| Background. Menopause is associated with an increase in adiposity along with increased risk of metabolic disease. Evidence suggests that declining levels of estrogen (E2) contribute to these changes however little is known about the molecular and biochemical mechanism by which E2 acts. Objective and specific aims. The aim of my dissertation work was to enhance our knowledge of E2's role in regulating adiposity and metabolism. To do this, I did a series of experiments, both in vivo and in vitro, examining genomic and non-genomic E2 actions on liver, muscle and adipose tissue biology. Research design and methods. To determine the effects of in vivo E2, C57/B6J mice were ovariectomized (OVX) and treated with either estrogen (E2) or control (C) subcutaneous implant pellets. Food intake was carefully controlled to eliminate the central effects of E2 on food intake. To follow-up on observations made in the in vivo studies, C2C12 myocytes and human differentiated preadipocytes (PA) were used to examine the direct effects of E2 on muscle and adipose tissue metabolism (respectively). Results. I demonstrated, for the first time, that E2 decreases adiposity and adipocyte size in OVX mice independent of changes in food intake. In addition, I identified novel genomic and non-genomic E2-dependent pathways by which E2 promotes fat oxidation, prevents TG accumulation, and enhances TG breakdown (lipolysis). This includes genomic regulation of SREBP-1c, PPAR-delta, and their downstream targets, as well as rapid activation of muscle AMP-activated protein kinase (AMPK) with E2-treatment. In vitro studies using human differentiated preadipocytes corroborate my in vivo findings on SREBP-1c expression, demonstrating E2-regulation of this lipogenic pathway. Lastly, I demonstrated a significant role for ER in adipogenesis and maintaining human adipocytes in the differentiated state. Conclusion. The results of my studies have greatly enhanced our knowledge of E2's role in adiposity and metabolism. I have identified multiple mechanisms by which E2 reduces adiposity and potentially improves metabolic health. The results of my findings have multiple implications specifically related to menopause, hormone replacement therapy, endocrine disorders which alter sex hormone levels, and the potential for gender-based medicine. |
