Ursolic acid increases energy expenditure through enhancing free fatty acid uptake and β‐oxidation via an UCP3/AMPK‐dependent pathway in skeletal muscle

• Published in: Molecular nutrition & food research 2015-08, Vol.59 (8), p.1491-1503
• Main Authors: Chu, Xia, He, Xuan, Shi, Zhiping, Li, Chunjuan, Guo, Fuchuan, Li, Songtao, Li, Ying, Na, Lixin, Sun, Changhao
• Format: Article
• Language: English
• Subjects: Absorption, Physiological; adenosine monophosphate; adenosine triphosphate; AMP-activated protein kinase; AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Anti-Obesity Agents - therapeutic use; beta oxidation; blood serum; burning; Cell Line; Diet, High-Fat - adverse effects; Dietary Supplements; energy expenditure; Energy Metabolism; Fatty acid β-oxidation; Fatty Acids, Nonesterified - blood; Fatty Acids, Nonesterified - metabolism; Free fatty acid uptake; free fatty acids; insulin resistance; Ion Channels - agonists; Ion Channels - antagonists & inhibitors; Ion Channels - genetics; Ion Channels - metabolism; Male; Mice; Mitochondrial Proteins - agonists; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Muscle, Skeletal - enzymology; Muscle, Skeletal - metabolism; obesity; Obesity - blood; Obesity - diet therapy; Obesity - etiology; Obesity - metabolism; palmitic acid; Random Allocation; rats; Rats, Sprague-Dawley; RNA Interference; Second Messenger Systems; skeletal muscle; Specific Pathogen-Free Organisms; triacylglycerols; Triterpenes - therapeutic use; Uncoupling Protein 3; Ursolic Acid
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201400670

SCOPE: Ursolic acid (UA) is a triterpenoid compound with multifold biological functions. Our previous studies have reported that UA protects against high‐fat diet‐induced obesity and improves insulin resistance (IR). However, the potential mechanisms are still undefined. Free fatty acid (FFA) metabolism in skeletal muscle plays a central role in obesity and IR. Therefore, in this study, we investigated the effect and the potential mechanisms of UA on skeletal muscle FFA metabolism. METHODS AND RESULTS: In diet‐induced obese rats, 0.5% UA supplementation for 6 weeks markedly reduced body weight, increased energy expenditure, decreased FFA level in serum and skeletal muscle and triglyceride content in skeletal muscle. In vitro, the data provided directly evidence that UA significantly increased fluorescently labeled FFA uptake and ³H‐labeled palmitic acid β‐oxidation. UA‐activated AMP‐activated protein kinase (AMPK) and downstream targets were involved in the increase of FFA catabolism. Moreover, upregulated uncoupling protein 3 (UCP3) by UA contributed to AMPK activation via elevating adenosine monophosphate/adenosine triphosphate ratio. CONCLUSION: UA increases FFA burning through enhancing skeletal muscle FFA uptake and β‐oxidation via an UCP3/AMPK‐dependent pathway, which provides a novel perspective on the biological function of UA against obesity and IR.