White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin Much attention has been dedicated over recent years towards a better understanding of brown and beige adipocytes, which are classically characterized by high mitochondrial content. However, the role of mitochondria in white adipocytes, beyond basic physiology and ?housekeeping?, remains vastly uncharacterized. We have developed systems in which we can address adipocyte-specific manipulation of mitochondrial function, in an inducible fashion. This allows for induction of key mitochondrial components in the adult mouse, excluding undesirable developmental effects. Over the previous funding period, we have examined a number of models in which adipocyte mitochondrial function was selectively enhanced or compromised. One of our new models allows us to specifically enhance mitochondrial reactive oxygen species (ROS) levels within the adipocyte. This has profound local and systemic effects that led us to the following hypothesis: THE LOWERING OF ADIPOCYTE MITOCHONDRIAL ROS LEVELS IS A PREREQUISITE FOR THE REMODELING AND ADAPTATION OF ADIPOSE TISSUE TO ALTERED SYSTEMIC METABOLIC CONDITIONS. By carefully timing and titrating mitochondrial activity and ROS levels, we will examine this hypothesis in the following areas: A) at the cellular level in the mature adipocyte; B) in the microenvironment at the level of whole adipose tissue remodeling; C) at the organismal level assessing systemic effects of adipocyte-derived ROS, with a specific focus on pancreatic beta cells. Specifically, we propose to address the underlying mechanisms with the following hierarchical approaches:
In Aim 1, we will examine the effects of adipocyte-specific mitochondrial dysfunction and mitochondria-generated ROS on the LOCAL cellular homeostasis of the adipocyte.
In Aim 2, we will define the effects of adipocyte-specific mitochondrial dysfunction and mitochondria-generated ROS on the local ADIPOSE TISSUE microenvironment, function and remodeling.
In Aim 3, we will address the effects of adipocyte-specific mitochondrial dysfunction and mitochondria-derived ROS on SYSTEMIC metabolic homeostasis. Combined, these studies enable us to carefully dissect the effects of altered mitochondrial function on adiponectin production, cellular physiology of the white adipocyte and adaptive remodeling of adipose tissue. While the established role of mitochondrial function in brown adipocytes is widely 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, this toolset helps us to methodically define the term ?dysfunction?. We also want 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. Furthermore, mitochondrial ROS exerts profound effects on the adaptive remodeling of fat pads as well as on the crosstalk of adipocytes with the beta cells in the pancreas.

Public Health Relevance

While we consider mitochondrial function primarily in the context of brown and beige adipose tissue, our recent data suggests that mitochondrial dysfunction at the level of the white adipocyte, can exert a significant metabolic impact. Here, we systematically examine how selective upregulation of reactive oxygen species (ROS) levels affects basic processes within the adipocyte, including the production of adipokines, such as adiponectin. We expand the analysis on ROS-mediated changes on whole adipose tissue physiology, as well as on inter-organ crosstalk with pancreatic ?-cells. We believe we can redefine ROS as a major culprit for the inability of adipose tissue to remodel. As such, the information gained from the experiments proposed here will help us to better understand the role ROS in the prevention of a healthy fat expansion.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK099110-06
Application #
9522380
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
2013-07-05
Project End
2023-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Wang, Qiong A; Zhang, Fang; Jiang, Lei et al. (2018) PPAR? and its Role in Adipocyte Homeostasis and Thiazolidinedione-Mediated Insulin Sensitization. Mol Cell Biol :
Crewe, Clair; Joffin, Nolwenn; Rutkowski, Joseph M et al. (2018) An Endothelial-to-Adipocyte Extracellular Vesicle Axis Governed by Metabolic State. Cell 175:695-708.e13
Scherer, Philipp E (2018) The many secret lives of adipocytes: implications for diabetes. Diabetologia :
Zhang, Fang; Hao, Guiyang; Shao, Mengle et al. (2018) An Adipose Tissue Atlas: An Image-Guided Identification of Human-like BAT and Beige Depots in Rodents. Cell Metab 27:252-262.e3
Kruglikov, Ilja L; Zhang, Zhuzhen; Scherer, Philipp E (2018) The Role of Immature and Mature Adipocytes in Hair Cycling. Trends Endocrinol Metab :
Xia, Jonathan Y; Sun, Kai; Hepler, Chelsea et al. (2018) Acute loss of adipose tissue-derived adiponectin triggers immediate metabolic deterioration in mice. Diabetologia 61:932-941
Kusminski, Christine M; Scherer, Philipp E (2018) New zoning laws enforced by glucagon. Proc Natl Acad Sci U S A 115:4308-4310
Ye, Risheng; Gordillo, Ruth; Shao, Mengle et al. (2018) Intracellular lipid metabolism impairs ? cell compensation during diet-induced obesity. J Clin Invest 128:1178-1189
Jun, Jonathan C; Devera, Ronald; Unnikrishnan, Dileep et al. (2017) Adipose HIF-1? causes obesity by suppressing brown adipose tissue thermogenesis. J Mol Med (Berl) 95:287-297
Rutkowski, Joseph M; Pastor, Johanne; Sun, Kai et al. (2017) Adiponectin alters renal calcium and phosphate excretion through regulation of klotho expression. Kidney Int 91:324-337

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