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. Using 1H-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.

Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota

“…Shotgun metagenomics sequencing analysis also showed that EODF upregulated the pathway of ‘Pyruvate fermentation to acetate and lactate by Lactobacillus reuteri ’ and ‘Pyruvate fermentation to acetate and lactate by unclassified bacteria’ (Figure S7). Intriguingly, recent studies indicate both acetate and lactate are beiging inducers (Hanatani et al, 2016; Kim et al, 2017; Sahuri-Arisoylu et al, 2016). In addition, both BAT and WAT express proton-linked monocarboxylate transporter 1 (MCT1) encoded by Mct1 , which drives acetate and lactate transport across the plasma membrane of adipocytes (den Besten et al, 2013; Iwanaga et al, 2009).…”

Piperine-A Major Principle of Black Pepper: A Review of Its Bioactivity and Studies

“…The study on piperine effect to LPS-stimulated human epithelial-like SW480, and HT-29 cells showed that it downregulates the MAPK pathways [100]. Piperine stimulates the p38 MAPK and induces the phosphorylation of AMP-activated protein kinase [101]. The study of Kumar et al [102] found that piperine inhibits TNF-α, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin.…”

Lactate fluxes mediated by the monocarboxylate transporter-1 are key determinants of the metabolic activity of beige adipocytes

“…This occurs through intracellular redox modifications subsequent to its transport. The regulation of UCP1 expression by lactate has been confirmed by others (21,22). This mechanism might be part of a redox regulatory and adaptive loop (17,23) where a high redox (NADH/NAD + ) pressure drives UCP1 expression, just as mitochondrial ROS positively control UCP1 protein activity (24).…”