Piperine regulates UCP1 through the AMPK pathway by generating intracellular lactate production in muscle cells

• Published in: Scientific reports 2017-01, Vol.7 (1), p.41066-41066, Article 41066
• Main Authors: Kim, Nami, Nam, Miso, Kang, Mi Sun, Lee, Jung Ok, Lee, Yong Woo, Hwang, Geum-Sook, Kim, Hyeon Soo
• Format: Article
• Language: English
• Subjects: 13/109; 13/89; 3T3-L1 Cells; 631/337/458/1733; 692/163/2743/137/773; 82/80; 96/106; 96/95; Acetyl-CoA carboxylase; Alkaloids - pharmacology; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animals; Benign; Benzodioxoles - pharmacology; Cell Line; Curcumin; Cytochrome P-450 Enzyme Inhibitors - pharmacology; Energy expenditure; Gene Expression Regulation; Glucose - metabolism; Humanities and Social Sciences; Intracellular; Intracellular signalling; Kinases; Lactic acid; Lactic Acid - metabolism; MAP kinase; Metabolic response; Metabolism; Metabolomics; Mice; Mitochondria; multidisciplinary; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - enzymology; Muscle Fibers, Skeletal - metabolism; Musculoskeletal system; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Piperidines - pharmacology; Piperine; Polyunsaturated Alkamides - pharmacology; Protein Processing, Post-Translational; Proteins; Proton Magnetic Resonance Spectroscopy; Rats; Science; Science (multidisciplinary); Signal Transduction; Skeletal muscle; Thermogenesis; Uncoupling protein 1; Uncoupling Protein 1 - genetics; Uncoupling Protein 1 - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep41066

This study characterizes the human metabolic response to piperine, a curcumin extract, and the details of its underlying molecular mechanism. Using 1 H-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.