Gallic Acid Regulates Body Weight and Glucose Homeostasis Through AMPK Activation

• Published in: Endocrinology (Philadelphia) 2015-01, Vol.156 (1), p.157-168
• Main Authors: Doan, Khanh V, Ko, Chang Mann, Kinyua, Ann W, Yang, Dong Joo, Choi, Yun-Hee, Oh, In Young, Nguyen, Nguyen Minh, Ko, Ara, Choi, Jae Won, Jeong, Yangsik, Jung, Min Ho, Cho, Won Gil, Xu, Shanhua, Park, Kyu Sang, Park, Woo Jin, Choi, Soo Yong, Kim, Hyoung Shik, Moh, Sang Hyun, Kim, Ki Woo
• Format: Article
• Language: English
• Subjects: Adipose tissue; Adipose tissue (brown); AMP-activated protein kinase; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Autophagy; Blood Glucose; Body fat; Body weight; Body Weight - physiology; Body weight gain; Diet; Dietary Fats - administration & dosage; Dietary Fats - adverse effects; Energy expenditure; Enzyme Activation; Food intake; Gallic acid; Gallic Acid - metabolism; Genes; Glucose; Glucose - metabolism; Hep G2 Cells; Homeostasis; Homeostasis - physiology; Humans; Insulin; Insulin resistance; Kinases; Metabolic disorders; Metabolic rate; Metabolic syndrome; Metabolism; Mice; Mice, Inbred C57BL; Molecular modelling; Obesity - chemically induced; Obesity - drug therapy; Peroxisome proliferator-activated receptors; Proteins; SIRT1 protein; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Thermogenesis; Transcription activation; Transcription Factors - genetics; Transcription Factors - metabolism; Trihydroxybenzoic acid; Uncoupling protein 1
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2014-1354

Gallic acid [3,4,5-trihydroxybenzoic acid (GA)], a natural phytochemical, is known to have a variety of cellular functions including beneficial effects on metabolic syndromes. However, the molecular mechanism by which GA exerts its beneficial effects is not known. Here we report that GA plays its role through the activation of AMP-activated protein kinase (AMPK) and by regulating mitochondrial function via the activation of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Sirtuin 1 (Sirt1) knockdown significantly blunted GA's effect on PGC1α activation and downstream genes, suggesting a critical role of the AMPK/Sirt1/PGC1α pathway in GA's action. Moreover, diet-induced obese mice treated with GA showed significantly improved glucose and insulin homeostasis. In addition, the administration of GA protected diet-induced body weight gain without a change in food intake. Biochemical analyses revealed a marked activation of AMPK in the liver, muscle, and interscapular brown adipose tissue of the GA-treated mice. Moreover, uncoupling protein 1 together with other genes related to energy expenditure was significantly elevated in the interscapular brown adipose tissue. Taken together, these results indicate that GA plays its beneficial metabolic roles by activating the AMPK/Sirt1/PGC1α pathway and by changing the interscapular brown adipose tissue genes related to thermogenesis. Our study points out that targeting the activation of the AMPK/Sirt1/PGC1α pathway by GA or its derivatives might be a potential therapeutic intervention for insulin resistance in metabolic diseases.