Researchers investigated whether raising circulating free fatty acid (FFA) levels could stimulate the production of new mitochondria in skeletal muscle. In rats, sustained elevations in FFAs increased the expression of enzymes involved in fat oxidation, the citric acid cycle, and the electron transport chain, while also increasing mitochondrial DNA and the muscle's capacity to oxidize fat. Together, these findings indicate that fatty acids do more than provide fuel—they can signal muscle cells to build more mitochondria.

The researchers found that this response was likely driven by activation of PPARδ, a nutrient-sensing receptor that regulates genes involved in fat metabolism and mitochondrial function. These findings support the idea that fat availability can directly influence mitochondrial biogenesis, helping explain how fasting, exercise, and low-carbohydrate diets—which all raise circulating fatty acids—may promote greater metabolic capacity and healthier skeletal muscle.

https://www.pnas.org/doi/10.1073/pnas.0704024104