CC002/Unc females are mouse models of exercise-induced paradoxical fat response

Abstract

Exercise results in beneficial health outcomes and protects against a variety of chronic diseases. However, U.S. exercise guidelines recommend identical exercise programs for everyone, despite individual variation in responses to these programs, including paradoxical fat gain. Experimental models of exercise‐induced paradoxical outcomes may enable the dissection of underlying physiological mechanisms as well as the evaluation of potential interventions. Whereas several studies have identified individual mice exhibiting paradoxical fat gain following exercise, no systematic effort has been conducted to identify and characterize models of paradoxical response. Strains from the Collaborative Cross (CC) genetic reference population were used due to its high levels of genetic variation, its reproducible nature, and the observation that the CC is a rich source of novel disease models, to assess the impact genetic background has on exercise responses. We identified the strain CC002/Unc as an exercise‐induced paradoxical fat response model in a controlled voluntary exercise study across multiple ages in female mice. We also found sex and genetic differences were consistent with this pattern in a study of forced exercise programs. These results provide a novel model for studies to determine the mechanisms behind paradoxical metabolic responses to exercise, and enable development of more rational personalized exercise recommendations based on factors such as age, sex, and genetic background.

High-Diversity Mouse Populations for Complex Traits

“…Extreme strains, which sometimes express a phenotype more strongly than the founder strains, can be used to test interventions. Trait correlations among the CC can identify multivariate outlier strains with traits within the normal range on two disease-relevant traits that do not exhibit the expected trait correlation; for example, a paradoxical increase in fat deposition in response to exercise [67].…”

“…DO mice have been successfully used for mapping multiple complex traits including cardiovascular phenotypes [68,69], metabolic syndrome related traits [70], environmental toxicity [71], cancer modifier traits [72], behavioral traits [73,74], and meiotic drive [40]. Early large-scale studies in incipient CC strains successfully mapped many traits [32] and CC lines were used to map motor performance and body weight [75], energy balance traits [76], exercise physiology [67], toxicology [77], perinatal nutrition in CC RIX lines [78], kidney phenotypes [79], and hematological phenotypes [80]. Although CC mice were intended as a genetic mapping population and were used as such in these early studies, the power of the extant strains is sufficient only to large-effects alleles, typically observed in studies of Mendelian traits [81].…”

Whole Genome Sequencing and Progress Toward Full Inbreeding of the Mouse Collaborative Cross Population

“…2008; Churchill et al 2012; Svenson et al 2012). Over the past several years, the CC has been used to model a wide range of biomedically relevant traits including: allergy (Orgel et al 2018), asthma (Donoghue et al 2017), behavior (Chesler 2014; Schoenrock et al 2018; Molenhuis et al 2018), bone development (Levy et al 2015), cancer (Dorman et al 2016; Reilly 2016), cellular immune phenotypes (Graham et al 2017), drug disposition (Nachshon et al 2016), exercise (McMullan et al 2018), fertility (Shorter et al 2017), glucose tolerance (Abu-Toamih Atamni et al 2017; Nashef et al 2017), infectious disease susceptibility (Durrant et al 2011; Ferris et al 2013; Rasmussen et al 2014; Gralinski et al 2015; Graham et al 2015; Graham et al 2016; Gralinski et al 2017; Green et al 2017; Abu Toamih Atamni et al . 2018; Zhang et al 2018; Collin et al 2019), motor performance and body weight (Mao et al 2015), spontaneous colitis (Rogala et al 2014), and toxicology (Cichocki et al 2017; Hartman et al 2017; Mosedale et al 2017; Venkatratnam et al 2017).…”

Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX)

“…The CC captures the complexity of the mammalian genome, and is an important resource for mapping complex traits and system genetics efforts (Aylor et al 2011;Kelada et al 2012;Ferris et al 2013;Gralinski et al 2015;Gralinski et al 2017;Shorter et al 2017;Srivastava et al 2017). The CC has also been a source of new models of human diseases (Rogala et al 2014;Graham et al 2016;Mcmullan et al 2018;Orgel et al 2019). By mating different CC strains, we can generate recombinant inbred inter-crosses (CC-RIX) (Zou et al 2005;Schoenrock et al 2018).…”