title: Piperine regulates UCP1 through the AMPK pathway by generating intracellular lactate production in muscle cells.
abstract: This study characterizes the human metabolic response to piperine, a curcumin extract, and the details of its underlying molecular mechanism. Using1H-NMR-based metabolome analysis, we showed the metabolic effect of piperine on skeletal muscle and found that piperine increased the level of intracellular lactate, an important metabolic intermediate that controls expression of several genes involved in mitochondrial activity. Piperine also induced the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target, acetyl-CoA carboxylase (ACC), while additionally stimulating glucose uptake in an AMPK dependent manner. Piperine also stimulates the p38 mitogen-activated protein kinase (p38 MAPK), an effect that was reversed by pretreatment with compound C, an AMPK inhibitor. Inhibition of p38 MAPK resulted in no piperine-induced glucose uptake. Increased level of lactate resulted in increased expression of mitochondrial uncoupling protein 1 (UCP1), which regulates energy expenditure, thermogenesis, and fat browning. Knock-down of AMPK blocked piperine-induced UCP1 up-regulation, demonstrating the required role of AMPK in this effect. Taken together, these results suggest that piperine leads to benign metabolic effects by activating the AMPK-p38 MAPK signaling pathway and UCP1 expression by activating intracellular lactate production in skeletal muscle.
authors.affiliation: Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 120-140, Republic of Korea.
authors.forename: Nami
authors.initials: N
authors.lastname: Kim
authors.affiliation: Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 120-140, Republic of Korea.
authors.forename: Miso
authors.initials: M
authors.lastname: Nam
authors.affiliation: Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 120-140, Republic of Korea.
authors.forename: Mi Sun
authors.initials: MS
authors.lastname: Kang
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul 136-701, Korea.
authors.forename: Jung Ok
authors.initials: JO
authors.lastname: Lee
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul 136-701, Korea.
authors.forename: Yong Woo
authors.initials: YW
authors.lastname: Lee
authors.affiliation: Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul 120-140, Republic of Korea.|Chemistry &Nanoscience, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Geum-Sook
authors.initials: GS
authors.lastname: Hwang
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul 136-701, Korea.
authors.forename: Hyeon Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D002460:Cell Line; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism*; D055432:Metabolomics; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D015398:Signal Transduction; D000071256:Uncoupling Protein 1 / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D000071256:Uncoupling Protein 1; D019344:Lactic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; C008922:piperine