Metabolome analysis reveals that cyclic adenosine diphosphate ribose contributes to the regulation of differentiation in mice adipocyte.

Adipocytes play a key role in energy storage and homeostasis. Although the role of transcription factors in adipocyte differentiation is known, the effect of endogenous metabolites of low molecular weight remains unclear. Here, we analyzed time-dependent changes in the levels of these metabolites throughout adipocyte differentiation, using metabolome analysis, and demonstrated that there is a positive correlation between cyclic adenosine diphosphate ribose (cADPR) and Pparγ mRNA expression used as a marker of differentiation. We also found that the treatment of C3H10T1/2 adipocytes with cADPR increased the mRNA expression of those marker genes and the accumulation of triglycerides. Furthermore, inhibition of ryanodine receptors (RyR), which are activated by cADPR, caused a significant reduction in mRNA expression levels of the marker genes and triglyceride accumulation in adipocytes. Our findings show that cADPR accelerates adipocytic differentiation via RyR pathway.

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44.

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.

The Thing Metabolome Repository family (XMRs): comparable untargeted metabolome databases for analyzing sample-specific unknown metabolites.

The identification of unknown chemicals has emerged as a significant issue in untargeted metabolome analysis owing to the limited availability of purified standards for identification; this is a major bottleneck for the accumulation of reusable metabolome data in systems biology. Public resources for discovering and prioritizing the unknowns that should be subject to practical identification, as well as further detailed study of spending costs and the risks of misprediction, are lacking. As such a resource, we released databases, Food-, Plant- and Thing-Metabolome Repository (http://metabolites.in/foods, http://metabolites.in/plants, and http://metabolites.in/things, referred to as XMRs) in which the sample-specific localization of unknowns detected by liquid chromatography-mass spectrometry in a wide variety of samples can be examined, helping to discover and prioritize the unknowns. A set of application programming interfaces for the XMRs facilitates the use of metabolome data for large-scale analysis and data mining. Several applications of XMRs, including integrated metabolome and genome analyses, are presented. Expanding the concept of XMRs will accelerate the identification of unknowns and increase the discovery of new knowledge.

Metabolomics reveals inosine 5'-monophosphate is increased during mice adipocyte browning.

Adipocyte browning is one of the potential strategies for the prevention of obesity-related metabolic syndromes, but it is a complex process. Although previous studies make it increasingly clear that several transcription factors and enzymes are essential to induce browning, it is unclear what dynamic and metabolic changes occur in induction of browning. Here, we analyzed the effect of a beta-adrenergic receptor agonist (CL316243, accelerator of browning) on metabolic change in mice adipose tissue and plasma using metabolome analysis and speculated that browning is regulated partly by inosine 5'-monophosphate (IMP) metabolism. To test this hypothesis, we investigated whether Ucp-1, a functional marker of browning, mRNA expression is influenced by IMP metabolism using immortalized adipocytes. Our study showed that mycophenolic acid, an IMP dehydrogenase inhibitor, increases the mRNA expression of Ucp-1 in immortalized adipocytes. Furthermore, we performed a single administration of mycophenolate mofetil, a prodrug of mycophenolic acid, to mice and demonstrated that mycophenolate mofetil induces adipocyte browning and miniaturization of adipocyte size, leading to adipose tissue weight loss. These findings showed that IMP metabolism has a significant effect on adipocyte browning, suggesting that the regulator of IMP metabolism has the potential to prevent obesity.

8-Prenyl daidzein and 8-prenyl genistein from germinated soybean modulate inflammatory response in activated macrophages.

Soy isoflavones have been shown to have anti-inflammatory properties; however, the anti-inflammatory effects of isoflavone metabolites produced during soybean germination remain unclear. We found that the daidzein and genistein derivatives, 8-prenyl daidzein (8-PD) and 8-prenyl genistein (8-PG), demonstrated a more potent effect than daidzein and genistein on repressing inflammatory responses in macrophages. Although IkB protein levels were unaltered, 8-PD and 8-PG repressed nuclear factor kappa B (NF-κB) activation, which was associated with reduced ERK1/2, JNK, and p38 MAPK activation and suppressed mitogen- and stress-activated kinase 1 phosphorylation. Inflammatory responses induced by the medium containing hypertrophic adipocyte secretions were successfully suppressed by 8-PD and 8-PG treatment. In the ex vivo study, 8-PD and 8-PG significantly inhibited proinflammatory C-C motif chemokine ligand 2 (CCL2) secretion from the adipose tissues of mice fed a long-term high-fat diet. The data suggest that 8-PD and 8-PG could regulate macrophage activation under obesity conditions.

Methylglyoxal induces multiple serine phosphorylation in insulin receptor substrate 1 via the TAK1-p38-mTORC1 signaling axis in adipocytes.

Certain metabolic intermediates produced during metabolism are known to regulate a wide range of cellular processes. Methylglyoxal (MG), a natural metabolite derived from glycolysis, has been shown to negatively influence systemic metabolism by inducing glucose intolerance, insulin resistance, and diabetic complications. MG plays a functional role as a signaling molecule that initiates signal transduction. However, the specific relationship between MG-induced activation of signal transduction and its negative effects on metabolism remains unclear. Here, we found that MG activated mammalian target of rapamycin complex 1 (mTORC1) signaling via p38 mitogen-activated protein kinase in adipocytes, and that the transforming growth factor-ß-activated kinase 1 (TAK1) is needed to activate p38-mTORC1 signaling following treatment with MG. We also found that MG increased the phosphorylation levels of serine residues in insulin receptor substrate (IRS)-1, which is involved in its negative regulation, thereby attenuating insulin-stimulated tyrosine phosphorylation in IRS-1. The negative effect of MG on insulin-stimulated IRS-1 tyrosine phosphorylation was exerted due to the MG-induced activation of the TAK1-p38-mTORC1 signaling axis. The involvement of the TAK1-p38-mTORC1 signaling axis in the induction of IRS-1 multiple serine phosphorylation was not unique to MG, as the proinflammatory cytokine, tumor necrosis factor-α, also activated the same signaling axis. Therefore, our findings suggest that MG-induced activation of the TAK1-p38-mTORC1 signaling axis caused multiple serine phosphorylation on IRS-1, potentially contributing to insulin resistance.

Screening of flavor compounds using Ucp1-luciferase reporter beige adipocytes identified 5-methylquinoxaline as a novel UCP1-inducing compound.

Uncoupling protein 1 (UCP1) in brown or beige adipocytes is a mitochondrial protein that is expected to enhance whole-body energy expenditure. For the high-throughput screening of UCP1 transcriptional activity regulator, we established a murine inguinal white adipose tissue-derived Ucp1-luciferase reporter preadipocyte line. Using this reporter preadipocyte line, 654 flavor compounds were screened, and a novel Ucp1 expression-inducing compound, 5-methylquinoxaline, was identified. Adipocytes treated with 5-methylquinoxaline showed increased Ucp1 mRNA expression levels and enhanced oxygen consumption. 5-Methylquinoxaline induced Ucp1 expression through peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), and 5-methylquinoxaline-induced PGC1α activation seemed to be partially regulated by its phosphorylation or deacetylation. Thus, our Ucp1-luciferase reporter preadipocyte line is a useful tool for screening of Ucp1 inductive compounds.

Glycerol kinase stimulates uncoupling protein 1 expression by regulating fatty acid metabolism in beige adipocytes.

Browning of adipose tissue is induced by specific stimuli such as cold exposure and consists of up-regulation of thermogenesis in white adipose tissue. Recently, it has emerged as an attractive target for managing obesity in humans. Here, we performed a comprehensive analysis to identify genes associated with browning in murine adipose tissue. We focused on glycerol kinase (GYK) because its mRNA expression pattern is highly correlated with that of uncoupling protein 1 (UCP1), which regulates the thermogenic capacity of adipocytes. Cold exposure-induced Ucp1 up-regulation in inguinal white adipose tissue (iWAT) was partially abolished by Gyk knockdown (KD) in vivo Consistently, the Gyk KD inhibited Ucp1 expression induced by treatment with the ß-adrenergic receptors (ßAR) agonist isoproterenol (Iso) in vitro and resulted in impaired uncoupled respiration. Gyk KD also suppressed Iso- and adenylate cyclase activator-induced transcriptional activation and phosphorylation of the cAMP response element-binding protein (CREB). However, we did not observe these effects with a cAMP analog. Therefore Gyk KD related to Iso-induced cAMP products. In Iso-treated Gyk KD adipocytes, stearoyl-CoA desaturase 1 (SCD1) was up-regulated, and monounsaturated fatty acids such as palmitoleic acid (POA) accumulated. Moreover, a SCD1 inhibitor treatment recovered the Gyk KD-induced Ucp1 down-regulation and POA treatment down-regulated Iso-activated Ucp1 Our findings suggest that Gyk stimulates Ucp1 expression via a mechanism that partially depends on the ßAR-cAMP-CREB pathway and Gyk-mediated regulation of fatty acid metabolism.

Long non-coding RNA 2310069B03Rik functions as a suppressor of Ucp1 expression under prolonged cold exposure in murine beige adipocytes.

Specific conditions, such as exposure to cold, can induce the production of brown-like adipocytes in white adipose tissue. These adipocytes express high levels of uncoupling protein 1 (UCP1) and energy expended by generating heat. Thus, these are a potential target for the prevention or treatment of obesity. The present study involved a comprehensive analysis of the adipose tissue to understand the relationship between long non-coding RNA (lncRNA) 2310069B03Rik and UCP1. Cold exposure increased both lncRNA 2310069B03Rik and Ucp1 expression in inguinal white adipose tissue (iWAT). However, overexpression of lncRNA 2310069B03Rik suppressed the Ucp1 mRNA expression and the promoter activity of UCP1 in the iWAT primary adipocytes. In addition, compared to the early induction of Ucp1 expression by cold stimulation, the induction of lncRNA 2310069B03Rik expression was later. These results suggest that lncRNA 2310069B03Rik functions as a suppression factor of Ucp1 expression.

α-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40.

Among dietary fatty acids with immunologic effects, ω-3 polyunsaturated fatty acids, such as α-linolenic acid (ALA), have been considered as factors that contribute to the differentiation of M2-type macrophages (M2 macrophages). In this study, we examined the effect of ALA and its gut lactic acid bacteria metabolites 13-hydroxy-9(Z),15(Z)-octadecadienoic acid (13-OH) and 13-oxo-9(Z),15(Z)-octadecadienoic acid (13-oxo) on the differentiation of M2 macrophages from bone marrow-derived cells (BMDCs) and investigated the underlying mechanisms. BMDCs were stimulated with ALA, 13-OH, or 13-oxo in the presence of IL-4 or IL-13 for 24 h, and significant increases in M2 macrophage markers CD206 and Arginase-1 (Arg1) were observed. In addition, M2 macrophage phenotypes were less prevalent following cotreatment with GPCR40 antagonists or inhibitors of PLC-ß and MEK under these conditions, suggesting that GPCR40 signaling is involved in the regulation of M2 macrophage differentiation. In further experiments, remarkable M2 macrophage accumulation was observed in the lamina propria of the small intestine of C57BL/6 mice after intragastric treatments with ALA, 13-OH, or 13-oxo at 1 g/kg of body weight per day for 3 d. These findings suggest a novel mechanism of M2 macrophage differentiation involving fatty acids from gut lactic acid bacteria and GPCR40 signaling.-Ohue-Kitano, R., Yasuoka, Y., Goto, T., Kitamura, N., Park, S.-B., Kishino, S., Kimura, I., Kasubuchi, M., Takahashi, H., Li, Y., Yeh, Y.-S., Jheng, H.-F., Iwase, M., Tanaka, M., Masuda, S., Inoue, T., Yamakage, H., Kusakabe, T., Tani, F., Shimatsu, A., Takahashi, N., Ogawa, J., Satoh-Asahara, N., Kawada, T. α-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40.

Soy hydrolysate enhances the isoproterenol-stimulated lipolytic pathway through an increase in ß-adrenergic receptor expression in adipocytes.

Activation of the adipose lipolytic pathway during lipid metabolism is mediated by protein kinase A (PKA), which responds to ß-adrenergic stimulation, leading to increased lipolysis. Soy is well known as a functional food and it is able to affect lipolysis in adipocytes. However, the mechanism by which soy components contribute to the lipolytic pathway remains to be fully elucidated. Here, we show that hydrolyzed soy enhances isoproterenol-stimulated lipolysis and activation of PKA in 3T3-L1 adipocytes. We also found that the expression of ß-adrenergic receptors, which coordinate the activation of PKA, is elevated in adipocytes differentiated in the presence of soy hydrolysate. The activity of the soy hydrolysate towards ß-adrenergic receptor expression was detected in its hydrophilic fraction. Our results suggest that the soy hydrolysate enhances the PKA pathway through the upregulation of ß-adrenergic receptor expression and thereby, increase lipolysis in adipocytes.

Endoplasmic Reticulum Stress Impaired Uncoupling Protein 1 Expression via the Suppression of Peroxisome Proliferator-Activated Receptor γ Binding Activity in Mice Beige Adipocytes.

Endoplasmic reticulum (ER) homeostasis is critical in maintaining metabolic regulation. Once it is disrupted due to accumulated unfolded proteins, ER homeostasis is restored via activation of the unfolded protein response (UPR); hence, the UPR affects diverse physiological processes. However, how ER stress influences adipocyte functions is not well known. In this study, we investigated the effect of ER stress in thermogenic capacity of mice beige adipocytes. Here, we show that the expression of uncoupling protein 1 (Ucp1) involved in thermoregulation is severely suppressed under ER stress conditions (afflicted by tunicamycin) in inguinal white adipose tissue (IWAT) both in vitro and in vivo. Further investigation showed that extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were both activated after ER stress stimulation and regulated the mRNA levels of Ucp1 and peroxisome proliferator-activated receptor γ (Pparγ), which is known as a Ucp1 transcriptional activator, in vitro and ex vivo. We also found that Pparγ protein was significantly degraded, reducing its recruitment to the Ucp1 enhancer, thereby downregulating Ucp1 expression. Additionally, only JNK inhibition, but not ERK, rescued the Pparγ protein. These findings provide novel insights into the regulatory effect of ER stress on Ucp1 expression via Pparγ suppression in beige adipocytes.

The hepatokine FGF21 is crucial for peroxisome proliferator-activated receptor-α agonist-induced amelioration of metabolic disorders in obese mice.

Obesity causes excess fat accumulation in white adipose tissues (WAT) and also in other insulin-responsive organs such as the skeletal muscle, increasing the risk for insulin resistance, which can lead to obesity-related metabolic disorders. Peroxisome proliferator-activated receptor-α (PPARα) is a master regulator of fatty acid oxidation whose activator is known to improve hyperlipidemia. However, the molecular mechanisms underlying PPARα activator-mediated reduction in adiposity and improvement of metabolic disorders are largely unknown. In this study we investigated the effects of PPARα agonist (fenofibrate) on glucose metabolism dysfunction in obese mice. Fenofibrate treatment reduced adiposity and attenuated obesity-induced dysfunctions of glucose metabolism in obese mice fed a high-fat diet. However, fenofibrate treatment did not improve glucose metabolism in lipodystrophic A-Zip/F1 mice, suggesting that adipose tissue is important for the fenofibrate-mediated amelioration of glucose metabolism, although skeletal muscle actions could not be completely excluded. Moreover, we investigated the role of the hepatokine fibroblast growth factor 21 (FGF21), which regulates energy metabolism in adipose tissue. In WAT of WT mice, but not of FGF21-deficient mice, fenofibrate enhanced the expression of genes related to brown adipocyte functions, such as Ucp1, Pgc1a, and Cpt1b Fenofibrate increased energy expenditure and attenuated obesity, whole body insulin resistance, and adipocyte dysfunctions in WAT in high-fat-diet-fed WT mice but not in FGF21-deficient mice. These findings indicate that FGF21 is crucial for the fenofibrate-mediated improvement of whole body glucose metabolism in obese mice via the amelioration of WAT dysfunctions.

10-oxo-12(Z)-octadecenoic acid, a linoleic acid metabolite produced by gut lactic acid bacteria, enhances energy metabolism by activation of TRPV1.

Gut microbiota can regulate the host energy metabolism; however, the underlying mechanisms that could involve gut microbiota-derived compounds remain to be understood. Therefore, in this study, we investigated the effects of KetoA [10-oxo-12(Z)-octadecenoic acid]-a linoleic acid metabolite produced by gut lactic acid bacteria-on whole-body energy metabolism and found that dietary intake of KetoA could enhance energy expenditure in mice, thereby protecting mice from diet-induced obesity. By using Ca2+ imaging and whole-cell patch-clamp methods, KetoA was noted to potently activate transient receptor potential vanilloid 1 (TRPV1) and enhance noradrenalin turnover in adipose tissues. In addition, KetoA up-regulated genes that are related to brown adipocyte functions, including uncoupling protein 1 (UCP1) in white adipose tissue (WAT), which was later diminished in the presence of a ß-adrenoreceptor blocker. By using obese and diabetic model KK-Ay mice, we further show that KetoA intake ameliorated obesity-associated metabolic disorders. In the absence of any observed KetoA-induced antiobesity effect or UCP1 up-regulation in TRPV1-deficient mice, we prove that the antiobesity effect of KetoA was caused by TRPV1 activation-mediated browning in WAT. KetoA produced in the gut could therefore be involved in the regulation of host energy metabolism.-Kim, M., Furuzono, T., Yamakuni, K., Li, Y., Kim, Y.-I., Takahashi, H., Ohue-Kitano, R., Jheng, H.-F., Takahashi, N., Kano, Y., Yu, R., Kishino, S., Ogawa, J., Uchida, K., Yamazaki, J., Tominaga, M., Kawada, T., Goto, T. 10-oxo-12(Z)-octadecenoic acid, a linoleic acid metabolite produced by gut lactic acid bacteria, enhances energy metabolism by activation of TRPV1.

Diversity of γ- glutamyl peptides and oligosaccharides, the "kokumi" taste enhancers, in seeds from soybean mini core collections.

Soybeans (Glycine max (L,) Merr,) contain γ-glutamyl peptides and oligosaccharides, and these components play an important role in imparting the "kokumi" taste to foods. To gain insight into the genetic diversities and molecular mechanisms of accumulation of γ-glutamyl peptides and oligosaccharides in soybean, we measured the contents of these components using the Japan and World mini core collections. Similar to other previously reported traits, wide variations were detected among the accessions in the core collections with respect to the content of γ-glutamyl peptides and oligosaccharides. We found a positive relationship between the content of γ-glutamyl tyrosine and γ-glutamyl phenylalanine and between the content of raffinose and stachyose. Furthermore, there were unique accessions that included high levels of γ-glutamyl peptides and oligosaccharides. These accessions may be helpful in understanding the accumulation mechanism of γ-glutamyl peptides and oligosaccharides and to increase the "kokumi" taste components in soybean by performing a genetic analysis.

ß-adrenergic Receptor Stimulation Revealed a Novel Regulatory Pathway via Suppressing Histone Deacetylase 3 to Induce Uncoupling Protein 1 Expression in Mice Beige Adipocyte.

Browning of adipose tissue has been prescribed as a potential way to treat obesity, marked by the upregulation of uncoupling protein 1 (Ucp1). Several reports have suggested that histone deacetylase (HDAC) might regulate Ucp1 by remodelling chromatin structure, although the mechanism remains unclear. Herein, we investigate the effect of ß-adrenergic receptor (ß-AR) activation on the chromatin state of beige adipocyte. ß-AR-stimulated Ucp1 expression via cold (in vivo) and isoproterenol (in vitro) resulted in acetylation of histone activation mark H3K27. H3K27 acetylation was also seen within Ucp1 promoter upon isoproterenol addition, favouring open chromatin for Ucp1 transcriptional activation. This result was found to be associated with the downregulation of class I HDAC mRNA, particularly Hdac3 and Hdac8. Further investigation showed that although HDAC8 activity decreased, Ucp1 expression was not altered when HDAC8 was activated or inhibited. In contrast, HDAC3 mRNA and protein levels were simultaneously downregulated upon isoproterenol addition, resulting in reduced recruitment of HDAC3 to the Ucp1 enhancer region, causing an increased H3K27 acetylation for Ucp1 upregulation. The importance of HDAC3 inhibition was confirmed through the enhanced Ucp1 expression when the cells were treated with HDAC3 inhibitor. This study highlights the novel mechanism of HDAC3-regulated Ucp1 expression during ß-AR stimulation.

Over-expression of PPARα in obese mice adipose tissue improves insulin sensitivity.

Peroxisome proliferator-activated receptor α (PPARα) is important in the regulation of lipid metabolism and expressed at high levels in the liver. Although PPARα is also expressed in adipose tissue, little is known about the relationship between its activation and the regulation of glucose metabolism. In this study, we developed adipose tissue specific PPARα over-expression (OE) mice. Metabolomics and insulin tolerance tests showed that OE induces branched-chain amino acid (BCAA) profile and improvement of insulin sensitivity. Furthermore, LC-MS and PCR analyses revealed that OE changes free fatty acid (FFA) profile and reduces obesity-induced inflammation. These findings suggested that PPARα activation in adipose tissue contributes to the improvement of glucose metabolism disorders via the enhancement of BCAA and FFA metabolism.

Isolation and characterization of key contributors to the "kokumi" taste in soybean seeds.

The water extract of soybean seeds (Glycine max (L.) Merr.) is nearly tasteless, but "kokumi" taste sensation was confirmed upon addition of a basic umami solution containing glutamic acid, inosine monophosphate, and sodium chloride. To identify the key contributors to the "kokumi" taste sensation in soybean seeds, sensory-guided fractionation, taste sensory analyses, and LC-MS/MS analyses were utilized. γ-glutamyl-tyrosine and γ-glutamyl-phenylalanine were identified as contributors to "kokumi taste"; specifically, these γ-glutamyl peptides imparted the "kokumi" taste sensation at a low taste threshold in a basic umami solution. Raffinose and stachyose, which are sufficiently present in soybean seeds, exhibited a synergistic effect in regard to the enhanced "kokumi" taste sensation of γ-glutamyl peptides. This is the first report that the combined use of γ-glutamyl peptides and oligosaccharides can increase the "kokumi" intensity, which suggests that soybean extracts or soymilk can be used to enhance the "kokumi" taste sensation in food products.

Geranylgeranyl pyrophosphate performs as an endogenous regulator of adipocyte function via suppressing the LXR pathway.

Isoprenoids such as geranylgeranyl pyrophosphate (GGPP) influence various biological processes. Here we show that GGPP inhibits adipocyte differentiation via the liver X receptors (LXRs) pathway. Intracellular GGPP levels and GGPP synthase (Ggps) mRNA expression increases during adipocyte differentiation. Ggps expression also increases in white adipose tissue of obese mice. GGPP addition reduces the expression of adipogenic marker genes such as adipocyte fatty acid binding protein, peroxisome proliferator-activated receptor γ, and insulin-stimulated glucose uptake. Similarly, over-expressing Ggps inhibits adipocyte differentiation. In contrast, Ggps knockdown promotes adipocyte differentiation. Inhibition of adipocyte differentiation by GGPP was partially reduced by LXR agonist T0901317. Furthermore, Ggps knockdown up-regulates LXR target genes during adipocyte differentiation. These results suggest that GGPP may act as an endogenous regulator of adipocyte differentiation and maturation through a mechanism partially dependent on the LXR pathway.

Metabolomics reveal 1-palmitoyl lysophosphatidylcholine production by peroxisome proliferator-activated receptor α.

PPARα is well known as a master regulator of lipid metabolism. PPARα activation enhances fatty acid oxidation and decreases the levels of circulating and cellular lipids in obese diabetic patients. Although PPARα target genes are widely known, little is known about the alteration of plasma and liver metabolites during PPARα activation. Here, we report that metabolome analysis-implicated upregulation of many plasma lysoGP species during bezafibrate (PPARα agonist) treatment. In particular, 1-palmitoyl lysophosphatidylcholine [LPC(16:0)] is increased by bezafibrate treatment in both plasma and liver. In mouse primary hepatocytes, the secretion of LPC(16:0) increased on PPARα activation, and this effect was attenuated by PPARα antagonist treatment. We demonstrated that Pla2g7 gene expression levels in the murine hepatocytes were increased by PPARα activation, and the secretion of LPC(16:0) was suppressed by Pla2g7 siRNA treatment. Interestingly, LPC(16:0) activates PPARα and induces the expression of PPARα target genes in hepatocytes. Furthermore, we showed that LPC(16:0) has the ability to recover glucose uptake in adipocytes induced insulin resistance. These results reveal that LPC(16:0) is induced by PPARα activation in hepatocytes; LPC(16:0) contributes to the upregulation of PPARα target genes in hepatocytes and the recovery of glucose uptake in insulin-resistant adipocytes.