Obesity is associated with adipose dysfunction, which contributes to insulin resistance, diabetes, and heart disease. It has been proposed that adipose dysfunction is caused by an inappropriate response to hypoxia that results in increased ECM expression and reduced angiogenesis. Our data indicate that adipocytemacrophage crosstalk results in increased expression of thrombospondin-1 (TSP-1), a multifunctional protein that promotes fibrosis by activating TGF-beta signaling. TGF-beta has multiple effects on adipose in addition to inducing fibrosis including inhibiting adipogenesis and complicated effects on angiogenesis. Recently, a whole-body knockout of SMAD3 to block TGF-beta signaling resulted in mice with improved metabolic function and browning of their white adipose;this was due in part to reversing the inhibition of TGF-beta on the expression of PGC-1 alpha. Our overall hypothesis is that increased TSP-1 expression and TGF-beta signaling in white adipose with obesity cause increased fibrosis, reduced capillary density, reduced PGC-1 alpha and reduced UCP-1 expression hence less """"""""browning"""""""", and impaired WAT function. Thus, inhibiting the TGF-beta pathway in humans may improve adipose function and reverse the effects of obesity on insulin resistance.
The first aim will characterize the white adipose ECM and capillary density of TSP-1 knockout mice and their littermate controls challenged with a high fat diet.
The second aim will knockout TGF-beta in adipose using cre/lox technology to elucidate the role of TGF-beta signaling on adipose function is response to high fat feeding.
The third aim will determine whether the dramatic reduction in adipocyte PGC-1 alpha by macrophage coculture is TGF-beta dependent.
The fourth aim will determine whether toll-like receptor (TLR) signaling is involved in the adipocyte-macrophage crosstalk that induces TSP-1 and TGF-beta signaling in macrophages. Thus, the two mouse models will indicate the contribution of TSP-1 and TGF- beta to adipose dysfunction with obesity. The coculture studies will begin to define the mechanisms by which adipocytes and macrophages communicate with each other to induce TSP-1 expression by both cells types and to decrease PGC-1 alpha expression in adipocytes.

Public Health Relevance

Adipose tissue becomes dysfunctional with obesity by a complex process. We hypothesize that TGF-beta signaling contributes to this by promoting adiopose fibrosis and by inhibiting the ability of adipose to metabolize fat;inhibiting TGF-beta signaling may be an effective method to combat obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103527-07
Application #
8733728
Study Section
Special Emphasis Panel (ZGM1-TWD-Y)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
7
Fiscal Year
2014
Total Cost
$255,066
Indirect Cost
$85,066
Name
University of Kentucky
Department
Type
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Song, Eun Suk; Jang, HyeIn; Guo, Hou-Fu et al. (2017) Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes. Proc Natl Acad Sci U S A 114:E2826-E2835
Bradford, Emily M; Ryu, Stacy H; Singh, Ajay Pal et al. (2017) Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease. J Immunol 199:1886-1897
Pumphrey, Ashley L; Ye, Shaojing; Yang, Zhengshi et al. (2017) Cardiac Chemical Exchange Saturation Transfer MR Imaging Tracking of Cell Survival or Rejection in Mouse Models of Cell Therapy. Radiology 282:131-138
Muniappan, Latha; Javidan, Aida; Jiang, Weihua et al. (2017) Calpain Inhibition Attenuates Adipose Tissue Inflammation and Fibrosis in Diet-induced Obese Mice. Sci Rep 7:14398
Adamiak, M; Abdelbaset-Ismail, A; Suszynska, M et al. (2017) Novel evidence that the mannan-binding lectin pathway of complement activation plays a pivotal role in triggering mobilization of hematopoietic stem/progenitor cells by activation of both the complement and coagulation cascades. Leukemia 31:262-265
Adamiak, Mateusz; Chelvarajan, Lakshman; Lynch, Kevin R et al. (2017) Mobilization studies in mice deficient in sphingosine kinase 2 support a crucial role of the plasma level of sphingosine-1-phosphate in the egress of hematopoietic stem progenitor cells. Oncotarget 8:65588-65600
Wysoczynski, Marcin; Adamiak, Mateusz; Suszynska, Malwina et al. (2017) Poor Mobilization in T-Cell-Deficient Nude Mice Is Explained by Defective Activation of Granulocytes and Monocytes. Cell Transplant 26:83-93
Brown, J Mark; Temel, Ryan E; Graf, Gregory A (2017) Para-bile-osis Establishes a Role for Nonbiliary Macrophage to Feces Reverse Cholesterol Transport. Arterioscler Thromb Vasc Biol 37:738-739
Akenhead, Michael L; Fukuda, Shunichi; Schmid-Schönbein, Geert W et al. (2017) Fluid shear-induced cathepsin B release in the control of Mac1-dependent neutrophil adhesion. J Leukoc Biol 102:117-126
Wang, Yu; Shoemaker, Robin; Powell, David et al. (2017) Differential effects of Mas receptor deficiency on cardiac function and blood pressure in obese male and female mice. Am J Physiol Heart Circ Physiol 312:H459-H468

Showing the most recent 10 out of 197 publications