DESCRIPTION (provided by applicant): Obesity impairs glucose and lipid metabolism, and increases the risk of coronary heart disease (CHD). Obese pre-menopausal females have ~1/2 the CHD risk of obese males; this protection is reduced when ovarian function is lost with menopause. There is an important therapeutic opportunity in understanding the mechanisms of this protection. The goal of this project is to define mechanisms by which female sex protects against obesity-induced glucose and lipid abnormalities, and see if we can augment this pathway in males. In the liver, the presence of impaired glucose and lipid biology in obesity has been attributed to a defect in insulin-induced AKT signaling to regulate glucose, but intact SREBP1c signaling to promote lipogenesis. This model is not sufficient to explain dyslipidemia with obesity. We've developed in-vivo approaches to understand the integrated relationships of adipose, muscle and liver, which allow us to provide a unifying model of both lipid and glucose abnormalities of obesity: Excess delivery of fatty acids (FA) to the liver arises due to impaired suppression of lipolysis by insulin. In response to this FA flux, the liver re-esterifies FA into triglyceride (TG) resulting in fatty liver and export of VLDL-TG. Fatty liver results in impaired insulin-regulation of glucose metabolism. While each of these steps is supported in the literature, the integrated control that determines the balance between health and disease has been elusive. Additionally, females are protected from FA-induced insulin resistance, which we propose is mediated by estrogen-regulated FA metabolism in muscle and liver. We've discovered that estrogen corrects both the glucose and lipid defects in obesity -promoting insulin- regulation of glucose metabolism, while blocking dyslipidemia. Using an innovative in vivo approach with dual tracers for glucose and lipid flux, we discovered that this protective effect requires estrogen signaling through estrogen receptor alpha (ERα). We coupled mRNA sequencing and mice lacking ERα in the liver and found that ERα influences numerous liver genes involved in glucose and lipid metabolism, and also indirectly regulates these pathways by induction of the negative transcriptional regulator Small Heterodimer Partner (SHP). This liver estrogen pathway is also important in males -and can likely be augmented to prevent CHD. We hypothesize three critical actions of estrogen mediated through ERα: 1) it limits FA delivery to the liver by promoting muscle FA oxidation (AIM1), 2) it activates via SHP a transcriptional network in the liver that promotes insulin suppression of gluconeogenesis, promotes FA oxidation, and prevents FA-driven VLDL production (AIM2). Males have low ERα signaling, but this protection and can be augmented (AIM3). Our studies are significant because they are expected to: 1) identify the physiological basis by which female sex reduces CHD risk and provide a foundation f...