Our overall objective is to elucidate the mechanisms that control formation and remodeling of adipose tissues and to determine whether and how these processes are altered by estrogen signaling. Modern life has provided unparalleled access to food supplies, contributing to a worldwide epidemic of obesity and secondary negative health consequences such as diabetes, fatty liver, cardiovascular disease, and even cancer. Thus there is an urgent need to better understand the mechanisms and molecules that control formation of adipocytes and the expansion of adipose tissue. Adipose tissue is highly dynamic, expanding and shrinking in response to various dietary, pharmacologic and hormonal stimuli. For example, estrogen deficiency (e.g., menopause) redistributes fat into metabolically maladaptive visceral fat depots, thereby predisposing or triggering diabetes. In contrast, estrogen shifts deposition into metabolically protective subcutaneous depots, thereby reducing metabolic diseases. Our initial data indicate that remodeling involves both hypertrophy and hyperplasia (stem cell recruitment). That new adipocytes form throughout life indicates the presence of a putative adipogenic stem cell. We recently identified such an adipose stem cell by designing, engineering, and studying mice that express molecular reporters in the adipose lineage. These unique reagents, termed Adipo-Trak, enable us to visualize adipose stem cells in vivo, as well as to follow their descendents as they divide, migrate and develop into mature adipocytes;thereby allowing us to assess estrogen-dependent remodeling. Health risks due to increased adiposity vary depending on adipose tissue deposition;intra-abdominal (visceral) adipose tissue (increased with menopause) carries a much greater risk for cardiovascular disease, diabetes, cancers, and other disorders, than does subcutaneous adipose tissue (induced by estrogen). The focus of this proposal is to delineate how estrogen remodels adipose tissue in this medically relevant manner. By integrating surgical (ovariectomy), pharmacological (estrogen), and genetic (adipose lineage specific estrogen receptor knockouts) manipulations, we will model these morphogenic transformations and determine how they affect adipose lineage specification using our newly developed Adipo-Trak mice. We will define the mechanistic underpinnings of the estrogenic- remodeling effects on adipose stem cells, adipose niche cells and adipocytes. We will also elucidate how physiological and pharmacological stimuli regulate the stem population and the growth of adipose tissue. These studies are designed to elucidate new aspects of adipose biology and metabolic control and how estrogen provides a protective effect, thereby highlighting those that are particularly relevant to new therapies for obesity and diabetes.

Public Health Relevance

The ability to regulate fat storage and metabolism are fundamental processes. However, the dual epidemics of obesity and diabetes endanger millions and are altering our health care landscape. This crisis that could be addressed by identifying genes that control formation, expansion, and remodeling of adipose tissue-for example that regulated by estrogen. We recently identified the adipose stem cell and found that it is important in the normal maintenance of adipose tissue mass and the response to diabetes treatments. Further, adipose lineage cells appear critical for the medically relevant adipose remodeling induced by estrogen or estrogen-deficiency. Our goal is to unravel the developmental, physiological and molecular mechanisms underlying these effects, which we believe will enhance our understanding of adipocyte biology and may lead to novel therapeutic targets for obesity and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK088220-04
Application #
8469854
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$473,844
Indirect Cost
$175,829
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Lapid, Kfir; Lim, Ajin; Clegg, Deborah J et al. (2014) Oestrogen signalling in white adipose progenitor cells inhibits differentiation into brown adipose and smooth muscle cells. Nat Commun 5:5196
Davis, Kathryn E; Carstens, Elizabeth J; Irani, Boman G et al. (2014) Sexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis. Horm Behav 66:196-207
Jiang, Yuwei; Berry, Daniel C; Tang, Wei et al. (2014) Independent stem cell lineages regulate adipose organogenesis and adipose homeostasis. Cell Rep 9:1007-22
Berry, Daniel C; Stenesen, Drew; Zeve, Daniel et al. (2013) The developmental origins of adipose tissue. Development 140:3939-49
Stenesen, Drew; Suh, Jae Myoung; Seo, Jin et al. (2013) Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies. Cell Metab 17:101-12
Wei, Wei; Zeve, Daniel; Wang, Xueqian et al. (2011) Osteoclast progenitors reside in the peroxisome proliferator-activated receptor ?-expressing bone marrow cell population. Mol Cell Biol 31:4692-705
Xu, Yong; Nedungadi, Thekkethil P; Zhu, Liangru et al. (2011) Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab 14:453-65
Tang, Wei; Zeve, Daniel; Seo, Jin et al. (2011) Thiazolidinediones regulate adipose lineage dynamics. Cell Metab 14:116-22
Wei, Wei; Zeve, Daniel; Suh, Jae Myoung et al. (2011) Biphasic and dosage-dependent regulation of osteoclastogenesis by ýý-catenin. Mol Cell Biol 31:4706-19