• Sclerostin influences body composition adaptations to exercise training

      Kurgan, Nigel; Applied Health Sciences Program
      Sclerostin is a secreted glycoprotein mainly produced by the osteocyte, which inhibits the canonical Wnt/ß-catenin signalling pathway. In mice, genetic deletion, or inhibition of sclerostin with a neutralizing antibody increases bone mass while also improving insulin sensitivity and lipid homeostasis. Despite sclerostin not being expressed by adipose tissue (AT), reductions in white AT (WAT) mass and adipocyte cross-sectional area can also be observed with sclerostin inhibition, ultimately conferring resistance to a high-fat diet. Resting circulating sclerostin has also been shown to decrease following exercise training. This dissertation includes six studies examining the hypothesis that sclerostin influences adaptations in fat mass in response to exercise training. Study 1 did not identify serum sclerostin’s response to acute exercise with a top-down proteomic analysis. Study 2 of this thesis utilized a targeted approach and found sclerostin increases in the circulation transiently following acute exercise in adolescents with excess adiposity while those with normal weight have a blunted response. Study 3 utilized a longitudinal study design and found a diet and exercise intervention that leads to a reduction in fat mass attenuates sclerostin’s post-exercise increase in adolescents with excess adiposity. Study 4 identified sclerostin was present in human AT and decreased following exercise training in adults with excess adiposity. Study 5 characterized sclerostin’s response to acute exercise within serum and WAT depots of a mouse model and showed that serum sclerostin is elevated during recovery only in obese mice compared to lean mice and the monomeric form of sclerostin is reduced in scWAT during recovery from acute exercise and is abolished in visceral WAT in response to an obesogenic diet. Study 6 showed that prevention in the reduction in sclerostin seen with exercise with daily injections of recombinant sclerostin also prevents the reduction in scWAT mass and adipocyte cell size and increased lean mass seen with exercise training. These changes may be related to a shift in fuel utilization. Taken together, this thesis provides evidence that sclerostin is influenced by adiposity and exercise training and fluctuations in sclerostin content can regulate adaptations in fat mass and lean mass, which may be mediated by changes in metabolism.