Age- and Sex-associated Production of Adipocytes from Bone Marrow Stem Cells

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 DESCRIPTION (provided by applicant): Veterans are more likely to be overweight than non-veterans of a similar age and sex. Moreover, a larger proportion of veterans who use Veteran Affairs (VA) care are obese than among those veterans who do not use VA care. Considering the significant burden from obesity among the veterans cared for by the VA system, understanding the mechanisms underlying, and consequences resulting from, increased accumulation of adiposity is critical for development of more successful programs to help veterans lose weight, attenuate further weight gain, and manage comorbid conditions. Development of these strategies will require a better understanding of the fat cell (adipocyte) populations that comprise fat tissue in different body locations, the developmental processes that govern their production, and their contribution to chronic disease. Importantly, adipocytes in different body regions exhibit distinct functional characteristics. These differences are generally attributed to changes in existing adipocytes or to the production of distinct adipocyte populations from adipose tissue-resident preadipocytes. Our novel and paradigm-shifting contribution to this field demonstrated that some white adipocytes are generated from non-resident progenitors arising from bone marrow. These unique cells may explain, in part, the heterogeneous composition and function of fat in different body regions, and the harmful impact of increased visceral adiposity that accompanies aging and the loss of circulating gonadal hormones. The goals of this pilot project are to evaluate age and sex as factors associated with the accumulation of bone marrow progenitor (BMP)-derived adipocytes and to assess the metabolic impact of BMP-derived adipocyte accumulation. We will accomplish these goals through a combination of human and small animal studies. To test whether BMP-derived adipocytes accumulate with age and have a harmful physiological impact (Aim 1), we will study mice in which BMP-derived adipocytes are selectively ablated or accumulate as usual (control). We hypothesize that BMP-derived adipocyte-deficient mice will have a healthier metabolic profile (i.e., lower inflammatory cytokines and better insulin sensitivity) compared to control mice. To test whether the accumulation of BMP-derived adipocytes in humans is directly related to age and sex (Aim 2a), we will obtain subcutaneous abdominal adipose tissue biopsies from women and men of a wide age range who have undergone bone marrow transplantation. We hypothesize that the number of BMP-derived adipocytes, as measured by adipocyte chimerism, will increase with age and time since transplant and be higher in women than men. In Aim 2b we seek to determine a biomarker to identify and measure the accumulation of BMP-derived adipocytes in healthy humans. We expect this pilot project to contribute novel discoveries of how BMP-derived adipocytes impact metabolic health and whether age and sex serve as important determinants of their accumulation. Understanding the accumulation of BMP-derived adipocytes and the resultant physiological consequences is expected to lead to novel therapies for preventing the negative health impacts of obesity and a more clear understanding of whether geriatric obesity differs from classic obesity. Furthermore, if our hypotheses are supported, this will lead to an array of novel research on causes of obesity-related diseases, an important health issue in both the aging veteran and civilian populations.