The goal of this project is to understand the mechanisms that control the development and function of human adipose tissue. Adipose tissue fulfills critical physiological roles, including the regulation of satiety, whole body energy homeostasis, longevity and reproductive health. Abnormalities of adipose tissue development result in ectopic lipid deposition in liver and muscle, accompanied by insulin resistance and metabolic disease. How the growth and differentiation of adipocytes is coordinated with the growth of the capillary network necessary to form functional adipose tissue in adults is not known. Using a novel method to assess adipose tissue capillary formation we find that insulin levels in humans positively correlate with enhanced adipose tissue angiogenesis. Moreover, insulin directly stimulates capillary outgrowth from explants from mouse epidydimal fat pads, in a manner that is strongly synergized by high-fat diet (HFD) feeding. These data support the hypothesis that adipose tissue angiogenesis and adipogenesis are coordinated to expand adipose tissue in response to excess caloric intake. We seek to uncover the cellular and molecular mechanisms by which adipose tissue angiogenesis is stimulated synergistically by high fat diet and insulin.
Specific Aim 1. To define the mechanisms by which high fat diet stimulates adipose tissue capillary sprout formation. We shall a) determine whether HFD feeding alters the number of potential endothelial cell precursors, in conjunction with increasing endothelial cell proliferation, b) define whether HFD induces the recruitment of hematopoietic-derived precursors into adipose tissue, and c) define the role of adipose tissue macrophages in mediating the increased capillary outgrowth seen in HFD. This latter is relevant for our understanding the relationships between inflammation, obesity, angiogenesis and insulin resistance.
Specific Aim 2. To define the mechanisms by which insulin stimulates capillary sprout formation. High- resolution microscopy techniques will be used to identify the cells that a) respond to insulin signaling, and b) proliferate in response to insulin. Probes for insulin signaling pathways, as well as BrDU tracing will be used to define the responsiveness of endothelial cells, adipose tissue-derived stem cells, or putative endothelial progenitor cells in the tissue. Preliminary data indicate that insulin stimulates the production of pro-angiogenic factors by adipocytes. We propose strategies to identify these factors through proteomic techniques.
Specific Aim 3. To define the mechanism by which HFD potentiates insulin stimulation of capillary sprout formation. We have identified growth factors and signaling pathways that are up-regulated by short term HFD, and that may mediate the synergistic effect of insulin on capillary outgrowth. We will directly determine the effects of these factors on capillary sprout formation and on the effects of insulin on this process. In addition, we will conduct an unbiased search for secreted factors from adipose tissue from HFD-fed animals that could enhance insulin action, using co-culture and biochemical approaches to indentify such factors. !

Public Health Relevance

We will be studying how blood vessels form in adipose tissue, a process known as angiogenesis. This process is required for adipose tissue to expand and adequately store excess calories. These studies will help us understand how adipose tissue expands and why adipose tissue is distributed into different regions (abdomen or limbs) in different individuals. It will also help us understand the potential mechanisms by which some but not all overweight individuals develop heart disease and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK089101-02
Application #
8309084
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2011-08-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$364,368
Indirect Cost
$142,868
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Rojas-Rodriguez, Raziel; Gealekman, Olga; Kruse, Maxwell E et al. (2014) Adipose tissue angiogenesis assay. Methods Enzymol 537:75-91
Gealekman, Olga; Gurav, Kunal; Chouinard, My et al. (2014) Control of adipose tissue expandability in response to high fat diet by the insulin-like growth factor-binding protein-4. J Biol Chem 289:18327-38
Corvera, Silvia; Gealekman, Olga (2014) Adipose tissue angiogenesis: impact on obesity and type-2 diabetes. Biochim Biophys Acta 1842:463-72
Young, James L; Mora, Alfonso; Cerny, Anna et al. (2012) CD14 deficiency impacts glucose homeostasis in mice through altered adrenal tone. PLoS One 7:e29688
Tran, Khanh-Van; Gealekman, Olga; Frontini, Andrea et al. (2012) The vascular endothelium of the adipose tissue gives rise to both white and brown fat cells. Cell Metab 15:222-9
Hardy, Olga T; Czech, Michael P; Corvera, Silvia (2012) What causes the insulin resistance underlying obesity? Curr Opin Endocrinol Diabetes Obes 19:81-7