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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Ye, Risheng; Wang, Miao; Wang, Qiong A et al. (2016) Autonomous interconversion between adult pancreatic α-cells and β-cells after differential metabolic challenges. Mol Metab 5:437-48
Dufurrena, Quinn; Amjad, Farhad M; Scherer, Philipp E et al. (2016) Alterations in pancreatic β cell function and Trypanosoma cruzi infection: evidence from human and animal studies. Parasitol Res :
Kruglikov, Ilja L; Scherer, Philipp E (2016) Dermal Adipocytes: From Irrelevance to Metabolic Targets? Trends Endocrinol Metab 27:1-10
Rutkowski, Joseph M; Pastor, Johanne; Sun, Kai et al. (2016) Adiponectin alters renal calcium and phosphate excretion through regulation of klotho expression. Kidney Int :
Kruglikov, Ilja L; Scherer, Philipp E (2016) Skin aging: are adipocytes the next target? Aging (Albany NY) 8:1457-69
Stern, Jennifer H; Rutkowski, Joseph M; Scherer, Philipp E (2016) Adiponectin, Leptin, and Fatty Acids in the Maintenance of Metabolic Homeostasis through Adipose Tissue Crosstalk. Cell Metab 23:770-84
Wernstedt Asterholm, Ingrid; Scherer, Philipp E (2016) Fibrosis-streaks and splatters: Some things are not always what they seem to be. Obesity (Silver Spring) 24:552-3
Han, Yong Hwan; Buffolo, Márcio; 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
Wernstedt Asterholm, Ingrid; Kim-Muller, Ja Young; Rutkowski, Joseph M et al. (2016) Pathological Type-2 Immune Response, Enhanced Tumor Growth, and Glucose Intolerance in Retnlβ (RELMβ) Null Mice: A Model of Intestinal Immune System Dysfunction in Disease Susceptibility. Am J Pathol 186:2404-16
Zhu, Yi; Gao, Yong; Tao, Caroline et al. (2016) Connexin 43 Mediates White Adipose Tissue Beiging by Facilitating the Propagation of Sympathetic Neuronal Signals. Cell Metab 24:420-33

Showing the most recent 10 out of 51 publications