# Dose‐Dependent Biphasic Effect of Palmitic Acid on Oligodendrocyte Function: Impacts on Viability, Differentiation, and Myelination

## TL;DR

Palmitic acid has a dual effect on brain cells that form myelin, with low doses being protective and high doses harmful.

## Contribution

The study reveals a biphasic, dose-dependent impact of palmitic acid on oligodendrocyte function and myelination.

## Key findings

- High-dose palmitic acid causes mitochondrial dysfunction and cell death in oligodendrocyte precursor cells.
- Low-dose palmitic acid activates Nrf2 and promotes myelination and neuroprotection.
- Low-dose palmitic acid enhances axonal myelination and remyelination in organotypic slice cultures.

## Abstract

Palmitic acid (PA), the most abundant saturated fatty acid (SFA) in humans, plays a key role in energy metabolism, membrane synthesis, and signaling. Oligodendrocyte precursor cells (OPCs), which generate mature oligodendrocytes (OLs) forming the myelin sheath, are responsive to metabolic and redox signals. Despite increasing interest in lipid metabolism and mitochondrial dynamics as regulators of OPC fate, the effects of PA remain unclear. This study investigates the biphasic, dose‐dependent effects of PA on OPCs using the oligodendrocyte precursor MO3.13 cell line and employs rat organotypic slice cultures to evaluate the effects of non‐toxic PA doses under pathological conditions and on axonal (re)‐myelination. In MO3.13 cells, high‐dose PA (100 µM) induces mitochondrial fragmentation and caspase‐7 activation, accompanied by reduced mitofusin‐2 (MFN2) and phosphorylated dynamin‐related protein 1 at Ser616 (p‐DRP1), indicating altered fusion‐fission balance and impaired reactive oxygen species (ROS) generation. In contrast, low‐dose PA (25 µM) triggers a protective response involving nuclear factor erythroid 2–related factor 2 (Nrf2) activation and upregulation of antioxidant and lipid‐regulatory genes (glutamate–cysteine ligase modifier subunit [GCLM], NAD(P)H dehydrogenase [quinone] 1 [NQO1], peroxisome proliferator‐activated receptor gamma [PPARγ], and cluster of differentiation 36 [CD36]) resulting in reduced intracellular ROS and enhanced lipid mobilization. PA 25 µM promotes OPC differentiation by inhibiting migration and cell cycle progression and increasing myelin basic protein (MBP) and proteolipid protein (PLP) expression. Notably, early exposure (1 day) favors mitochondrial fusion, whereas prolonged exposure (4 days) shows a physiological shift to fission. PA 25 µM prevents neurodegeneration in hippocampal organotypic slice cultures exposed to a neuroinflammatory insult. In cerebellar organotypic slice cultures, PA 25 µM enhances axonal myelination and accelerates remyelination following lysolecithin‐induced demyelination. These findings highlight the physiological relevance of low‐dose PA in modulating OLs.

Schematic diagram showing dose‐dependent effects of PA in oligodendrocyte precursor MO3.13 cells and rodent organotypic hippocampal and cerebellar slice cultures. High doses lead to cell death accompanied by mitochondrial impairment, whereas low doses activate the Nrf2 antioxidant response and exert neuroprotective effect while balancing mitochondrial dynamics and promoting cellular differentiation and axonal myelination.