REDUCTIONS IN ESTROGENIC FUNCTION LEAD TO METABOLIC DYSFUNCTION IN ADIPOSE TISSUE AND SKELETAL MUSCLE.

Abstract

This dissertation research is comprised of three studies which investigated the effects of reduced ovarian hormones induced by surgical ovariectomy (OVX) on metabolic parameters in adipose tissue and skeletal muscle. Reduced ovarian function is associated with changes in body composition that result in increased risk for development of the metabolic syndrome and cardiovascular disease. It is hypothesized that ovarian hormones protect women from the development of metabolic disease by significantly influencing the metabolic phenotype of adipose tissue and skeletal muscle. Study #1 examined the efficacy of voluntary wheel running or 17beta-estradiol supplementation as interventions to ameliorate the detrimental effects of OVX on adipose tissue. OVX resulted in significant increases in visceral fat mass and basal lipolysis that 17beta-estradiol delivery completely attenuated compared to the control (SHAM) mice. Wheel running in the OVX mice completely attenuated increased circulating glucose levels and partially attenuated increased visceral fat mass, but failed to prevent changes in lipolytic function. Study #2 determined that cellular regulation of lipolysis in visceral adipose tissue during an acute exercise bout was impaired in the OVX compared to the SHAM group. In the final study, it was determined that adipose tissue expansion following OVX was mediated by adipocyte hypertrophy as measured by significant increases in adipocyte size. Using a novel co-culture approach containing isolated single skeletal muscle fibers and adult adipocytes the interactive effects of OVX and adipocyte exposure on skeletal muscle metabolic function were investigated. Both control and co-cultured skeletal muscle fibers from OVX animals displayed impaired insulin-stimulated glucose uptake coupled with impaired insulin signaling compared to SHAM fibers. Co-culture with adipocytes attenuated insulin-stimulated glucose uptake in SHAM fibers when adipocytes were of visceral, but not subcutaneous origin and this effect was independent of intramuscular lipid content. Collectively, these studies provide unique insight into cellular alterations in metabolic regulation that may contribute to metabolic diseases such as insulin resistance in women when ovarian hormone levels are reduced.