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-1ß, 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.

Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-{alpha}-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-1ß, 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.

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.

Conjugated linoleic acid-mediated inflammation and insulin resistance in human adipocytes are attenuated by resveratrol.

Inflammation plays a role in trans-10, cis-12 (10,12)-conjugated linoleic acid (CLA)-mediated delipidation and insulin resistance in adipocytes. Given the anti-inflammatory role of resveratrol (RSV), we hypothesized that RSV would attenuate inflammation and insulin resistance caused by 10,12 CLA in human adipocytes. RSV blocked 10,12 CLA induction of the inflammatory response by preventing activation of extracellular signal-related kinase and induction of inflammatory gene expression (i.e., IL-6, IL-8, IL-1beta) within 12 h. Similarly, RSV suppressed 10,12 CLA-mediated activation of the inflammatory prostaglandin pathway involving phospholipase A(2), cyclooxygenase-2, and PGF(2alpha). In addition, RSV attenuated 10,12 CLA increase of intracellular calcium and reactive oxygen species associated with cellular stress, and activation of stress-related proteins (i.e., activating transcription factor 3, JNK) within 12 h. 10,12 CLA-mediated insulin resistance and suppression of fatty acid uptake and triglyceride content were attenuated by RSV. Finally, 10,12 CLA-mediated decrease of peroxisome proliferator-activated receptor gamma (PPARgamma) protein levels and activation of a peroxisome proliferator response element (PPRE) reporter were prevented by RSV. RSV increased the basal activity of PPRE, suggesting that RSV increases PPARgamma activity. Collectively, these data demonstrate for the first time that RSV prevents 10,12 CLA-mediated insulin resistance and delipidation in human adipocytes by attenuating inflammation and cellular stress and increasing PPARgamma activity.