# Molecular Mechanism of Brown Adipose Tissue Regression

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $578,051

## Abstract

Abstract
 Our preliminary data demonstrates that in both Adipoq and UCP1-specific Stx4 knockout mice results in
the activation of pyroptotic brown adipocyte cell death through the NLRP1 (NOD-like receptor protein 1)
signaling pathway. In parallel, brown adipose function and to a lesser extent mass declines during aging and
this age-associated decline in BAT thermogenesis occur concomitant with the induction of pyroptosis.
Furthermore, in both modes the regression of BAT results in the reduction in insulin sensitivity, energy
expenditure and cold tolerance that can be reversed by over expression of Stx4 in brown/beige adipocytes
(UCP1-Stx4 transgenic mice) or by blocking of pyroptosis using an inhibitor of caspase 1. In addition, aged and
Stx4 knockout mice have reduced protein levels of the cell survival receptors Ntrk3, a brown adipocyte
selective tyrosine receptor kinase within brown adipose tissue. Based upon these data, we are proposing a
multi-principal investigator (MPI) application to understand the molecular basis for the decline in brown adipose
tissue mass and function during the normal development of aging and the functional/physiological
consequences of preserving brown mass and function, in terms of energy balance, insulin sensitivity and
metabolic homeostasis. In this proposal, we will determine 1) the specific pathways and signaling events
responsible for brown adipocyte pyroptosis and functional consequences of preserving BAT using
both pharmacological and genetic interventions; 2) the functional role of the neurotropic tyrosine
receptor kinase Ntrk3 in regulating BAT mass, function and brown adipocyte pyroptosis; and 3)
changes in tissue cellular identity and its role during age-dependent BAT dysfunction and regression.
The findings obtained from this proposal will then allow to develop strategies to prevent age-dependent
regression of BAT that will likely provide a more tractable and effective therapeutic approach than the induction
of beige adipose tissue to improve glucose metabolism, increase energy expenditure and prevent weight gain.

## Key facts

- **NIH application ID:** 10393046
- **Project number:** 5R01DK128839-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Daorong Feng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $578,051
- **Award type:** 5
- **Project period:** 2021-04-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10393046

## Citation

> US National Institutes of Health, RePORTER application 10393046, Molecular Mechanism of Brown Adipose Tissue Regression (5R01DK128839-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10393046. Licensed CC0.

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