Measurement of Bone Marrow-derived Adipocytes in Humans

University Of Colorado Denver, Aurora CO

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Abstract

DESCRIPTION (provided by applicant): Obesity is a strong predictor of chronic disease but the specific accumulation of abdominal fat has emerged as a cardiometabolic risk factor independent of overall obesity. The recognition that adipose tissue is not just an inert fat storag organ, but rather an active endocrine organ secreting a variety of cytokines that have wide reaching actions has provided a potential mechanistic link between regional adiposity and disease risk. Recent preclinical advances in adipocyte biology revealed that new adipocytes arise from a heterogeneous population of both resident and non-resident progenitor cells, a feature that may determine the phenotype of the resultant adipocytes. Mouse models have provided preliminary evidence for accumulation of a unique lineage of non- resident progenitor cells, arising from the bone marrow, which may be regulated in an age- and depot-specific manner. This lineage is of particular interest because of its detrimental phenotypic signature (e.g., insulin resistance, increased inflammatory markers, and decreased leptin) and its preferential accumulation in females with age, particularly in visceral depots. The global aim of this proposal is to perform the first investigation and characterization of bone marrow progenitor (BMP)-derived adipocytes in human adipose tissue. The first step in accomplishing this novel project will be to utilize an analogous approach to the bone marrow transplant strategy used in the previous animal studies, by obtaining adipose tissue samples from patients with a history of bone marrow transplantation. Identification of cells of bone marrow origin in this population is possible by microchimerism analysis (Aim 1), a technique regularly utilized clinically as an indicator of transplant engraftment. In conjunction with the chimerism analysis, we will use flow cytometry to determine a distinct cell surface marker (Aim 1) and gene expression analysis to delineate a unique genetic 'fingerprint' (Aim 2), both of which will be used in future studies to identify BMP-derived adipocytes in the general human population (non- bone marrow transplant patients). Finally, the cell surface marker and genetic 'fingerprint' identified in Aims 1 and 2 wil be utilized to measure BMP-derived adipocytes in subcutaneous and visceral adipose tissue from healthy adults (no history of BMT) (Aim 3). These studies will confirm that BMP-derived adipocytes are present in human adipose tissue and that they demonstrate the same negative phenotype as in the mouse model. The results of this investigation will provide the knowledge and tools necessary to continue studies of this unique adipocyte lineage in many models of human disease and obesity and may reveal potential mechanistic targets for future therapies to reduce the negative health outcomes associated with abdominal adiposity.