Quercetin Reduces Tumor Necrosis Factor Alpha-Induced Muscle Atrophy by Upregulation of Heme Oxygenase-1.

The inflammatory cytokine tumor necrosis factor α (TNFα), upregulated in the obese condition, promotes protein degradation and is implicated in obesity-related skeletal muscle atrophy and age-related sarcopenia. Quercetin, a flavonoid, elicits antioxidative and anti-inflammatory activities. In this study, we investigated the effect of quercetin on TNFα-induced skeletal muscle atrophy as well as its potential mechanism of action. In this study, we observed that quercetin suppressed expression of TNFα-induced atrophic factors such as MAFbx/atrogin-1 and MuRF1 in myotubes, and it enhanced heme oxygenase-1 (HO-1) protein level accompanied by increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in myotubes. The HO-1 inhibitor ZnPP suppressed the inhibitory actions of quercetin on TNFα-induced atrophic responses and degradation of IκB-α in myotubes. Moreover, quercetin supplementation to high-fat diet-fed obese mice inhibited obesity-induced atrophic responses in skeletal muscle, accompanied by upregulation of HO-1 and inactivation of nuclear factor-kappa B (NF-κB), and the quercetin actions were attenuated in Nrf2-deficient mice. These findings suggest that quercetin protects against TNFα-induced muscle atrophy under obese conditions through Nrf2-mediated HO-1 induction accompanied by inactivation of NF-κB. Quercetin may be used as a dietary supplement to protect against obesity-induced skeletal muscle atrophy.

Suksdorfin Promotes Adipocyte Differentiation and Improves Abnormalities in Glucose Metabolism via PPARγ Activation.

Although the Apiaceae herb family has been traditionally used for the management of type 2 diabetes, its molecular mechanism has not been clarified. Coumarin derivatives, which are abundant in plants of the Apiaceae family, were evaluated for their effects on adipogenesis. We found that suksdorfin significantly promoted adipocyte differentiation and enhanced production of adiponectin, an anti-diabetic adipokine. We also demonstrated that suksdorfin activates peroxisome proliferator-activated receptor gamma (PPARγ), a master regulator of adipogenesis. Furthermore, we showed metabolic disorders in obese diabetic KK-Ay mice were attenuated by suksdorfin feeding. Suksdorfin intake induced adipocyte miniaturization and increased expression levels of PPARγ target genes related to adipocyte differentiation. These results indicated that suksdorfin induces adipogenesis in white adipose tissue (WAT) via the activation of PPARγ, leading to improvement of obesity-induced metabolic disorders. Therefore, suksdorfin-mediated amelioration of WAT dysfunctions might be responsible for the anti-diabetic effects of traditional herbal medicine therapy with Apiaceae.

Quercetin Protects Obesity-Induced Hypothalamic Inflammation by Reducing Microglia-Mediated Inflammatory Responses via HO-1 Induction.

Obesity-induced hypothalamic inflammation is characterized by activation of microglia, which are resident macrophages of the central nervous system, and is implicated in the derangement of energy homeostasis, metabolic complications, and neurodegenerative diseases. Quercetin, a naturally occurring flavonoid, is known to protect against oxidative stress and inflammation-related metabolic complications. Here, we demonstrate that quercetin reduces obesity-induced hypothalamic inflammation by inhibiting microglia-mediated inflammatory responses, and the beneficial action of quercetin is associated with heme oxygenase (HO-1) induction. Quercetin markedly reduced the production of inflammatory mediators (monocyte chemoattractant protein (MCP)-1, interleukin (IL-6), IL-1ß, nitric oxide) by microglia stimulated with saturated fatty acid palmitate and/or lipid-laden microglia-conditioned medium. Quercetin also upregulated the expression of HO-1 in palmitate-treated lipid-laden microglia, and the actions of quercetin against microglia activation accompanied by IκBα degradation were abolished by a HO-1 inhibitor. Moreover, quercetin supplementation reduced the levels of inflammatory cytokines and microglia activation markers in the hypothalamus of high fat diet (HFD)-fed obese mice, which was accompanied by upregulation of HO-1. These findings indicate that quercetin suppresses microglia-mediated inflammatory responses via the induction of HO-1, and hence protects against obesity-induced hypothalamic inflammation.

Hypothalamic lipid-laden astrocytes induce microglia migration and activation.

Obesity-induced hypothalamic inflammation is closely associated with various metabolic complications and neurodegenerative disorders. Astrocytes, the most abundant glial cells in the central nervous system, play a crucial role in pathological hypothalamic inflammatory processes. Here, we demonstrate that hypothalamic astrocytes accumulate lipid droplets under saturated fatty acid-rich conditions, such as obese environment, and that the lipid-laden astrocytes increase astrogliosis markers and inflammatory cytokines (TNFα, IL-1ß, IL-6, MCP-1) at the transcript and/or protein level. Medium conditioned by the lipid-laden astrocytes stimulate microglial chemotactic activity and upregulate transcripts of the microglia activation marker Iba-1 and inflammatory cytokines. These findings indicate that the lipid-laden astrocytes formed in free fatty acid-rich obese condition may participate in obesity-induced hypothalamic inflammation through promoting microglia migration and activation.

The Soy Peptide Phe-Leu-Val Reduces TNFα-Induced Inflammatory Response and Insulin Resistance in Adipocytes.

Obesity-induced adipose inflammation plays a crucial role in the development of obesity-induced metabolic disorders such as insulin resistance and type 2 diabetes. In the presence of obesity, hypertrophic adipocytes release inflammatory mediators, including tumor necrosis factor-alpha (TNFα) and monocyte chemoattractant protein-1 (MCP-1), which enhance the recruitment and activation of macrophages, and in turn augment adipose inflammation. We demonstrate that the soy peptide Phe-Leu-Val (FLV) reduces inflammatory responses and insulin resistance in mature adipocytes. Specifically, the soy peptide FLV inhibits the release of inflammatory cytokines (TNFα, MCP-1, and IL-6) from both TNFα-stimulated adipocytes and cocultured adipocytes/macrophages. This inhibition is mediated by the inactivation of the inflammatory signaling molecules c-Jun N-terminal kinase (JNK) and IκB kinase (IKK), and the downregulation of IκBα in the adipocytes. In addition, soy peptide FLV enhances insulin responsiveness and increases glucose uptake in adipocytes. More importantly, we, for the first time, found that adipocytes express peptide transporter 2 (PepT2) protein, and the beneficial action of the soy peptide FLV was disrupted by the peptide transporter inhibitor GlySar. These findings suggest that soy peptide FLV is transported into adipocytes by PepT2 and then downregulates TNFα-induced inflammatory signaling, thereby increasing insulin responsiveness in the cells. The soy peptide FLV, therefore, has the potential to prevent obesity-induced adipose inflammation and insulin resistance.

Quercetin suppresses MIP-1α-induced adipose inflammation by downregulating its receptors CCR1/CCR5 and inhibiting inflammatory signaling.

Obesity-induced inflammation is characterized by recruitment of adipose tissue macrophages that release inflammatory cytokines and chemokines. MIP-1α (macrophage inflammatory protein 1α)/CCL3, a CC chemokine, induces monocyte/macrophage infiltration and thus is implicated in obesity-induced adipose inflammation. Quercetin has been shown to modulate obesity-induced inflammation, but the mechanism of its action remains unclear. Here we demonstrate that quercetin decreases MIP-1α release from adipocytes and macrophages and from cocultured adipocytes/macrophages; it also opposes MIP-1α-induced macrophage infiltration and activation. The inhibitory action of quercetin on the MIP-1α-induced inflammatory responses of macrophages is mediated by downregulation of CCR1/CCR5, and inhibition of activation of JNK, p38 mitogen-activated-protein kinase (MAPK), and IKK as well as IκBα degradation. These findings suggest that quercetin may be a useful agent against obesity-induced adipose tissue inflammation.

Diet enriched with korean pine nut oil improves mitochondrial oxidative metabolism in skeletal muscle and brown adipose tissue in diet-induced obesity.

In this study, we investigated effects of pine nut oil (PNO) on high-fat-diet (HFD)-induced obesity and metabolic dysfunction in skeletal muscle and brown adipose tissue (BAT). Male C57BL/6 mice were fed a HFD with 15% energy from lard and 30% energy from either soybean oil (SBO-HFD) or PNO (PNO-HFD) for 12 weeks. The PNO-HFD resulted in less weight gain and intramuscular lipid accumulation than the SBO-HFD and was accompanied by upregulation of transcripts and proteins related to oxidative metabolism and phosphorylation of AMP-activated protein kinase (AMPK), as well as molecules selectively expressed in type I and type IIa muscle fibers. In addition, uncoupling protein-1 was upregulated in BAT. These beneficial metabolic effects were partly associated with the dual ligand activity of pinolenic acid, which is abundant in PNO, for peroxisome proliferator-activated receptors α and δ. Our findings suggest that PNO may have potential as a dietary supplement for counteracting obesity and metabolic dysregulation.

Dietary capsaicin attenuates metabolic dysregulation in genetically obese diabetic mice.

Metabolic dysregulation (e.g., hyperglycemia, hyperinsulinemia, hyperlipidemia, etc.) is a hallmark of obesity-related diseases such as insulin resistance, type 2 diabetes, and fatty liver disease. In this study, we assessed whether dietary capsaicin attenuated the metabolic dysregulation in genetically obese diabetic KKAy mice, which have severe diabetic phenotypes. Male KKAy mice fed a high-fat diet for 2 weeks received a 0.015% capsaicin supplement for a further 3 weeks and were compared with nonsupplemented controls. Dietary capsaicin markedly decreased fasting glucose/insulin and triglyceride levels in the plasma and/or liver, as well as expression of inflammatory adipocytokine genes (e.g., monocyte chemoattractant protein-1 and interleukin-6) and macrophage infiltration. At the same time expression of the adiponectin gene/protein and its receptor, AdipoR2, increased in adipose tissue and/or plasma, accompanied by increased activation of hepatic AMP-activated protein kinase, a marker of fatty acid oxidation. These findings suggest that dietary capsaicin reduces metabolic dysregulation in obese/diabetic KKAy mice by enhancing expression of adiponectin and its receptor. Capsaicin may be useful as a dietary factor for reducing obesity-related metabolic dysregulation.

Inflammatory components of adipose tissue as target for treatment of metabolic syndrome.

Obesity is an independent risk factor in the etiology of various metabolic diseases such as insulin resistance, type 2 diabetes and cardiovascular diseases. In this chapter, we discuss obesity-induced inflammation as a potential link with obesity-related metabolic syndrome, and discuss how obesity-related inflammatory components such as immune cells, and cytokines/chemokines and adipocy-tokines, provoke obesity-related pathologies. In particular, we focus on the hypothesis that anti-inflammatory food factors/phytochemicals may be useful for inhibiting the initiation and development of obesity-induced inflammation and metabolic syndrome.

Capsaicin, a spicy component of hot pepper, induces apoptosis by activation of the peroxisome proliferator-activated receptor gamma in HT-29 human colon cancer cells.

Capsaicin (N-vanillyl-8-methyl-alpha-nonenamide), a spicy component of hot pepper, is a homovanillic acid derivative that preferentially induces certain cancer cells to undergo apoptosis and has a putative role in cancer chemoprevention. Peroxisome proliferator-activated receptor gamma(PPARgamma), a member of the nuclear receptor superfamily, is a ligand-dependent transcription factor. PAPRgamma activation results in growth arrest and/or apoptosis in a variety of cancer cells. In the present study, we investigated the potential of capsaicin to induce apoptotic cell death in human colon cancer cells and the association of PPARgamma in the capsaicin action. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. PPARgamma and vanilloid receptor type 1 (VR-1) expressions at the protein or mRNA levels were detected by western blot analysis and reverse transcription-polymerase chain reaction. Apoptotic cell death was determined by DNA fragmentation and quantified by enzyme-linked immunosorbent assay. HT-29 human colon cancer cells expressed PPARgamma and VR-1. Treatment with capsaicin or the PPARgamma ligand troglitazone induced apoptotic cell death in a dose-dependent manner in HT-29 human colon cancer cells. Capsaicin-induced cell death was completely blocked by bisphenol A diglycidyl ether, a specific PPARgamma antagonist. Capsazepine, a specific antagonist for vanilloid receptor, did not inhibit capsaicin-induced apoptosis. Our data suggest that capsaicin-induced apoptotic cell death in HT-29 human colon cancer cells could be associated with the PPARgamma pathway without the involvement of the vanilloid receptor. Capsaicin may have a beneficial effect for the treatment of colon cancer.