The past 3 years have yielded a wealth of information on the physiological role of adiponectin, an adipocyte-specific secretory protein. Adiponectin has gained widespread acceptance as a valuable indicator of systemic insulin sensitivity. However, the precise mechanism of action that leads to the systemic insulin sensitizing effects observed upon exposure to higher levels of the protein in circulation remains elusive. We propose to examine the biogenesis of the molecule at the level of the adipocyte, look at factors that interact with the protein in circulation and take advantage of a number of genetic mouse models to examine systemic effects of adiponectin. Specifically, we aim to:
Specific Aim 1) To determine how adipocytes control the assembly and release of adiponectin complexes. A very significant percentage of adiponectin synthesized does not get exported and is degraded intracellularly. We want to understand whether a specific subpopulation of adiponectin molecules is earmarked for degradation, which (if any) stimuli can re-direct this population towards secretion, and whether the oligomerization state plays a role in this process. Furthermore, we want to determine which chaperones are critically involved in the assembly of the bioactive, high molecular weight form, and which residues in adiponectin play a major role in this process.
Specific Aim 2) To examine which (if any) serum factors are associated with adiponectin and whether such serum factors play a critical role in adiponectin function. For this purpose, we have generated a battery of monoclonai antibodies that allow us to immuno-precipitate adiponectin from serum under a number of different conditions to test whether different metabolic states affect cause changes in specific serum factors associated with adiponectin under those conditions.
Specific Aim 3) To explore the role of adiponectin systemically, taking advantage of a number of different animal models that we have generated. We have generated mouse models that either lack adiponectin, overexpress adiponectin, secrete adiponectin from liver, express the mutant (Cys39Ser) version of adiponectin that fails to assemble into higher order complexes as well as a novel transgenic mouse model that allows the inducible ablation of adipocytes. Intercrosses between these mouse models will allow us to define the mechanism of action of adiponectin in vivo and shed light on structure/function relationships of this adipokine. It is expected that these studies will contribute fundamental insights towards understanding the role of adiponectin in insulin sensitization in hepatocytes, the secretory pathway of adipocvtes, and interactions with serum factors important for its function.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Haft, Carol R
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University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
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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
Kruglikov, Ilja L; Scherer, Philipp E (2017) General theory of skin reinforcement. PLoS One 12:e0182865
Crewe, Clair; An, Yu Aaron; Scherer, Philipp E (2017) The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J Clin Invest 127:74-82

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