Fetal hyperglycemia occurs when the developing fetus is exposed to high levels of glucose. For example in humans, this is the case when the mother has diabetes. Fetal hyperglycemia is linked to health complications for the fetus, including preeclamsia, fetal macrosomia and even fetal death. In addition, fetal hyperglycemia also increases the risk for the individual to develop a variety of diseases later in life. Adults exposed to fetal hyperglycemia are more susceptible to obesity, insulin resistance, type 2 diabetes, cardiovascular diseases and several metabolic syndromes. To date, the physiological and molecular mechanisms that underlie the link between fetal hyperglycemia and the adult sequelae are poorly understood. The central goal of this project is to examine the physiological and molecular basis of metabolic diseases in adults exposed to high levels of glucose only during embryogenesis. To accomplish this goal, we have recently developed a zebrafish model of fetal hyperglycemia. Zebrafish offers several advantages to complete this project. From a biological point of view, zebrafish embryos have the unique feature of being a “closed system” i.e for the first 5 days of development, the embryo solely relies on the yolk sac reserved deposited by the mother during ovulation and no energy exchange happens with the exterior world prior the end of embryogenesis. Therefore, in zebrafish we can directly expose the embryos to known concentration of glucose. Thus, specific aim 1 will test the hypothesis that fetal hyperglycemia leads to an increase in BMI, fat mass and insulin resistance in adults fed normal diet. Specific aim 2 will test the hypothesis that embryonic hyperglycemia increases glycolysis while decreasing β-oxidation in embryos and in adults. Specific aim 3 will test the hypothesis that fetal hyperglycemia causes hyperlipidemia and non-alcoholic fatty liver disease in adults. Specific aim 4 will test the hypothesis that embryonic hyperglycemia increases the levels of circulating lipids and causes atherosclerosis later in life. Successful completion of this proposal will lead to a better understanding of the physiological and molecular consequences of fetal hyperglycemia and will help in defining strategic therapeutic interventions to prevent the development of metabolic diseases in adults exposed to glucose during embryogenesis.
Obesity and hypertension (i.e. metabolic syndrome) are highly prevalent in patients who experience myocardial infarction (MI). In addition to increasing the risk of developing MI, these risk factors also promote adverse left ventricular remodeling after MI and thus increase the development of heart failure after MI. However, the mechanisms by which obesity and hypertension interact to promote aberrant post-MI outcomes are not well understood. One possible mechanism is through inflammation, in which monocytes/macrophages play key roles. While macrophages are critical for normal wound healing and resolution of inflammation, they can also promote inadequate healing and exacerbate inflammation during chronic disease states. Following MI, monocytes quickly invade the necrotic LV and differentiate into M1 pro-inflammatory macrophages to generate an inflammatory response, then as wound healing progresses differentiate or "polarize" into M2 anti-inflammatory macrophages to resolve inflammation. Immune cell metabolism (immunometabolism) has been identified as a key factor dictating polarization; however, the role of immunometabolism following MI has not been investigated. Cardiac metabolism is impaired by chronic stressors on the heart, such as obesity and hypertension, and these changes in metabolismcontribute to disease progression. Thus, the main goal of this study is to identify how obesity and hypertension interact to affect cardiac macrophage polarization and metabolism after MI, and whether manipulating macrophage metabolism can improve post-MI outcomes in metabolic syndrome. To accomplish this goal, mice will be fed a chronic high fat and high fructose (i.e. Western) diet to induce obesity, and hypertension will be surgically induced by abdominal aortic coarctation. Mice will then be given MI by permanent coronary artery ligation. Macrophage polarization and metabolic phenotypes will be assessed by fluorescence activated cell sorting (FACS), RNA-Seq, and glucose and fatty acid oxidation. In Aim 2, mice will be administered 2-deoxyglucose to perturb glucose metabolism and sodium nitrite to enhance mitochondrial fatty acid oxidation. Macrophage phenotypes will be linked to post-MI outcomes such as survival, cardiac function, and cardiac remodeling.