# Palmitic acid induces UCP1-independent mitochondrial depolarization specifically in brown adipose tissue

## TL;DR

This study shows that palmitic acid can cause mitochondrial depolarization in brown fat without UCP1, suggesting a new way brown fat generates heat.

## Contribution

The study identifies palmitic acid as a direct inducer of UCP1-independent mitochondrial depolarization in brown adipose tissue.

## Key findings

- Cold-mimicking stimulation causes mitochondrial depolarization in UCP1-deficient brown adipocytes.
- Palmitic acid levels increase during cold-mimicking stimulation in a lipolysis-dependent manner.
- Palmitic acid reduces mitochondrial membrane potential specifically in brown adipose tissue mitochondria.

## Abstract

Brown adipose tissue (BAT) is a major site of nonshivering thermogenesis, where mitochondria generate heat instead of ATP. The thermogenesis occurs through the activity of uncoupling protein 1 (UCP1), which specifically resides in the mitochondrial inner membrane and dissipates the mitochondrial proton gradient upon activation by long-chain free fatty acids. Although UCP1-independent proton leak has been reported, the mechanism underlying UCP1-independent mitochondrial membrane depolarization remains largely unknown. Here, using primary brown adipocytes, we found that cold-mimicking stimulation induces mitochondrial membrane depolarization even under UCP1 KO and knockdown conditions. Furthermore, during cold-mimicking stimulation, palmitic acid shows the most prominent increase in a lipolysis-dependent manner. Notably, palmitic acid directly decreases mitochondrial membrane potential specifically in mitochondria isolated from BAT but not in those isolated from liver or brain. These findings suggest that palmitic acid contributes to mitochondrial depolarization in BAT, thereby contributing to UCP1-independent depolarization.