(625.9) Keratinocyte-associated Protein 3 May Participate in the Stress Response to Impact Adiposity

Poster Board Number: E673

Alexandria Szalanczy (Wake Forest School of Medicine), Gina Giorgio (Wake Forest School of Medicine), Emily Goff (Wake Forest School of Medicine), Osborne Seshie (Wake Forest School of Medicine), Michael Grzybowski (Medical College of Wisconsin), Jason Klotz (Medical College of Wisconsin), Mackenzie Roberts (Wake Forest School of Medicine), Aron Geurts (Medical College of Wisconsin), Eva Redei (Northwestern University Feinberg School of Medicine), Leah Solberg Woods (Wake Forest School of Medicine)

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 Krtcap3 in adiposity, we developed an in vivo whole-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 vivo study, 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 Krtcap3 in 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 Krtcap3 may be responsive to stress, we measured Krtcap3 expression in key stress response tissues between unstressed rats and rats injected with a high dose of CORT (40 mg/kg). We found that Krtcap3 is highly expressed in the pituitary gland, with expression significantly decreased following the CORT injection. Although expression of Krtcap3 is very low in blood, we also saw a significant decrease in Krtcap3 expression in the blood after the CORT injection. In contrast, Krtcap3 has low expression in the adrenal glands, with no change after the CORT injection. These results indicate that Krtcap3 may 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 Krtcap3 expression is protective against chronic stress, and that this can impact feeding behavior to influence adiposity.

R01 DK106386, T32 DA041349