? DESCRIPTION (provided by applicant): 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.

R01DK109547

2016-04-01

2021-01-31