YU, RINA, CHU-SOOK KIM, BYUNG-SE KWON, AND TERUO KAWADA. Mesenteric adipose tissue-derived monocyte chemoattractant protein-1 plays a crucial role in adipose tissue macrophage migration and activation in obese mice. Obesity. 2006;14:1353-1362. Objective: To determine whether chemokines, which play a pivotal role in monocyte/macrophage trafficking, modulate macrophage infiltration into and activation in the adipose tissues. Research Methods and Procedures: Various types of adipose tissue were isolated from different fat depots (e.g., mesenteric, epididymal, renal, and subcutaneous adipose tissues) from obese mice fed a high-fat diet and from non-obese controls fed a standard diet. The isolated tissues were cultured for 24, 48, and 72 hours. The level of monocyte chemoattractant protein-1 (MCP-1) expression and the amount of protein released were measured by reverse transcriptase-polymerase chain reaction or enzymelinked immunosorbent assay, respectively. Chemotaxis assay was performed to measure the degree of macrophage migration. Macrophage activation was estimated by measuring the concentrations of nitric oxide and tumor necrosis factor ␣. Results: The level of MCP-1 mRNA expression, protein content, and the amount of protein released significantly increased in the adipose tissues from the obese mice compared with those from the non-obese mice. The mesenteric adipose tissue produced the highest levels of MCP-1 protein among the four different fat depots. Mesenteric adipose tissue-conditioned medium induced the highest degree of macrophage migration and strongly induced macrophages to produce proinflammatory mediators such as nitric oxide and tumor necrosis factor ␣. The neutralization of MCP-1 in the adipose tissue-conditioned medium significantly inhibited the migration and activation of macrophages. Discussion: Our findings suggest that MCP-1 plays a crucial role in adipose tissue inflammatory response by activating and inducing the infiltration of macrophages into adipose tissues. MCP-1 may be closely associated with visceral obesity-related complications and, thus, may be a useful therapeutic target for modulating visceral obesityrelated diseases.
Adipokines are involved in the obesity-induced chronic inflammatory response that plays a crucial role in the development of obesity-related pathologies such as type II diabetes and atherosclerosis. We here demonstrate that capsaicin, a naturally occurring phytochemical, can suppress obesity-induced inflammation by modulating adipokine release from and macrophage behavior in obese mice adipose tissues. Capsaicin inhibited the expressions of IL-6 and MCP-1 mRNAs and protein release from the adipose tissues and adipocytes of obese mice, whereas it enhanced the expression of the adiponectin gene and protein. The action of capsaicin is associated with NF-jB inactivation and/or PPARc activation. Moreover, capsaicin suppressed not only macrophage migration induced by the adipose tissue-conditioned medium, but also macrophage activation to release proinflammatory mediators. Capsaicin may be a useful phytochemical for attenuating obesity-induced inflammation and obesity-related complications.
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.
Abietic acid is one of the terpenoids, which are multifunctional natural compounds. It has been reported that abietic acid suppresses e¡ects on in£ammation. However, the mechanism underlying the anti-in£ammatory e¡ects remains unclear. The present work indicates that abietic acid suppresses the protein expression of tumor necrosis factor-K K and cyclooxygenase 2, which are involved in in£ammation, in lipopolysaccharidestimulated macrophages. Moreover, this e¡ect resembles that of thiazolidinedione, a synthetic peroxisome proliferator-activated receptor-Q Q (PPARQ Q) ligand. Indeed, abietic acid activates PPARQ Q in luciferase reporter assays. The activity of abietic acid induces PPARQ Q target gene expression in RAW264.7 macrophages and 3T3-L1 adipocytes. These data indicate that abietic acid is a PPARQ Q ligand and that its anti-in£ammatory e¡ect is partly due to the activation of PPARQ Q in stimulated macrophages. The present work suggests a novel possibility that abietic acid, a naturally occurring compound, can be used not only for anti-in£ammation but also for regulating lipid metabolism and atherosclerosis. ß
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