2015 Grant Award - Michael B. Stout, Ph.D.
Mitigation of Obesity-related Metabolic Dysfunction by 17α-estradiol: A Novel Therapeutic Strategy
Michael B. Stout, Ph.D.
Kogod Center on Aging, Mayo Clinic
Obesity is a strong risk factor for a multitude of metabolic and cardiovascular diseases. White adipose tissue (WAT) plays a central role in the onset and progression of obesity-related diseases due to its regulation of macronutrient homeostasis and systemic inflammation. In obesity, WAT insulin responsiveness and inflammatory status are perturbed in a manner that leads to the expansion of visceral adiposity and hepatic lipid deposition; both of which are causally related to insulin resistance and type 2 diabetes. It is well established that estrogen activity in female rodents and pre-menopausal humans provides a metabolic advantage over males, which translates to diminished WAT inflammation, lipid redistribution, and metabolic dysfunction in the setting of obesity. However, exogenous administration of 17β-estradiol (17β-E2) often has deleterious effects related to cardiovascular event risk, various forms of cancer, and feminization in males. We found that a naturally occurring enantiomer of 17β-E2, 17α-estradiol (17α-E2), has shown promise as a potential therapeutic option for reducing adiposity, WAT inflammation, and ectopic lipid accumulation. In addition to these enhancements, we discovered that 17α-E2 also dramatically improves metabolic homeostasis in male mice without eliciting any characteristics indicative of feminization. We hypothesize that 17α-E2 elicits these beneficial effects through positively modulating WAT macrophage infiltration and phenotype; thereby increasing lipid oxidation in adipose and liver. We propose to test this hypothesis by directly assessing WAT resident macrophage populations and phenotypes through flow cytometry, flow sorting, and qPCR array techniques in animals administered 17α-E2. In addition, we will isolate primary adipocytes and hepatocytes from 17α-E2 treated animals and assess oxygen consumption and palmitate oxidation with Seahorse technology. Our proposed research will fill fundamental knowledge gaps related to the mitigation of several obesity-related sequelae by 17α-E2.