# Dysfunctional TRIM31 of POMC Neurons Provokes Hypothalamic Injury and Peripheral Metabolic Disorder under Long‐Term Fine Particulate Matter Exposure

## TL;DR

Long-term exposure to fine particulate matter causes brain and metabolic issues, and a protein called TRIM31 in specific brain cells helps prevent these effects.

## Contribution

The study identifies TRIM31 in POMC+ neurons as a key regulator of PM2.5-induced hypothalamic injury and metabolic dysfunction.

## Key findings

- TRIM31 knockout in POMC+ neurons worsened PM2.5-induced metabolic and neurological damage.
- TRIM31 overexpression reduced neuronal death and inflammation caused by PM2.5.
- TRIM31 activates Nrf2 signaling to protect against PM2.5 stress.

## Abstract

Particulate matter ≤2.5 µm (PM2.5) elevates risks of neurological and chronic metabolic diseases, but the underlying mechanisms linking PM2.5‐induced central nervous system (CNS) injury to metabolic dysfunction remain unclear. Hypothalamic pro‐opiomelanocortin‐expressing (POMC+) neurons regulate systemic metabolic homeostasis, and tripartite motif‐containing protein 31 (TRIM31) modulates inflammation and metabolism. Here, we investigated whether TRIM31 in POMC+ neurons mediates PM2.5‐induced hypothalamic injury and peripheral metabolic disorders in mice subjected to 24‐week PM2.5 exposure. TRIM31 knockout in POMC+ neurons (POMCCre/+;TRIM31flox/flox
) exacerbated PM2.5‐;induced increases in mean blood pressure and fat weight, liver weight reduction, adipocyte hypertrophy, hepatic lipid deposition, energy expenditure abnormalities and insulin resistance. It also aggravated hypothalamic damage (downregulated NeuN, POMC and MC4R) and amplified neuroinflammation and oxidative stress. Conversely, AAV‐mediated TRIM31 overexpression in POMC+ neurons alleviated these pathological phenotypes. In vitro, TRIM31 deletion promoted reactive oxygen species (ROS) and inflammation in PM2.5‐challenged hypothalamic neurons and microglia, while TRIM31 overexpression exerted opposite effects; microglial TRIM31 depletion exacerbated neuronal death via conditioned medium. Mechanistically, TRIM31 directly interacted with Nrf2, enhancing its K63‐linked polyubiquitination and reducing K48‐linked polyubiquitination to activate Nrf2 signaling, which was required for TRIM31‐mediated attenuation of neuronal death and inflammation under PM2.5 stress. Collectively, our findings identify the TRIM31/Nrf2 axis as a key molecular switch governing POMC+ neuronal loss, hypothalamic injury and consequent peripheral metabolic disorders triggered by long‐term PM2.5 exposure.

Particulate matter ≤2.5 µm (PM2.5) elevates risks of neurological and chronic metabolic diseases, but the underlying mechanisms linking PM2.5‐induced central nervous system (CNS) injury to metabolic dysfunction remain unclear. Hypothalamic pro‐opiomelanocortin‐expressing (POMC+) neurons regulate systemic metabolic homeostasis, and tripartite motif‐containing protein 31 (TRIM31) modulates inflammation and metabolism. Here, we investigated whether TRIM31 in POMC+ neurons mediates PM2.5‐induced hypothalamic injury and peripheral metabolic disorders in mice subjected to 24‐week PM2.5 exposure. TRIM31 knockout in POMC⁺ neurons (POMCCre/+; TRIM31flox/flox) exacerbated PM2.5‐induced increases in mean blood pressure and fat weight, liver weight reduction, adipocyte hypertrophy, hepatic lipid deposition, energy expenditure abnormalities and insulin resistance. It also aggravated hypothalamic damage (downregulated NeuN, POMC and MC4R) and amplified neuroinflammation and oxidative stress. Conversely, AAV‐mediated TRIM31 overexpression in POMC⁺ neurons alleviated these pathological phenotypes. In vitro, TRIM31 deletion promoted reactive oxygen species (ROS) and inflammation in PM2.5‐challenged hypothalamic neurons and microglia, while TRIM31 overexpression exerted opposite effects; microglial TRIM31 depletion exacerbated neuronal death via conditioned medium. Mechanistically, TRIM31 directly interacted with Nrf2, enhancing its K63‐linked polyubiquitination and reducing K48‐linked polyubiquitination to activate Nrf2 signaling, which was required for TRIM31‐mediated attenuation of neuronal death and inflammation under PM2.5 stress. Collectively, our findings identify the TRIM31/Nrf2 axis as a key molecular switch governing POMC⁺ neuronal loss, hypothalamic injury and consequent peripheral metabolic disorders triggered by long‐term PM2.5 exposure.