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Characterizing the Role of Keratinocyte-associated Protein 3 in Obesity and Stress in a Novel Rat Model

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Characterizing the Role of Keratinocyte-associated Protein 3 in Obesity and Stress in a Novel Rat Model
Szalanczy, Alexandria
Approximately 650 million adults worldwide have obesity and suffer from increased mortality and healthcare costs. Obesity is a complex disease influenced by genetic background, environmental factors, and their interactions. Despite extensive efforts, known genes and variants still only explain a fraction of the heritability of obesity. Further, most research focuses on the impact of diet, with less appreciation for other environmental factors such as exposure to stress, which has consistently been linked to worsened metabolic and mental health. Given the complex nature of obesity, there is a need for investigations to consider multiple perspectives. This dissertation aimed to characterize the role of a novel obesity gene, Keratinocyte-associated protein 3 (Krtcap3) that was identified by a genome-wide association study in rats. To do so, we developed a novel knock-out (KO) rat model (WKY-Krtcap3em3Mcwi) expecting that KO rats would have increased adiposity compared to wild-type (WT) rats. We first confirmed that when exposed to a high-fat diet (HFD), female KO rats had increased fat mass relative to WT, yet when we conducted a second in vivo study, we no longer saw differences in adiposity by genotype. This was because WT rats ate more and had increased adiposity in the second study compared to the first, with no changes in KO rats. We identified a significant environmental change between the two studies, supported by measurements of the stress hormone corticosterone (CORT) that suggested different responses between WT and KO rats to environmental stress. Further, KO rats strongly reacted to separation at euthanasia, but WT did not, indicating type of stress matters. A third in vivo study where we administered chronic stress to WT and KO rats identified genotype-specific metabolic and behavioral responses to stress, supported that stressor type matters, and found differential expression of the glucocorticoid receptor between WT and KO rats. While direct CORT administration did not alter adiposity in the rats, it did point to a role of Krtcap3 in the pituitary gland. Together, these data identify Krtcap3 as a novel stress gene that influences response to different stressors, potentially with downstream consequences for obesity and mental health.
Solberg Woods, Leah C (advisor)
Kavanagh, Kylie (committee member)
Olivier, Michael (committee member)
Key, Chia Chi (committee member)
Lowther, Todd (committee member)
2023-09-08T08:35:29Z (accessioned)
2023 (issued)
Molecular Medicine and Translational Science (discipline)
2024-03-07 (terms)
2024-03-07 (liftdate)
http://hdl.handle.net/10339/102628 (uri)
en (iso)
Wake Forest University

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