Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis

Significance Baicalin is a major flavonoid component from the herbal medicine Scutellaria baicalensis that has been shown to have an antisteatosis effect. Through quantitative chemoproteomic profiling, we discovered that baicalin acts as a natural allosteric activator of carnitine palmitoyltransferase 1 (CPT1), the rate-limiting enzyme of fatty acid β-oxidation (FAO). By directly binding to CPT1 and activating its activity to accelerate fatty acid degradation, baicalin can significantly ameliorate symptoms associated with hepatic steatosis and reduce diet-induced obesity (DIO). Our study provides an example of a natural product agonist for CPT1. The results provide mechanistic insights to explain the bioactivity of baicalin in reducing lipid accumulation and introduce exciting opportunities for developing novel flavonoid-based FAO activators for pharmacologically treating DIO and associated metabolic disorders. , Obesity and related metabolic diseases are becoming worldwide epidemics that lead to increased death rates and heavy health care costs. Effective treatment options have not been found yet. Here, based on the observation that baicalin, a flavonoid from the herbal medicine Scutellaria baicalensis , has unique antisteatosis activity, we performed quantitative chemoproteomic profiling and identified carnitine palmitoyltransferase 1 (CPT1), the controlling enzyme for fatty acid oxidation, as the key target of baicalin. The flavonoid directly activated hepatic CPT1 with isoform selectivity to accelerate the lipid influx into mitochondria for oxidation. Chronic treatment of baicalin ameliorated diet-induced obesity (DIO) and hepatic steatosis and led to systemic improvement of other metabolic disorders. Disruption of the predicted binding site of baicalin on CPT1 completely abolished the beneficial effect of the flavonoid. Our discovery of baicalin as an allosteric CPT1 activator opens new opportunities for pharmacological treatment of DIO and associated sequelae.