Two thirds of Americans are overweight or obese, and similar statistics have been reported in other developed nations. Excess body fat is linked to type 2 diabetes, cardiovascular disease, certain forms of cancer and other disorders. Increases in visceral adiposity are in particular linked to these comorbidities whereas increases in subcutaneous fat correlate with a lower risk for these conditions. The differential impact of visceral versus subcutaneous fat on health is due in large part to the presence of distinct adipocyte populations in these adipose depots. The goal of our research is to understand how these distinct adipocyte populations are generated, and devise strategies to regulate their production and thereby control the effects of excess adipose tissue on health. Over the last 8 years we have identified a population of adipocytes that are produced from stem cells in the bone marrow. These stem cells leave the marrow and travel to fat tissue where they become new adipocytes. These marrow progenitor-derived adipocytes accumulate preferentially in abdominal fat, and exhibit potentially harmful characteristics.
This first aim of this project is designed to determine whether marrow progenitor-derived adipocytes are generated via a hematopoietic-to-mesenchymal transition, a novel developmental pathway. If so, then this developmental process may be a potential target for therapies to modulate the cellular composition of adipose tissue.
The second aim of the project will investigate the role of the cell surface protein, integrin b1, in driving the hematopoietic-to-mesenchymal transition. These mechanistic studies should highlight specific molecular targets that control the production of marrow progenitor-derived adipocytes. Finally, aim 3 will test whether marrow progenitor-derived adipocytes, even if generated in relatively low numbers, affect adipose tissue development and function, and whole body physiology in a negative manner. Beyond our genome-wide expression profiling, nothing is known about the functional significance of this unique adipocyte population, making these experiments of paramount importance. Successful completion of these studies will define a novel developmental process, a hematopoietic-to-mesenchymal in the production of a subset of physiologically important adipocytes. The experiments will also begin to elucidate the mechanisms that promote this transition, and demonstrate that these mechanisms are capable of regulating the cellular composition and function of adipose tissue. These mechanisms have the tremendous potential to modulate adipose tissue function for the benefit of human health.

Public Health Relevance

Obesity is a major medical problem for which there are few effective therapies. This project will investigate the processes and events that control the production of potentially harmful fat cells. Successful completion of these studies will identify new targets for controlling the production of harmful fat-storing cells and prevent fat-related chronic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK109547-04
Application #
9626404
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Haft, Carol R
Project Start
2016-04-01
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Gavin, Kathleen M; Kohrt, Wendy M; Klemm, Dwight J et al. (2018) Modulation of Energy Expenditure by Estrogens and Exercise in Women. Exerc Sport Sci Rev 46:232-239
Gavin, Kathleen M; Sullivan, Timothy M; Kohrt, Wendy M et al. (2018) Ovarian Hormones Regulate the Production of Adipocytes From Bone Marrow-Derived Cells. Front Endocrinol (Lausanne) 9:276
Reusch, Jane E B; Kumar, T Rajendra; Regensteiner, Judith G et al. (2018) Identifying the Critical Gaps in Research on Sex Differences in Metabolism Across the Life Span. Endocrinology 159:9-19
Gavin, Kathleen M; Majka, Susan M; Kohrt, Wendy M et al. (2017) Hematopoietic-to-mesenchymal transition of adipose tissue macrophages is regulated by integrin ?1 and fabricated fibrin matrices. Adipocyte 6:234-249
Ye, Haobin; Adane, Biniam; Khan, Nabilah et al. (2016) Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche. Cell Stem Cell 19:23-37
Gavin, Kathleen M; Gutman, Jonathan A; Kohrt, Wendy M et al. (2016) De novo generation of adipocytes from circulating progenitor cells in mouse and human adipose tissue. FASEB J 30:1096-108