Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Deconstructing the diet-induced remodeling of adipose tissue

Award Number: R01DK134534
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2027

Group Awards By:

View Award Description

Deconstructing the diet-induced remodeling of adipose tissue - 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 progenitors. At the completion of these aims, we will have defined new mechanisms regulating WAT remodeling during obesity and identified targets for development of anti- obesity therapeutics.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $625,033 )
2026	2026	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/26/2026	NON-COMPETING CONTINUATION	$625,033
2026	2026	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	4	3/20/2026	NON-COMPETING CONTINUATION	$0
2026	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	3/19/2026	NON-COMPETING CONTINUATION	$0
2026	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/18/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $625,033

Issue Date FY: 2025 ( Subtotal = $625,033 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/28/2025	NON-COMPETING CONTINUATION	$62,502
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/28/2025	NON-COMPETING CONTINUATION	$562,531
														Subtotal = $625,033

Issue Date FY: 2024 ( Subtotal = $600,032 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/1/2024	NON-COMPETING CONTINUATION	$562,531
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/20/2024	NON-COMPETING CONTINUATION	$37,501
														Subtotal = $600,032

Issue Date FY: 2023 ( Subtotal = $641,074 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/1/2023	NEW	$641,074
														Subtotal = $641,074

Grand Total All Awards = $2,491,172

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Deconstructing the diet-induced remodeling of adipose tissue

Award Number: R01DK134534

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer