Dietary Achievable Dose of Protocatechuic Acid, a Metabolite of Flavonoids, Inhibits High‐Fat Diet‐Induced Obesity in Mice

Scope Protocatechuic acid (PCA), a gut microbiota metabolite of flavonoids, inhibits dietary obesity and increases uncoupling protein 1 (UCP1), a critical regulator responsible for adipose thermogenesis; however, these effects are achieved at dietary unachievable (pharmacological) dose. It evaluates whether dietary achievable dose of PCA inhibits adiposity by activating adipose thermogenesis. Methods and Results Six‐week‐old male C57BL/6J mice are fed a high‐fat diet (HFD) alone (control) or supplemented with 0.003% PCA w/w for 16 weeks. PCA consumption does not affect food intake but appreciably reduces body weight gain, improves insulin sensitivity, and attenuates hepatic steatosis. These effects are associated with no significant changes in the abundance of UCP1 in adipose tissues. Instead, PCA consumption increases the abundance and enzymatic activity of carnitine palmitoyltransferase 1 (the first rate‐limiting enzyme in fatty acid oxidation) in the livers, inguinal white, and brown adipose tissues. Surprisingly, PCA at physiologically achievable dose does not affect the abundance and enzymatic activity of carnitine acyltransferase‐1 expression and the capacity of fatty acid oxidation in 3T3‐L1‐derived white or brown adipocytes and human hepatoma HepG2 cells. Conclusions Dietary achievable dose of PCA attenuates HFD‐induced adiposity, which is likely achieved by increasing fatty acid oxidation other than activating adipose thermogenesis.