# Defining the role of an endothelial-adipocyte precursor axis in adipocyte hyperplasia

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $540,289

## Abstract

Project Summary
 Obesity, which is defined as the excess accumulation of white adipose tissue (WAT) is associated with the
development of numerous metabolic, inflammatory, and cardiovascular derangements. However, it is the
accumulation of visceral adipose (VWAT) that is associated with metabolic diseases, while the accumulation of
subcutaneous adipose (SWAT) is thought to protect against the development of obesity-associated disease. Sex
hormones are known to influence both the accumulation of adipose, adipose distribution between VWAT and
subcutaneous adipose (SWAT), and the development of metabolic disease, but the precise mechanisms by which
sex hormones influence adipose function and distribution remain unclear.
 We have previously shown that there is an obesity-specific mechanism of adipogenesis that drives adipocyte
hyperplasia in a sex-specific pattern. Estrogen plays a role in this process, where exogenous estrogen drives a
female-like patterning (both VWAT and SWAT) of adipocyte hyperplasia in male mice, while the absence of systemic
estrogen in female mice results in male-like patterning (VWAT only response). Our preliminary data indicates that in
the absence of systemic estrogen, estrogen signaling still plays a direct role in VWAT adipocyte hyperplasia at the
onset of obesity. We show here that it is VWAT endothelial cells that express aromatase and thereby produce the
estrogen required for adipocyte hyperplasia in males and ovariectomized females. We propose that aromatase
expression in VWAT endothelium is controlled by glucocorticoids, linking the VWAT-specific actions of estrogen to
the hypothalamic-pituitary-adrenal (HPA) axis. Based on our preliminary data, we hypothesize that estrogen and
glucocorticoids participate in an endothelial cell-adipocyte precursor axis that regulates obesogenic adipogenesis,
thereby influencing distribution of WAT and impacting metabolic disease. Here we will establish the role of adipose-
produced estrogen in obesity and metabolic disease, determine the mechanisms that regulate aromatase in VWAT
endothelial cells and define the molecular mechanisms of that regulate estrogen action in adipocyte precursors.

## Key facts

- **NIH application ID:** 10813020
- **Project number:** 5R01DK132563-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Matthew S Rodeheffer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $540,289
- **Award type:** 5
- **Project period:** 2023-03-22 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813020

## Citation

> US National Institutes of Health, RePORTER application 10813020, Defining the role of an endothelial-adipocyte precursor axis in adipocyte hyperplasia (5R01DK132563-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10813020. Licensed CC0.

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