Pterostilbene modulates skeletal muscle lipid metabolism through PPARδ stabilization

Ectopic lipid accumulation in skeletal muscle is a major health concern, driven by factors like high-fat diets, lack of exercise, and aging. Unlike subcutaneous fat, these intracellular lipid droplets interfere with normal muscle function and reduce the body’s ability to efficiently use glucose and fatty acids. This condition impairs metabolic flexibility and leads to insulin resistance. Therefore, finding ways to control excessive lipid buildup in skeletal muscle is crucial for extending a healthy lifespan and preventing lifestyle-related disorders.

Peroxisome proliferator-activated receptor δ (PPARδ) signaling plays a crucial role in suppressing intracellular lipid accumulation by stimulating fatty acid oxidation. While food-derived bioactive compounds have attracted attention for their potential to regulate PPARδ signaling, the molecular mechanisms remain poorly understood.

In a recent study, a team of researchers from Japan, led by Associate Professor Takakazu Mitani from Shinshu University, identified a natural dietary compound, pterostilbene, that stabilizes PPARδ and modulates intracellular lipid metabolism. The naturally occurring polyphenol found in blueberries, grapes, and other berries, has previously been associated with beneficial metabolic effects in the liver and adipose tissue. However, its role in skeletal muscle was not well characterized. Their research was made available online on July 16, 2026, and will be published in Volume 83 of the Food Bioscience journal on September 01, 2026.

“We currently lack approved treatments specifically targeting myosteatosis,” says Dr. Mitani. “This critical gap led our team to screen food-derived compounds for natural, dietary interventions. During the screening, we identified pterostilbene and focused our investigation on uncovering its precise mechanism of action.”

The researchers used cultured C2C12 mouse skeletal muscle cells to screen a panel of food-derived phytochemicals for their ability to reduce abnormal intracellular lipid accumulation. Pterostilbene showed the most pronounced suppressive effects on intracellular lipid accumulation while maintaining normal muscle cell growth and differentiation.

Follow-up experiments revealed that the compound does not stop fatty acids from entering muscle cells. Instead, treated cells showed an increase in extracellular glycerol release, a key indicator of fat breakdown. Together with increased expression of genes involved in fatty acid oxidation, these findings indicate that pterostilbene promotes intracellular lipolysis and lipid catabolism.

Investigation of the underlying molecular machinery revealed that pterostilbene significantly enhances PPARδ signaling. Surprisingly, pterostilbene did not activate PPARδ in the conventional way. Most experimental drugs designed to stimulate PPARδ function by binding directly to the receptor. Instead, pterostilbene increased the amount of PPARδ protein available inside cells by preventing its degradation through the ubiquitin–proteasome pathway. The non-canonical mechanism stabilizes PPARδ and enhances its transcriptional activity, thereby upregulating genes associated with lipid metabolism.

“Our findings establish a scientific framework for developing functional foods and nutritional supplements that target muscle fat metabolism. However, beyond the potential of pterostilbene itself, this work provides an experimental framework for identifying other natural compounds that can stabilize the PPARδ protein,” mentioned Dr. Mitani.

As metabolic diseases continue to rise worldwide, this study provides a foundation for investigating dietary strategies for obesity, type 2 diabetes, and age-related metabolic decline. While these molecular-level findings do not yet prove direct preventive or clinical efficacy, they offer the food and healthcare industries a promising candidate bio-ingredient for functional product development. Moving forward, rigorous in vivo studies evaluating efficacy, safety, and target selectivity will be required to translate these cellular mechanisms into practical pharmaceutical and nutritional applications.

About Shinshu University

Shinshu University is a national university founded in 1949 and located nestling under the Japanese Alps in Nagano known for its stunning natural landscapes. Shinshu University was selected for the Forming Japan’s Peak Research Universities (J-PEAKS) Program by the Japanese government. This initiative seeks to promote the formation of university consortia that will enhance research capabilities across Japan. For more information visit https://www.shinshu-u.ac.jp/english/ or follow us on X (Twitter) @ShinshuUni for our latest news.

About Associate Professor Takakazu Mitani from Shinshu University, Japan

Dr. Takakazu Mitani is an Associate Professor in the Department of Agricultural and Life Sciences, Faculty of Agriculture, Shinshu University. He obtained his PhD from Osaka Prefecture University. His research focuses on food chemistry and molecular nutrition, specifically exploring how food-derived bioactive compounds regulate metabolic pathways. By bridging the gap between nutritional science and therapeutic applications, his research establishes a foundation for innovative functional foods designed to combat major metabolic health challenges, including obesity and type 2 diabetes.