Keratinocyte-Associated Protein 3 is a novel gene for adiposity with differential effects in males and females

Objective Despite the obesity crisis in the United States, the underlying genetics are poorly understood. Our lab previously identified Keratinocyte-associated protein 3, Krtcap3, as a candidate gene for adiposity where increased expression of Krtcap3 correlated with decreased fat mass. Here we seek to confirm that Krtcap3 expression affects adiposity traits. Methods We developed an in vivo whole-body Krtcap3 knock-out (KO) rat model. Wild-type (WT) and KO rats were placed onto a high-fat or low-fat diet at six weeks of age and were maintained on diet for 13 weeks, followed by assessments of metabolic health. We hypothesized that Krtcap3 -KO rats will have increased adiposity and a worsened metabolic phenotype relative to WT. Results We found that KO male and female rats have significantly increased body weight versus WT. KO females ate more, had more fat mass, but were also more insulin sensitive than WT. Alternatively, KO males weighed more and were more insulin resistant than WT, with no differences in eating or fat mass. Conclusions This study validates Krtcap3 in body weight regulation and demonstrates sex-specific effects on food intake, adiposity, and insulin sensitivity. Future studies will investigate how Krtcap3 is acting and seek to better understand these sex differences. Study Importance Questions What is already known about this subject? Over 900 low-risk, common genetic variants for BMI have been identified, but these still only explain a fraction of the heritability and many of the underlying causal genes remain unknown Krtcap3 has been identified as a candidate gene for obesity in both rats and humans, but no verification or functional studies have been done What are the new findings in your manuscript? Identified Krtcap3 as a novel gene that impacts feeding behavior and adiposity in female rats Determined that Krtcap3 impacts insulin sensitivity differentially in male and female rats How might your results change the direction of research or the focus of clinical practice? This work may lead to identification of new pathways that contribute to obesity without metabolic complications, which will advance understanding of the biology of obesity and potentially identify novel drug targets This work highlights the need to investigate sex differences in the genetics of obesity