Chia-Chi Chuang

Saturated Fatty Acid-Mediated Inflammation and Insulin Resistance in Adipose Tissue: Mechanisms of Action and Implications

This review highlights the inflammatory and insulin-antagonizing effects of saturated fatty acids (SFA), which contribute to the development of metabolic syndrome. Mechanisms responsible for these unhealthy effects of SFA include: 1) accumulation of diacylglycerol and ceramide; 2) activation of nuclear factor-kappaB, protein kinase C-, and mitogen-activated protein kinases, and subsequent induction of inflammatory genes in white adipose tissue, immune cells, and myotubes; 3) decreased PPARgamma coactivator-1 alpha/beta activation and adiponectin production, which decreases the oxidation of glucose and fatty acids (FA); and 4) recruitment of immune cells like macrophages, neutrophils, and bone marrow-derived dendritic cells to WAT and muscle. Several studies have demonstrated potential health benefits of substituting SFA with unsaturated FA, particularly oleic acid and (n-3) FA. Thus, reducing consumption of foods rich in SFA and increasing consumption of whole grains, fruits, vegetables, lean meats and poultry, fish, low-fat dairy products, and oils containing oleic acid or (n-3) FA is likely to reduce the incidence of metabolic disease.

Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-α–mediated inflammation and insulin resistance in primary human adipocytes

BACKGROUND Quercetin and trans-resveratrol (trans-RSV) are plant polyphenols reported to reduce inflammation or insulin resistance associated with obesity. Recently, we showed that grape powder extract, which contains quercetin and trans-RSV, attenuates markers of inflammation in human adipocytes and macrophages and insulin resistance in human adipocytes. However, we do not know how quercetin and trans-RSV individually affected these outcomes. OBJECTIVE The aim of this study was to examine the extent to which quercetin and trans-RSV prevented inflammation or insulin resistance in primary cultures of human adipocytes treated with tumor necrosis factor-α (TNF-α)-an inflammatory cytokine elevated in the plasma and adipose tissue of obese, diabetic individuals. DESIGN Cultures of human adipocytes were pretreated with quercetin and trans-RSV followed by treatment with TNF-α. Subsequently, gene and protein markers of inflammation and insulin resistance were measured. RESULTS Quercetin, and to a lesser extent trans-RSV, attenuated the TNF-α-induced expression of inflammatory genes such as interleukin (IL)-6, IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) and the secretion of IL-6, IL-8, and MCP-1. Quercetin attenuated TNF-α-mediated phosphorylation of extracellular signal-related kinase and c-Jun-NH₂ terminal kinase, whereas trans-RSV attenuated only c-Jun-NH₂ terminal kinase phosphorylation. Quercetin and trans-RSV attenuated TNF-α-mediated phosphorylation of c-Jun and degradation of inhibitory κB protein. Quercetin, but not trans-RSV, decreased TNF-α-induced nuclear factor-κB transcriptional activity. Quercetin and trans-RSV attenuated the TNF-α-mediated suppression of peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ target genes and of PPARγ protein concentrations and transcriptional activity. Quercetin prevented the TNF-α-mediated serine phosphorylation of insulin receptor substrate-1 and protein tyrosine phosphatase-1B gene expression and the suppression of insulin-stimulated glucose uptake, whereas trans-RSV prevented only the TNF-α-mediated serine phosphorylation of insulin receptor substrate-1. CONCLUSION These data suggest that quercetin is equally or more effective than trans-RSV in attenuating TNF-α-mediated inflammation and insulin resistance in primary human adipocytes.

Potential Mechanisms by Which Polyphenol-Rich Grapes Prevent Obesity-Mediated Inflammation and Metabolic Diseases

Obesity and metabolic disease-related health problems (e.g., type 2 diabetes, atherosclerosis, and hypertension) are the most prevalent nutrition-related issues in the United States. An emerging feature of obesity and type 2 diabetes is their linkage with chronic inflammation that begins in white adipose tissue and eventually becomes systemic. One potential strategy to reduce inflammation and insulin resistance is consumption of polyphenol-rich foods like grapes or their by-products, which have anti-inflammatory properties. Polyphenols commonly found in grape products have been reported to reduce inflammation by (a) acting as an antioxidant or increasing antioxidant gene or protein expression, (b) attenuating endoplasmic reticulum stress signaling, (c) blocking proinflammatory cytokines or endotoxin-mediated kinases and transcription factors involved in metabolic disease, (d) suppressing inflammatory- or inducing metabolic-gene expression via increasing histone deacetylase activity, or (e) activating transcription factors that antagonize chronic inflammation. Thus, polyphenol-rich grape products may reduce obesity-mediated chronic inflammation by multiple mechanisms, thereby preventing metabolic diseases.

Grape powder extract attenuates tumor necrosis factor α-mediated inflammation and insulin resistance in primary cultures of human adipocytes

Grapes are rich in phenolic phytochemicals that possess anti-oxidant and anti-inflammatory properties. However, the ability of grape powder extract (GPE) to prevent inflammation and insulin resistance in human adipocytes caused by tumor necrosis factor α (TNFα), a cytokine elevated in plasma and white adipose tissue (WAT) of obese, diabetic individuals, is unknown. Therefore, we examined the effects of GPE on markers of inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes treated with TNFα. We found that GPE attenuated TNFα-induced expression of inflammatory genes including interleukin (IL)-6, IL-1β, IL-8, monocyte chemoattractant protein (MCP)-1, cyclooxygenase (COX)-2 and Toll-like receptor (TLR)-2. GPE attenuated TNFα-mediated activation of extracellular signal-related kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK) and activator protein-1 (AP-1, i.e., c-Jun). GPE also attenuated TNFα-mediated IκBα degradation and nuclear factor-kappa B (NF-κB) activity. Finally, GPE prevented TNFα-induced expression of protein tyrosine phosphatase (PTP)-1B and phosphorylation of serine residue 307 of insulin receptor substrate-1 (IRS-1), which are negative regulators of insulin sensitivity, and suppression of insulin-stimulated glucose uptake. Taken together, these data demonstrate that GPE attenuates TNFα-mediated inflammation and insulin resistance in human adipocytes, possibly by suppressing the activation of ERK, JNK, c-Jun and NF-κB.

Xanthones from Mangosteen Inhibit Inflammation in Human Macrophages and in Human Adipocytes Exposed to Macrophage-Conditioned Media

Obesity-associated inflammation is characterized by recruitment of macrophages (MPhi) into white adipose tissue (WAT) and production of inflammatory cytokines, leading to the development of insulin resistance. The xanthones, alpha- and gamma-mangostin (MG), are major bioactive compounds found in mangosteen that are reported to have antiinflammatory and antioxidant properties. Thus, we examined the efficacy of MG to prevent lipopolysaccharide (LPS)-mediated inflammation in human MPhi (differentiated U937 cells) and cross-talk with primary cultures of newly differentiated human adipocytes. We found that alpha- and gamma-MG attenuated LPS-induced expression of inflammatory genes, including tumor necrosis factor-alpha, interleukin-6, and interferon gamma-inducible protein-10 in a dose-dependent manner in MPhi. We also found that alpha- and gamma-MG attenuated LPS-activated mitogen-activated protein kinases (MAPK) and activator protein (AP)-1, but only gamma-MG reduced nuclear factor-kappaB (NF-kappaB). In addition, alpha- and gamma-MG attenuated LPS suppression of PPARgamma gene expression in a dose-dependent manner. Notably, the ability of MPhi-conditioned media to cause inflammation and insulin resistance in primary cultures of human adipocytes was attenuated by pretreating MPhi with gamma-MG. Taken together, these data demonstrate that MG attenuates LPS-mediated inflammation in MPhi and insulin resistance in adipocytes, possibly by preventing the activation of MAPK, NF-kappaB, and AP-1, which are central to inflammatory cytokine production in WAT.

Xanthones from Mangosteen Prevent Lipopolysaccharide-Mediated Inflammation and Insulin Resistance in Primary Cultures of Human Adipocytes

The xanthones, alpha- and gamma-mangostin (MG), are major bioactive compounds found in mangosteen and are reported to have antiinflammatory properties in several murine models. Given the association between obesity, chronic low-grade inflammation, and insulin resistance, we examined the effects of alpha- and gamma-MG on markers of inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes treated with lipopolysaccharide (LPS). alpha- and gamma-MG decreased the induction by LPS of inflammatory genes, including tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, monocyte chemoattractant protein-1, and Toll-like receptor-2. Moreover, alpha- and gamma-MG attenuated LPS activation of the mitogen-activated protein kinases (MAPK) c-jun NH(2)-terminal kinase, extracellular signal-related kinase, and p38. alpha- and gamma-MG also attenuated LPS activation of c-Jun and activator protein (AP)-1 activity. gamma-MG was more effective than alpha-MG on an equimolar basis. Furthermore, gamma-MG but not alpha-MG attenuated LPS-mediated IkappaB-alpha degradation and nuclear factor-kappaB (NF-kappaB) activity. In addition, gamma-MG prevented the suppression by LPS of insulin-stimulated glucose uptake and PPAR-gamma and adiponectin gene expression. Taken together, these data demonstrate that MG attenuates LPS-mediated inflammation and insulin resistance in human adipocytes, possibly by inhibiting the activation of MAPK, NF-kappaB, and AP-1.

A polyphenol-rich fraction obtained from table grapes decreases adiposity, insulin resistance and markers of inflammation and impacts gut microbiota in high-fat-fed mice

The objective of this study was to determine if consuming an extractable or nonextractable fraction of table grapes reduced the metabolic consequences of consuming a high-fat, American-type diet. Male C57BL/6J mice were fed a low fat (LF) diet, a high fat (HF) diet, or an HF diet containing whole table grape powder (5% w/w), an extractable, polyphenol-rich (HF-EP) fraction, a nonextractable, polyphenol-poor (HF-NEP) fraction or equal combinations of both fractions (HF-EP+NEP) from grape powder for 16weeks. Mice fed the HF-EP and HF-EP+NEP diets had lower percentages of body fat and amounts of white adipose tissue (WAT) and improved glucose tolerance compared to the HF-fed controls. Mice fed the HF-EP+NEP diet had lower liver weights and triglyceride (TG) levels compared to the HF-fed controls. Mice fed the HF-EP+NEP diets had higher hepatic mRNA levels of hormone sensitive lipase and adipose TG lipase, and decreased expression of c-reactive protein compared to the HF-fed controls. In epididymal (visceral) WAT, the expression levels of several inflammatory genes were lower in mice fed the HF-EP and HF-EP+NEP diets compared to the HF-fed controls. Mice fed the HF diets had increased myeloperoxidase activity and impaired localization of the tight junction protein zonula occludens-1 in ileal mucosa compared to the HF-EP and HF-NEP diets. Several of these treatment effects were associated with alterations in gut bacterial community structure. Collectively, these data demonstrate that the polyphenol-rich, EP fraction from table grapes attenuated many of the adverse health consequences associated with consuming an HF diet.

Low level of trans-10, cis-12 conjugated linoleic acid decreases adiposity and increases browning independent of inflammatory signaling in overweight Sv129 mice.

The objective of this study was to determine the extent to which a low level of trans-10, cis-12 (10,12) conjugated linoleic acid (CLA) decreases adiposity and increases browning in overweight mice, its dependence on inflammatory signaling and potential synergistic effects of daily exercise. Young, Sv129 male mice were fed a high-fat diet for 5 weeks to make them fat and glucose intolerant and then switch them to a low-fat diet with or without 0.1% 10,12 CLA, sodium salicylate or exercise for another 7 weeks. 10,12 CLA decreased white adipose tissue (WAT) and brown adipose tissue mass, and increased the messenger RNA and protein levels, and activities of enzymes associated with thermogenesis or fatty acid oxidation in WAT. Mice fed 10,12 CLA had lower body temperatures compared to controls during cold exposure, which coincided with decreased adiposity. Although sodium salicylate decreased 10,12 CLA-mediated increases in markers of inflammation in WAT, it did not affect other outcomes. Exercise had no further effect on the outcomes measured. Collectively, these data indicate that 10,12 CLA-mediated reduction of adiposity is independent of inflammatory signaling, and possibly due to up-regulation of fatty acid oxidation and heat production in order to regulate body temperature. Although this low level of 10,12 CLA reduced adiposity in overweight mice, hepatomegaly and inflammation are major health concerns.