Huei-Fen Jheng

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.

Xanthoangelol and 4-hydroxyderrcin suppress obesity-induced inflammatory responses.

Obesity‐induced inflammation plays a pivotal role in the pathogenesis of insulin resistance and type 2 diabetes. Xanthoangelol (XA) and 4‐hydroxyderrcin (4‐HD), phytochemicals extracted from Angelica keiskei, have been reported to possess various biological properties. Whether XA and 4‐HD alleviate obesity‐induced inflammation and inflammation‐induced adipocyte dysfunction was investigated.

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 β‐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. FASEB J. 31, 5036–5048 (2017). www.fasebj.org

Dietary low-fat soy milk powder retards diabetic nephropathy progression via inhibition of renal fibrosis and renal inflammation

Scope: Diabetic nephropathy (DN) is a major cause of end‐stage renal disease. Here, we examined the effect of long‐term consumption of a low‐fat soy milk powder (LFSMP) on the diabetic kidney structure and function. Methods and results: KKAy mice were fed a casein‐, LFSMP‐, or high‐fat soy mixture powder (HFSMP)‐based diet for 4 months. Plasma and urine were subjected to a biochemical assay every 2–4 wk. Renal morphology and protein expression were evaluated by histochemical staining and western blots. Although HFSMP‐based diet showed no protective effect on DN. LFSMP‐fed mice exhibited lower water intake, urine output, and urinary albumin, and glucose excretion. Furthermore, strong preservation of renal structural proteins and low urinary N‐acetyl‐beta‐d‐glucosaminidase activity were observed in LFSMP‐fed mice, indicating alleviation of renal injury. LFSMP‐fed mice showed a lesser degree of mesangial matrix expansion, of tubulointerstitial fibrosis, and of myofibroblast differentiation. Finally, milder renal inflammation was found in LFSMP‐fed mice, as evidenced by a decrease in urinary monocyte chemoattractant protein‐ 1 excretion and lesser macrophage infiltration into the tubulointerstitium. Conclusion: The present data suggests that long‐term consumption of LFSMP but not HFSMP retards DN progression via suppressing renal injury, myofibroblast differentiation, and renal macrophage infiltration in diabetic condition.

Synthesized enone fatty acids resembling metabolites from gut microbiota suppress macrophage-mediated inflammation in adipocytes

SCOPE Recent reports indicate that gut microbiota and their metabolites may regulate host inflammatory conditions, including the chronic inflammation of obese adipose tissues. In this study, we investigated whether specific synthesized fatty acids, identical to the metabolites generated by gut microbiota, act as anti-inflammatory factors in obesity-induced inflammation. METHODS AND RESULTS We first used lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages to examine the anti-inflammatory effect of fatty acids synthesized to resemble representative polyunsaturated fatty acid metabolites from gut microbiota. Fatty acids containing an enone structure showed the most potent anti-inflammatory activity. Enone fatty acids also displayed anti-inflammatory effects on macrophages cocultured with hypertrophied 3T3-L1 or immortalized primary adipocytes; and macrophages stimulated with 3T3-L1 adipocyte conditioned medium. Consistently, the beneficial outcome was revealed in the case of LPS- and obesity-induced inflammatory cytokine stimulation in ex vivo adipose tissues. Furthermore, these fatty acids recovered the suppression of β-adrenergic receptor-stimulated uncoupling protein 1 expression and secretion of adiponectin in C3H10T1/2 and 3T3-L1 adipocytes, respectively, under inflammatory conditions, suggesting that enone fatty acids can ameliorate dysfunctions of adipocytes induced by inflammation. CONCLUSION These findings indicate that synthesized enone fatty acids show potent anti-inflammatory effects, leading to the improvement of inflammation-induced dysfunctions in adipocytes.

4-Hydroxyderricin, as a PPARγ Agonist, Promotes Adipogenesis, Adiponectin Secretion, and Glucose Uptake in 3T3-L1 Cells

Adipocyte differentiation plays a pivotal role in maintaining the production of small-size adipocytes with insulin sensitivity, and impaired adipogenesis is implicated in insulin resistance. 4-Hydroxyderricin (4-HD), a phytochemical component of Angelica keiskei, possesses diverse biological properties such as anti-inflammatory, antidiabetic, and antitumor. In the present study, we investigated the effects of 4-HD on adipocyte differentiation. 4-HD promoted lipid accumulation in 3T3-L1 cells, upregulated both peroxisome proliferator-activated receptor (PPAR)-γ mRNA and protein expression, and acted as a ligand for PPARγ in the luciferase assay. Moreover, 4-HD increased the mRNA and protein expression levels of adiponectin. Additionally, it promoted insulin-dependent glucose uptake into 3T3-L1 adipocytes and increased Akt phosphorylation and glucose transporter (GLUT) 4 mRNA expression. In summary, these findings suggest that 4-HD, which promoted adipogenesis and insulin sensitivity in 3T3-L1 cells, might be a phytochemical with potent insulin-sensitizing effects.

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.

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 a‐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‐β 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. FASEB J. 32, 304‐318 (2018). www.fasebj.org

A Phytol‐Enriched Diet Activates PPAR‐α in the Liver and Brown Adipose Tissue to Ameliorate Obesity‐Induced Metabolic Abnormalities

SCOPE Peroxisome proliferator-activated receptor alpha (PPAR-α) is a ligand-activated transcription factor that regulates lipid and carbohydrate metabolism. We investigate the effects of naturally occurring PPAR-α agonists, phytol, and its metabolite phytanic acid, on obesity-induced metabolic disorders using a mouse model. METHODS AND RESULTS A luciferase reporter assay shows that phytanic acid potently activates PPAR-α among PPAR subtypes. In high-fat-diet-induced, severely obese mice, a phytol-enriched diet increases phytanic acid levels in the liver and adipose tissue, where PPAR-α is abundantly expressed. A phytol-enriched diet ameliorates severe obesity and the related metabolic abnormalities of white adipose tissue. Moreover, the expression of PPAR-α target genes in the liver and brown adipose tissue is enhanced by a phytol-enriched diet, suggesting that phytol and phytanic acid activate PPAR-α in these organs. We confirm that phytanic acid treatment induced PPAR-α target gene expression in both primary hepatocytes and brown adipocytes from wild-type mice, but not in these cells from PPAR-α-deficient mice. CONCLUSION A phytol-enriched diet may increase phytanic acid levels in the liver and brown adipocytes, thereby activating PPAR-α in these organs and ameliorating obesity-induced metabolic diseases.

The Mevalonate Pathway is Indispensable for Adipocyte Survival

Summary The mevalonate pathway is essential for the synthesis of isoprenoids and cholesterol. Adipose tissue is known as a major site for cholesterol storage; however, the role of the local mevalonate pathway and its synthesized isoprenoids remains unclear. In this study, adipose-specific mevalonate pathway-disrupted (aKO) mice were generated through knockout of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (HMGCR). aKO mice showed serious lipodystrophy accompanied with glucose and lipid metabolic disorders and hepatomegaly. These metabolic variations in aKO mice were dramatically reversed after fat transplantation. In addition, HMGCR-disrupted adipocytes exhibited loss of lipid accumulation and an increase of cell death, which were ameliorated by the supplementation of mevalonate and geranylgeranyl pyrophosphate but not farnesyl pyrophosphate and squalene. Finally, we found that apoptosis may be involved in adipocyte death induced by HMGCR down-regulation. Our findings indicate that the mevalonate pathway is essential for adipocytes and further suggest that this pathway is an important regulator of adipocyte turnover.