# Deconstructing the diet-induced remodeling of adipose tissue

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $600,032

## Abstract

Project Summary
Obesity is a major risk factor for several metabolic diseases most notably diabetes and cardiovascular disease.
During diet-induced obesity, visceral white adipose tissue (vWAT) responds to caloric excess through the
recruitment of new fat cells (hyperplasia) and enlargement of existing white adipocytes (hypertrophy). To
facilitate this adipocyte expansion, the stromal vascular compartment consisting of mesenchymal stromal cells
(MSC) and immune cells undergo dramatic changes in cell number and gene expression leading to WAT fibrosis
and inflammation, thereby exacerbating metabolic dysfunction. To investigate the mechanisms controlling
hyperplasia, we applied single cell RNA sequencing (scRNAseq) to define the cellular landscape of the stroma
and examine how it changes during diet-induced obesity. We observed an extensive increase in macrophages
including CD9+ senescent macrophages which secreted profibrogenic factors most notably osteopontin. We also
identified four distinct populations of MSCs and an early adipocyte progenitor cluster expressing both PDGFRα
and PDGFRβ. In an obese state, these cells enhanced their ECM production thereby contributing to fibrosis. In
the case of hypertrophy, adipocytes progressively increase their volume as they take up and store excess
calories. This expansion along with reduced angiogenesis causes local hypoxia that induces the deposition of
pericellular ECM. The combination of ECM production from MSCs and adipocytes leads to formation of a stiff
and inflexible barrier against further adipocyte expansion and adipocyte dysfunction. To identify mechanisms
responsible for the dysfunction, we performed a RNAseq analysis of isolated adipocytes to assess global
pathway changes occurring during a prolonged HFD. The studies revealed that adipocytes respond dramatically
to the diet by enhancing expression of genes encoding ECM, focal adhesion, and cytoskeletal proteins. In fact,
the transcriptional signature of the resultant pathological adipocytes was similar to fibroblastic-like or progenitor
cells. The transcriptional mechanisms regulating both hyperplasia and hypertrophy are still poorly defined. Our
earlier studies discovered that the transcriptional cofactor myocardin-related transcription factor, MRTFA
contributes to diet-induced metabolic disruption of adipose tissue by regulating the fate of MSCs to favor
fibrogenesis over adipogenesis. We hypothesize that MRTFA integrates multiple fibrogenic signals leading to
ECM production by MSCs producing mechanical stress on adipocytes leading to their fibroblastic-like phenotype
and adipose tissue dysfunction. We propose three aims:1: Determine the effect of conditional deletion of MRTFA
in adipogenic progenitors on the cellular composition and function of adipose tissue in obese mice. 2: Define the
signaling pathways regulating adipocyte progenitor cell fate in response to diet. 3: Identify transcriptional
mechanisms regulating the fate of vascular proge...

## Key facts

- **NIH application ID:** 10798262
- **Project number:** 5R01DK134534-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** STEPHEN ROBERT FARMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $600,032
- **Award type:** 5
- **Project period:** 2023-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798262

## Citation

> US National Institutes of Health, RePORTER application 10798262, Deconstructing the diet-induced remodeling of adipose tissue (5R01DK134534-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10798262. Licensed CC0.

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