Date of Award
Fall 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Molecular, Cellular, and Developmental Biology
First Advisor
Rodeheffer, Matthew
Abstract
In obesity, white adipose tissue (WAT) distribution differs between the sexes, with men preferentially accumulating visceral WAT (VWAT) and females exhibiting subcutaneous WAT (SWAT) accumulation bias. Obesogenic adipocyte hyperplasia (increase in adipocyte number) contributes to the sexually dimorphic pattern of fat distribution in mice driven by cues in the tissue microenvironment, with females displaying hyperplasia in both VWAT and SWAT, while males have VWAT-specific hyperplasia, implicating a role for sex hormones in this process during obesity. Sex hormones play a pivotal role in physiology and disease. Estrogen, the female sex hormone, has been long implicated in having protective roles against obesity mainly through its signaling via estrogen receptor alpha (ERα). However, the direct impact of estrogens in WAT function and growth are not understood.In my thesis work, I dissect the role of estrogen signaling in WAT growth using several approaches and mouse models that target adipocyte cells, adipocyte precursor cells (APs) and endothelial cells (ECs) within WAT. By studying the natural hormonal cycle in female mice, I found that estrogen drives adipocyte hyperplasia in females to promote obesity when the onset of a HFD coincides with an estrogen surge (proestrus). Transcriptome analysis of APs reveals estrogen signaling is upregulated by a HFD in both fat depots of females, and surprisingly, in the hyperplastic VWAT of males. However, loss of ERα in APs via PdgfRα-cre leads to exacerbated obesity upon HFD feeding in both male and female mice, with SWAT-specific expansion in male mice while deletion of ERα from adipocytes using Adiponectin-cre does not affect adipose mass. Further characterization of the AP-ERα-KO mice reveals females are infertile and have increased plasma levels of various sex hormones, including estradiol (females only) and androgens (both sexes). These findings compromise the study of estrogen signaling within the adipocyte lineage using the PdgfRα-cre strain. However, through AP transplant studies, I demonstrate that the increased AP hyperplasia in AP-ERα-KO male SWAT is not due to AP-intrinsic mechanisms, but are rather mediated by off-target effects. Importantly, transplanted AP-ERα-KO cells fail to proliferate in female SWAT and male VWAT tissues on HFD, indicating that under normal tissue microenvironment, ERα is required for AP proliferation in both sexes. Contrary to females, males do not have high circulating estrogen levels. But WAT is a major site of estrogen production. Thus, I assessed Cyp19a1 expression (aromatase: estrogen-producing enzyme) in WAT cell populations and found it exclusively in ECs. Deletion of Cyp19a1 in ECs inhibits HFD-induced VWAT hyperplasia and ameliorates obesity in males while female KOs respond normally to the HFD. However, upon gonadectomy, females have reduced obesity by decreases in both hypertrophy and hyperplasia. Lastly, I identify the estrogen-inactivating enzyme, Sult1e1, is a male-specific regulator of AP hyperplasia and its deletion in APs triggers proliferation under normal diet conditions in males. Together, these data indicate that gonadal estrogen drives ERα-dependent adipocyte hyperplasia in premenopausal females while EC-derived estrogen is an important component of the WAT microenvironment that promotes hyperplasia in males and postmenopausal females, effectively influencing the differential fat distribution between the sexes.
Recommended Citation
Saavedra-Peña, Rocío del Mar, "The Role of Estrogen Signaling in Sexually Dimorphic Adipose Expansion" (2022). Yale Graduate School of Arts and Sciences Dissertations. 788.
https://elischolar.library.yale.edu/gsas_dissertations/788
