Investigating Ubiquitin Like Modifier, UBD, Linking Genetic Variation to Weight Loss After Exercise

Obesity incidence worldwide continues to rise annually and is considered a major contributor to the pathobiology of other life-threatening diseases including cardiometabolic disorders and cancers. Globally, obesity is responsible for over 67.5 billion dollars of healthcare expenditure and over 4 million days lost to absenteeism in the workforce. Therapeutics targeting increased adiposity besides prescribed exercise are minimal. Additionally, mechanisms that underlie adipose tissue weight loss in response to exercise training remain inadequately understood. We utilized mouse genetics and a human Genome Wide Association Study (GWAS) to identify candidate genes driving reductions in adiposity associated with daily exercise. In a 100-strain mouse panel, we performed Ribonucleic Acid (RNA) sequencing on gonadal and inguinal fat pads from sedentary (SED) vs exercise trained (TRN) animals. We identified transcripts associated with fat pad mass after 30 days of volitional activity. We cross-referenced putative exercise-responsive and adipocyte-regulatory transcripts against other mouse panels from our laboratory, as well as human exercise studies. Adipose tissue RNA sequencing data from the METabolic Syndrome In Men (METSIM) study of 10,000 Finnish men, was plotted against self-reported activity level. We performed caloric modification studies in 5 strains of mice to determine whether TRN-impacted targets were differentially expressed in adipose tissue in response to caloric intake. We mined adipose tissue RNA sequencing data from the 4-core genotype mouse panel to determine target regulation by sex (chromosomes vs hormones). Adipose Ubiquitin D1 (UBD1) transcript was inversely associated with exercise-induced adipose tissue weight loss (P=5.2*10 -13 ). Moreover, adipose tissue UBD1 expression was elevated in females compared to males (P<0.01), and its expression was impacted by caloric intake and X chromosome-linked mechanism(s). Gene dosing studies in adipocytes to interrogate molecular actions of UBD1 on adipocyte metabolism are underway. UBD1 is an exercise-responsive transcript with sexually dimorphic expression. Reduction in adipose tissue expression following 30 days of wheel running was highly associated with exercise-induced adipose tissue weight loss in a large panel of mice, and this relationship was confirmed in human subjects. These data suggest that repression of specific targets in adipose tissue, including UBD1, may in part underlie the remarkable remodeling that occurs in adipose tissue depots as a consequence of daily physical activity. Identification of the molecular transducers that deliver the health benefits associated with exercise training will improve clinical care of individuals suffering from cardiometabolic related diseases