PROJECT SUMMURY Obesity rates are increasing in the United States, with recent statistics estimating more than 35.7% of adults and 16.9% of children and adolescents are considered obese. Obesity is a risk factor for insulin resistance, the metabolic syndrome and cardiovascular disease. Despite its public health importance, the pathogenesis of obesity is not well understood. Increased oxidative stress in adipose tissue of obese humans and animals in response to excess nutrient intake has been documented. However, the role of adipose oxidative stress in the pathogenesis of obesity and its associated metabolic alterations in not understood. To address this, we generated mice with increased superoxide production in adipocytes through deletion of manganese superoxide dismutase (MnSOD), the sole enzyme responsible for detoxifying superoxide to hydrogen peroxide in the mitochondrial matrix. The adipocyte- specific MnSOD KO (AdSod2KO) mice are lean, have increased whole body fat oxidation and resist diet-induced glucose intolerance, insulin resistance and hepatic steatosis. The overarching goal of this proposal is to elucidate the mechanisms underlying enhanced fat oxidation and improved metabolic homeostasis in response to HFD in AdSod2KO mice. This proposal has two specific aims:
Specific Aim 1 will identify the underlying mechanisms by which adipocyte MnSOD deletion and/or oxidative stress enhanced whole body fat oxidation. Under this aim, we will first determine the contribution of white and brown adipose tissue, liver and skeletal muscle in enhancing whole body fat oxidation, then investigate whether the increase in whole body fat oxidation results from coupled or uncoupled mitochondrial oxidation of fatty acid and finally identify redox-dependent mechanisms that can increase fatty acid oxidation in white adipose tissue.
Specific Aim 2 will determine tissue-specific mechanisms by which MnSOD deletion and/or enhanced oxidative stress in mature adipocytes protects against HFD-induced glucose intolerance, insulin resistance and hepatic steatosis in mice. Under this aim, we will examine whether adipocyte MnSOD deletion affects lipolysis, determine if adipocyte MnSOD deletion and/or oxidative stress enhance whole body insulin sensitivity during HFD and ?-cell function and identify known and unknown adipose-secreted factors that could mediate the beneficial systemic effect on metabolism during HF feeding in AdSod2KO mice. These studies have high impact on obesity research as it provides a new paradigm for adipose tissue oxidative stress and its impact on whole body energy metabolism and insulin sensitivity. We believe that this research will provide new insights on the redox-regulation of metabolism and could identify new targets that could be modulated to enhance whole body fat oxidation and protects from the development of insulin resistance and diabetes during obesity.
The obesity epidemic is growing in the United States and the Western countries. With increased availability of nutrient-dense food and the adoption of sedentary life style, obesity is affecting more and more children. Obesity is associated with the development of insulin resistance and diabetes and the cost of diabetes alone is dramatically increasing in our country. Thus, studies that investigate the impact of adipose tissue deregulation on whole body insulin sensitivity and glucose homeostasis are timely. We have discovered a new branch of adipose tissue's regulation of whole body metabolism that involves redox regulation of fatty acid oxidation metabolism. This project investigates the mechanisms by which adipose oxidative stress confers protection against dietary obesity. We believe that the current proposal is novel and could provide important insights on adipose specific redox-dependent regulation of whole body metabolism and insulin sensitivity.
|Han, Yong Hwan; Buffolo, MÃ¡rcio; Pires, Karla Maria et al. (2016) Adipocyte-Specific Deletion of Manganese Superoxide Dismutase Protects From Diet-Induced Obesity Through Increased Mitochondrial Uncoupling and Biogenesis. Diabetes 65:2639-51|
|Boudina, Sihem; Graham, Timothy E (2014) Mitochondrial function/dysfunction in white adipose tissue. Exp Physiol 99:1168-78|