, primarily occurring before the COVID-19 shut down, we found that female KO rats have significantly increased food intake and fat mass compared to WT rats, supporting a role of Krtcap3in adiposity. We conducted a second study in 2020-2021, when traffic in the vivarium was lighter due to COVID-19, and were unable to replicate the initial differences in food intake or fat mass between WT and KO rats. Compared to Study 1, WT rats ate more and had a corresponding increase in adiposity, with no corresponding change in KO rats. We hypothesized that with decreased traffic the environment in Study 2 became less stressful for the WT rats, who then began to eat more. KO rats appeared to be resistant to the effects of chronic stress, and thus ate similar amounts between the two studies. Supporting this difference, measurements of corticosterone (CORT) in rats between Study 1 and Study 2 revealed that WT rats had increased CORT in Study 1 relative to Study 2, with no differences in CORT between the studies for the KO rats. To determine if Krtcap3may be responsive to stress, we measured Krtcap3expression in key stress response tissues between unstressed rats and rats injected with a high dose of CORT (40 mg/kg). We found that Krtcap3is highly expressed in the pituitary gland, with expression significantly decreased following the CORT injection. Although expression of Krtcap3is very low in blood, we also saw a significant decrease in Krtcap3expression in the blood after the CORT injection. In contrast, Krtcap3has low expression in the adrenal glands, with no change after the CORT injection. These results indicate that Krtcap3may play a role in the negative feedback regulation of the HPA axis, potentially explaining the differences in food intake and fat mass between studies 1 and 2 discussed above. Future studies will seek to confirm that decreased Krtcap3expression is protective against chronic stress, and that this can impact feeding behavior to influence adiposity.