Over the past decade, efforts in the field have focused on the connection between mitochondrial dysfunction and the etiology of obesity, insulin resistance and the progression of type 2 diabetes mellitus (T2DM). Numerous studies indicate that such metabolic disorders are accompanied by reduced mitochondrial content, compromised mitochondrial respiratory capacity, heightened oxidative stress, impaired -oxidation and, consequently, altered whole-body lipid and glucose metabolism. In parallel, both the production and the release of the adipokine adiponectin are frequently impaired as well. Our data indicate that altered mitochondrial activity and adiponectin production are tightly linked. In the studies outlined in this proposal, we will better define the impact of mitochondrial function o white adipose tissue physiology and establish which metabolic intermediates are the critical drivers connecting mitochondrial activity and adiponectin production. We propose to approach these questions by surveying the effects of a number of different manipulations of mitochondrial activity in adipocytes and cataloguing the common denominators and distinct features between the models that lead to systemic metabolic benefits and the induction of adiponectin. We will approach this in a hierarchical fashion by focusing on broad inducers of the mitochondrial program in the white adipocyte (Aim 1), followed by a more specific manipulation of mitochondrial activity (Aim 2) in which we employ gain and loss of function models of two critical mitochondrial proteins, mitoNEET and the mitochondrial dicarboxylate carrier. This will allow us to effectively manipulate mitochondrial activity in a very-targeted fashion. In the last aim (Aim 3, we will develop a system that will allow us to acutely phase out overall mitochondrial function selectively in adipocytes in a highly-titratable fashion. Combined, these studies enable us to carefully dissect the effects of altered mitochondrial function on adiponectin production and overall cellular physiology of the white adipocyte. While the established role of mitochondrial function in brown adipocytes is well appreciated, our data argues that the relevance of mitochondrial function in the white adipocyte has been mistakenly undervalued. We have generated a unique toolset that allows us to systematically approach the question of "mitochondrial dysfunction" and, in fact, helps us to methodically define the term "dysfunction". We also have the desire to better understand the mechanisms governing adiponectin production and release. Based upon our preliminary data, we strongly believe that mitochondrial activity plays an essential role in this process. Results from our studies will help us define mechanistically why adipocytes regulate adiponectin release into circulation by gauging mitochondrial activity, leading to a better teleological understanding of the role of adiponectin within the system.
Obesity is on the rise, and we need to identify new areas that can be targeted for improvements in systemic metabolism. While the brown adipocyte and its unique mitochondrial infrastructure has gotten a lot of attention, our recent data suggests that the classical and far more abundant white adipocyte also offers huge potential to cope with metabolic challenges. Here, we systematically examine how selective changes at the level of mitochondrial function in white adipocytes influence energy homeostasis and exert beneficial effects on adipokine release. This should identify new target areas for anti-diabetic and anti-cardiovascular disease intervention.
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