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Principal Investigator: Dwight J Klemm
Organization: VA EASTERN COLORADO HEALTH CARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
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.
Terms: <Abdomen><Ablation><Adipocytes><Adipose Cell><Adipose tissue><Age><Aging><Antibody Therapy><Aquadiol><Area><Attenuated><BAT uncoupling protein><Biogenesis><Blood Precursor Cell><Body Composition><Body Tissues><Body fat><Bone Development><Bone Marrow><Bone Marrow Reticuloendothelial System><Buttocks><CD11b><CD140a Antigens><CR3A><Cancers><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellularity><Characteristics><Communities><Coxa><Data><Diabetes Mellitus><Dimenformon><Diogyn><Diogynets><Disease><Disorder><ERalpha><ERα><ESR1><ESR1 gene><Energy Expenditure><Energy Metabolism><Estrace><Estradiol><Estradiol Receptor alpha><Estradiol Receptor α><Estradiol-17 beta><Estradiol-17beta><Estraldine><Estrogen Receptor 1><Estrogen Receptor alpha><Estrogen Receptor α><Estrogen deficiency><Estrogens><Exhibits><FSH Receptors><Fat Cells><Fats><Fatty Tissue><Fatty acid glycerol esters><Female><Follicle Stimulating Hormone><Follicle Stimulating Hormone Receptor><Follitropin><Gene Expression><Genes><Gonadal Hormones><Gonadal Steroid Hormones><HPO axis><Health><Health Care Systems><Healthcare Systems><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Heterogeneity><Hip><Hip region structure><Hormone Receptor><Human><ITGAM><ITGAM gene><Incidence><Individual><Inflammation><Inflammatory><Integrins><Integrins Extracellular Matrix><Intermediary Metabolism><Intracellular Communication and Signaling><Isoforms><Knock-out><Knockout><Leptin><Life><Link><Lipocytes><Lung Diseases><Lysozyme><MAC1A><MO1A><Macrophage><Malignant Neoplasms><Malignant Tumor><Mature Lipocyte><Mature fat cell><Measures><Medical><Menopause><Mesenchymal><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitochondria><Modern Man><Muramidase><Murine><Mus><Myelogenous><Myeloid><Mφ><N-Acetylmuramide Glycanhydrolase><NR3A1><Ob Gene Product><Ob Protein><Obese Gene Product><Obese Protein><Obesity><Oophorectomy><Operative Procedures><Operative Surgical Procedures><Origin of Life><Ovarian Ablation><Ovarian hormone><Ovariectomy><Ovocyclin><Ovocylin><PDGF alpha Receptor><PDGF receptor α><PDGF-R-alpha><PDGFR-α><PDGFRα><Patients><Peptidoglycan N-acetylmuramoylhydrolase><Phenotype><Platelet-Derived Growth Factor Receptor Alpha Polypeptide><Platelet-Derived Growth Factor alpha Receptor><Process><Production><Progynon><Proliferating><Protein Isoforms><Pulmonary Diseases><Pulmonary Disorder><Receptor Protein><Reporting><Research><Role><Scientific Inquiry><Sex Hormones><Sex Steroid Hormones><Signal Transduction><Signal Transduction Systems><Signaling><Stromal Cells><Surgical><Surgical Interventions><Surgical Procedure><Testing><Therapeutic Estradiol><Therapeutic Estrogen><Tissues><Veterans><Veterans Health Administration><Veterans Health Affairs><Weight Gain><Weight Increase><Woman><abdominal adiposity><abdominal fat><adipose><adiposity><ages><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><attenuate><attenuates><biological signal transduction><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><body weight gain><body weight increase><brown adipose tissue uncoupling protein><cardiovascular disorder><co-morbid><co-morbidity><combat><comorbidity><corpulence><cytokine><deficiency in estrogen><diabetes><disease of the lung><disorder of the lung><energy balance><female gonadectomy><gonadal steroids><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><hormonal signals><hormone signals><hypothalamic pituitary ovarian axis><interest><lung disorder><male><malignancy><military veteran><mitochondrial><mouse model><murine model><neoplasm/cancer><new approaches><novel approaches><novel strategies><novel strategy><ovarian suppression><patient population><platelet-derived growth factor receptor α><prevent><preventing><progenitor><progenitor cell population><progenitor population><receptor><sex steroid><social role><stem and progenitor cell population><stem cell population><surgery><thermogenin><uncoupling protein 1><veteran population><white adipose tissue><wt gain><yellow adipose tissue>