# Project 1:  Regulation of obesity through BMP signaling pathways in brown adipose tissue

> **NIH NIH P20** · MAINEHEALTH · 2020 · $303,861

## Abstract

An understanding of adipose tissue regulation has broad clinical implications, because obesity correlates with
increased risk of diabetes, stroke, heart disease and cancer. Brown adipose tissue dissipates calories as heat
through non-shivering thermogenesis, and its activity correlates positively with decreased metabolic syndrome
in mice and humans, making it an appealing therapeutic target. Studies with bone morphogenetic protein
(BMP) ligand and receptor null mice reveal an essential role for this signaling pathway in the development of
brown adipogenic precursors and their differentiation into mature brown adipose tissue. BMPs signal through
several distinct pathways, however, the precise roles that these pathways play in control of brown adipocyte
development and function are not well understood, and represent promising therapeutic targets to address
obesity and related co-morbidities. The first aim of this proposal is to use mouse models to determine if
genetic manipulation of the genes that underlie BMP signaling can be used to enhance brown adipogenesis
and function. To do this, master regulator genes that control BMP signaling will be ablated specifically in brown
adipogenic precursors to determine their function. Thermogenic activity will be studied in live mutant mice
using sophisticated metabolic monitoring techniques under conditions of cold-induced stress. The results of
these studies allow testing of these genes in human models of brown adipocytes to determine their therapeutic
value. A major obstacle with the study of human brown adipocytes is that isolation of primary cells requires
invasive methods of procurement, and isolated cells have limited renewability or must be immortalized to
interrogate them fully. In addition, the diverse environmental influences on primary brown adipocytes from
different individuals makes it more difficult to directly study genetic factors that may lead to disrupted brown
adipose metabolism. Brown adipocytes that have been derived from induced pluripotent stem (iPS) cells using
BMP ligands have the potential to enhance our understanding of brown adipocyte development, metabolism,
and its genetic variation in humans. The second aim of this proposal is to develop human iPS cell-derived
brown adipose tissue models using advanced cellular purification and tissue culture techniques. Human iPS
cells will be derived from patients in a non-invasive manner, which will greatly facilitate the derivation of brown
adipose samples across large cohorts of the human population that can be studied under defined tissue culture
environments. Human iPS cell-derived brown adipocytes will be optimized for maximum thermogenic capacity
through small molecule manipulation of BMP signaling pathways, and expanded in 3-dimensional biopolymer
scaffolds to test their ability to control diet induced obesity in immune-compromised mice after tissue
engraftment. Overall, the results of these studies will elucidate mechanisms that unde...

## Key facts

- **NIH application ID:** 10009423
- **Project number:** 5P20GM121301-04
- **Recipient organization:** MAINEHEALTH
- **Principal Investigator:** Aaron Clifford Brown
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $303,861
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10009423

## Citation

> US National Institutes of Health, RePORTER application 10009423, Project 1:  Regulation of obesity through BMP signaling pathways in brown adipose tissue (5P20GM121301-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10009423. Licensed CC0.

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