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

Abstract

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.

Chronic stress from adolescence to adulthood increases adiposity and anxiety in rats with decreased expression of Krtcap3

“…This could be explained by the fact that serum CORT increased only in the KO rats as opposed to WT, in contrast to our previous work where CORT was higher in the WT rats (Szalanczy et al, 2023). Although we are unable to make direct comparisons between the studies, that decreased expression of Krtcap3 leads to increased eating and adiposity under conditions of chronic stress is consistent with the previous findings (Szalanczy et al, 2022;Szalanczy et al, 2023) and further supports a role of Krtcap3 in the stress response. Whether the role of Krtcap3 in the stress response is protective or deleterious, however, is still an open question and future studies will be needed to address this.…”

“…We previously generated a whole-body in vivo Krtcap3-KO on the WKY (WKY/NCrl; RGD_1358112) inbred rat strain (WKY-Krtcap3 em3Mcwi ) and established a breeding colony at Wake Forest University School of Medicine (WFUSOM) in 2019 (Szalanczy et al, 2022). At Building A of WFUSOM, rats were housed in ventilated cages (46 cm × 24 cm × 20 cm) at 22 °C in a 12 h light/dark cycle (dark from 18:00 to 6:00) at standard temperature and humidity conditions, and given ad libitum access to water.…”

Genetic mapping of multiple metabolic traits identifies novel genes for adiposity, lipids and insulin secretory capacity in outbred rats

“…This is consistent with the negative correlation between Krtcap3 liver expression and associated phenotypes ( R p ~ −0.25 – Figure 4C ), suggesting that the WKY haplotype increases the expression of liver Krtcap3 leading to reduced accumulation of fat pad and TRIG. We have recently shown that Krtcap3 knock-out rats exhibit increased body weight, with female rats showing increased fat pad weights and insulin sensitivity [32], thereby validating this gene. Several additional genes were identified as partial mediators, with different genes acting in adipose vs liver ( Table 2 ), indicating multiple causal genes may underlie this locus.…”

“…Krtcap3 does not fall within human GWAS loci for BMI or WHR, but has been identified as a pleiotropic gene for obesity, dyslipidemia and type 2 diabetes using a multi-variate analysis [43]. Recent work by our group confirmed Ktrcap3’ s role in adiposity using a rat Krtcap3 knock-out; both male and female knock-out rats have increased body weight, with females showing increased adiposity and insulin sensitivity [32]. Interestingly, Krtcap3 is unlikely the only gene acting in this locus.…”

“…Adcy3 is associated with monogenic and polygenic obesity in humans[44,45,46,47], and has been shown to act via coding variation that impacts protein folding or function [48,49], and altered expression [44]. Based on our functional validation of Krtcap3 [32] coupled with strong support for Adcy3 in human studies, it is likely both genes are causal for adiposity. In addition, our work identifies several partial mediators in both liver and adipose tissue, emphasizing the complexity of the Chr6 adiposity locus.…”