Utilization of MoTrPAC data to characterize white adipose tissue molecular aging and its potential mitigation with endurance training-from a sex-specific perspective

Battelle Pacific Northwest Laboratories, Richland WA

Investigators

Abstract

ABSTRACT - Pacific Northwest National Laboratory – PNNL The pathogenesis, presentation and risk of cardiometabolic risk factors and diseases differs by sex. The subcutaneous white adipose tissue (scWAT) is a dynamic storage and endocrine organ with central roles in mediating cardiometabolic disease risk throughout the lifespan. As we and others previously demonstrated, the scWAT of adult female rodents and humans displays a metabolically healthy and cardioprotective phenotype relative to that of males. However, declines in female sex hormones that occur with age shift scWAT phenotypes to more closely resemble that of males and drive age-associated increases in cardiometabolic disease risk. Regular endurance exercise training (EET) substantially reduces cardiometabolic disease and all-cause mortality risk throughout the lifespan, yet the systemic molecular mechanisms of the health benefits of EET warrant additional investigation, especially in terms of sex and age-associated differences. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) seeks to develop a molecular map of exercise to better understand the role of exercise on health and disease. Here we propose to utilize both publicly and privately available data from MoTrPAC to uncover molecular features of scWAT aging and the impact of EET on scWAT molecular aging features in males and females. This proposal seeks to address the following: Aim 1) define scWAT molecular aging including the impact of sex on scWAT molecular aging phenotypes in the sedentary state; 2) determine the impact of age and sex on the scWAT response to EET. We will accomplish this by first comparing differences in the scWAT molecular landscape of sedentary 6 mo F344 rats (MoTrPAC publicly available data set) to 18 mo F344 rats (MoTrPAC currently privately available data set) (Aim 1A). Then we will examine correlations between scWAT sample-level multiomic features and the age of sedentary human participants separately by sex to identify age-associated molecular features shared between human and rat (Aim 1B). We will then compare differences in the multiomic response to EET by comparing feature level and pathway enrichments responses in 6 and 18 mo male and female rats (Aim 2). Comparison of scWAT sexual dimorphism and the dynamic response to exercise training by sex and age through utilization of multiomic data sets generated by MoTrPAC offers unprecedented potential to understand scWAT molecular aging and its association with disease-associate phenotypes—all data and analyses will be made publicly available to facilitate dissemination to the scientific community. Findings thus offer the potential to elucidate molecular drivers of sexual dimorphism in scWAT aging biology and inform future studies towards a precision medicine approach.