Diminished Sex Hormone Levels Stimulate Production of Inflammatory Bone Marrow-Derived Adipocytes

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Menopause is a normal occurrence in all women and a gradual process that begins in the 5th decade of life. Menopause is characterized by the loss of ovarian hormones that ultimately leads to a number of comorbidities including weight gain, redistribution of fat from hips, waist and buttocks to the abdomen, and decreased metabolic activity. Female US military veterans are the fastest growing patient population in the Veterans Administration Health Care system, and more than a third of those patients are pre-, post- or currently menopausal. However, the mechanisms by which menopausal changes in ovarian hormone production regulate body fat content and metabolism is an unexplored area in VA research. We have discovered a subpopulation of adipocytes in adipose depots of mice and humans generated from hematopoietic stem cells, termed bone marrow-derived adipocytes (BMDA). These cells are produced in numbers sufficient to influence adipose tissue function, and their production is increased by loss of gonadal sex hormones in mouse models that mimic menopause in women. These observations were noteworthy because BMDAs differ from conventional adipocytes and possess a potentially detrimental phenotype, characterized by elevated production of inflammatory cytokines. Recent preliminary data demonstrates that BMDA are produced from adipose tissue stromal cells that express both myeloid and mesenchymal marker that we have termed “myeloid adipocyte progenitors” or MAPs. Since evidence supporting the proliferation of mature adipocytes remains controversial, the ability of gonadal hormones to regulate BMDA abundance can be attributed to the production and/or proliferation of MAPs. This project will test the hypothesis that estrogen and follicle stimulating hormone differentially regulate the production of MAPs (and BMDAs), altering the cellular composition of adipose and resulting in significant changes in metabolic and inflammatory phenotype. Three Specific Aims will test this hypothesis by determining whether 1) ablation of ovarian hormone receptors, or 2) direct depletion of ovarian hormones regulates BMDA abundance. A third aim will measure changes in body composition and metabolic parameters in mice with depletion of MAPs and ovarian hormones. Successful completion of these studies has the potential to establish the crucial contribution of MAPs to adipose tissue heterogeneity and changes to adipose tissue function with loss of ovarian hormone production. A better understanding of this phenomenon will highlight opportunities to control the cellular composition and function of adipose tissue as a novel strategy to combat menopausal comorbidities.