Ovarian hormone suppression and regulation of adipogenesis in women

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DESCRIPTION (provided by applicant): Estradiol (E2) deficiency triggers weight gain, and specifically abdominal fat gain, in women. The shift toward central adiposity after menopause likely contributes to increased risk for the metabolic syndrome and associated chronic diseases (i.e., type 2 diabetes, coronary artery disease, hypertension). The long-term aim is to understand the mechanisms by which E2 deficiency mediates increases in abdominal adiposity. The primary aim (PA1) of the R21 is to determine whether ovarian hormone suppression in premenopausal women, which is known to cause fat gain, triggers an increase in adipogenesis (i.e., increase in cell number) in abdominal adipose tissue. This will be assessed by measuring the changes in cell size distribution and the incorporation of deuterium (2H) into DNA of cells in the non-stromal (i.e., mature adipocyte) fraction. Secondary aims are to determine: SA2) effects of ovarian hormone suppression on mRNA expression of factors involved in adipogenesis (C/EBP1, PPAR3) and markers of macrophage infiltration (CD68, Emr-1) and inflammation (IL-6, TNF-1); and SA3) whether new adipocytes arise from non-resident bone marrow progenitor (BMP) cells using cell surface markers (Notch 4, Platelet-derived Growth Factor Receptor (PDGFR) 2, Integrin 15, CD36) that enable detection by flow cytometry. To achieve these aims, 24 premenopausal women will be studied before and after 30 and 60 days of ovarian hormone suppression via gonadotropin releasing hormone agonist therapy with add-back of placebo (GnRHAG+PL) or estradiol (GnRHAG+E2). Hypotheses are: H1a) GnRHAG+PL for 60 days will result in a larger increase in small adipocytes (<40 5m) when compared with GnRHAG+E2. Because fat mass increases during GnRHAG+PL, an increase in the number of small adipocytes will be interpreted as an increase in adipogenesis and not as evidence of adipocyte atrophy; H1b) The incorporation of 2H in the non-stromal cell fraction DNA will be increased in response to GnRHAG+PL, as compared with GnRHAG+E2. Because the non-stromal fraction contains mature adipocytes, an increase in 2H- enriched DNA should reflect adipogenesis; H2) Ovarian hormone suppression will increase mRNA expression of factors associated with adipogenesis, macrophage infiltration, and inflammation (C/EBP1, PPAR3, CD68, Emr-1, IL-6, TNF-1) when compared with baseline (before vs after GnRHAG+PL) and when compared with E2 add-back (GnRHAG+PL vs GnRHAG+E2); and H3) Ovarian hormone suppression will increase BMP-derived adipocytes when compared with baseline (before vs after GnRHAG+PL) and when compared with E2 add-back (GnRHAG+PL vs GnRHAG+E2). To the best of our knowledge, this will be the first in vivo study of the role of E2 as a regulator of adipogenesis in humans. Because it is believed that adipocytes are programmed to achieve a certain volume of fat, an increase in adipocyte number would lead to a gain in fat mass that would be very difficult to reverse. Thus, identifying strategies that effectively prevent an increase in adipogenesis during ovarian hormone withdrawal would be of high clinical importance. PUBLIC HEALTH RELEVANCE: Women are largely protected against abdominal adiposity prior to the menopause. The loss of estrogen at the time of the menopause triggers an increase in abdominal fat accumulation, which likely contributes to increased risk for the metabolic syndrome, type 2 diabetes mellitus, coronary artery disease, and hypertension. The proposed studies will test the novel hypothesis that estrogen deficiency results in abdominal fat gain by triggering an increase in the number of fat cells.