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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several lines of epidemiological evidence have suggested that non-alcoholic steatohepatitis (NASH) is closely associated with obesity in humans. However, the precise mechanisms of the progression of NASH and its key metabolic abnormalities remain to be elucidated. We found that long-term high-fat diet (HFD) exposure induces NASH, with excess body weight, hyperinsulinemia and hypercholesteremia in mice. Longitudinal analysis of the model showed that steatohepatitis was induced after onset of metabolic abnormalities. In addition, we found that expression of MCP-1 mRNA was induced in the liver before induction of TNFalpha and type I collagen alpha1 mRNAs, and prior to onset of steatohepatitis. We confirmed that hepatic MCP-1 contents were increased in mice fed HFD for 50 weeks, although the precise role of MCP-1 in the development of NASH remains to be addressed. The mouse model was also characterized by moderate reductions in catalase activity and glutathione content, as well as by overexpression of fatty acid synthase, acetyl-CoA carboxylase 1 and FAT/CD36 mRNAs in the liver. The murine NASH model apparently mimics clinical aspects of the condition and provides insight into NASH.
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PMID:Longitudinal analysis of murine steatohepatitis model induced by chronic exposure to high-fat diet. 1730 Jun 98

Type 2 diabetes and obesity with enlarged fat cells are associated with low-grade systemic inflammation, impaired adipogenesis as well as the recruitment of inflammatory cells into the adipose tissue. Cytokines like TNFalpha and IL-6 are secreted by the inflammatory cells and have been shown to impair normal adipocyte differentiation. An important mechanism whereby these cytokines inhibit adipogenesis is by maintaining an active Wnt-signaling pathway. Also other cytokines like MCP-1 and resistin are involved in the inflammatory process and are secreted by macrophages. If these cytokines also affect Wnt-signaling and adipocyte differentiation is currently unclear. In the present study, we show that while TNFalpha is able to maintain an active Wnt-signaling, induce inflammation and completely block adipose cell differentiation, no effect was found by either MCP-1 or resistin on these processes. Addition of the thiazolidinedione, pioglitazone, was found to antagonize the effect of TNFalpha on the Wnt-signaling process and, consequently, promote adipogenesis.
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PMID:Wnt-signaling is maintained and adipogenesis inhibited by TNFalpha but not MCP-1 and resistin. 1744 72

Adipokines including chemokines are able to induce insulin resistance in human skeletal muscle cells, which may also be relevant for the observed link between obesity and diabetes. This study is aimed to analyze the expression of chemokine CC motif receptors (CCRs) in the insulin-resistant state in human skeletal muscle cells. Differentiated skeletal muscle cells were incubated for 24-72 hours with high concentrations of glucose and insulin (GI) or TNFalpha. In addition, myocytes were co-stimulated with monocyte chemotactic protein (MCP)-1 or adipocyte-conditioned medium (CM) and TNFalpha for 24 and 48 hours. Treatment with GI rapidly induced insulin resistance whereas TNFalpha impaired insulin signaling in a more chronic fashion (48-72 h). CM and MCP-1 also induced insulin resistance that was, however, not increased by co-stimulation with TNFalpha. Expression of CCR2 was decreased during differentiation but up-regulated in insulin-resistant myocytes after treatment with GI (24-72 h) and TNFalpha (72 h). Expression of CCR4 and CCR10 was down-regulated after treatment with TNFalpha, MCP-1, and CM. Our data show that the expression of CCR2, CCR4, and CCR10 is differentially regulated by different insulin resistance-inducing treatments in myotubes. However, we could not find a clear correlation between the level of insulin resistance and CCR expression in myotubes. In conclusion, we propose that upregulation of CCR2 in skeletal muscle does not represent a major step leading to muscle insulin resistance.
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PMID:Expression of chemokine receptors in insulin-resistant human skeletal muscle cells. 1744 60

It is now recognized that cross-talk between adipocytes and adipose tissue stromal cells such as macrophages contributes to local and systemic inflammation. One factor from adipocytes that may participate in this interaction and that is frequently elevated in inflammatory conditions such as obesity, insulin resistance, and type 2 diabetes is free fatty acids (FFA). To investigate the potential for FFA to enhance macrophage inflammation, we exposed U937 macrophages to physiological levels (150 microM) of FFA. Palmitic acid (PA), the predominant saturated FFA released from adipose tissue, but not unsaturated FFA, induced an approximately 6-fold (p<0.05) increase in IP-10 gene expression (and 2- to 4-fold increases in IL-8, MCP-1, COX-2, and MIG). PA also induced an approximately 2-fold increase (p<0.05) in active NF-kappaB, and two structurally distinct NF-kappaB inhibitors effectively blocked PA-induced IP-10 gene expression. Conditioned medium from PA-treated cells increased lymphocyte migration 41% (p<0.05) which was significantly reduced by IP-10-neutralizing antibody. These results suggest that elevated concentrations of PA commonly present in obese and insulin resistant individuals can increase NF-kappaB-mediated expression of IP-10 in macrophages. These events in turn may lead to an increasing feed-forward loop of chronic inflammation.
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PMID:Palmitic acid induces IP-10 expression in human macrophages via NF-kappaB activation. 1746 67

Adipocyte-derived factors might play a role in the development of hepatic insulin resistance. Resistin was identified as an adipokine linking obesity and insulin resistance. Resistin is secreted from adipocytes in rodents but in humans it was proposed to originate from macrophages and its impact for insulin resistance has remained elusive. To analyze the role of adipokines in general and resistin as a special adipokine, we cultured the human liver cell line HepG2 with adipocyte-conditioned medium (CM) containing various adipokines such as IL-6 and MCP-1, and resistin. CM and resistin both induce insulin resistance with a robust decrease in insulin-stimulated phosphorylation of Akt and GSK3. Insulin resistance could be prevented by co-treatment with troglitazone but not by co-stimulation with adiponectin. As human adipocytes do not secrete resistin, HepG2 cells were also treated with resistin added into CM. CM with resistin addition induced stronger insulin resistance than CM alone pointing to a specific role of resistin in the initiation of hepatic insulin resistance in humans.
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PMID:Conditioned medium obtained from in vitro differentiated adipocytes and resistin induce insulin resistance in human hepatocytes. 1771 71

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-kappaB inactivation and/or PPARgamma 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.
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PMID:Capsaicin, a spicy component of hot peppers, modulates adipokine gene expression and protein release from obese-mouse adipose tissues and isolated adipocytes, and suppresses the inflammatory responses of adipose tissue macrophages. 1771 33

Obese adipose tissue is characterized by an enhanced infiltration of macrophages. It is considered that the paracrine loop involving monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha between adipocytes and macrophages establishes a vicious cycle that augments the inflammatory changes and insulin resistance in obese adipose tissue. Polyphenols, which are widely distributed in fruit and vegetables, can act as antioxidants and some of them are also reported to have anti-inflammatory properties. Tomato is one of the most popular and extensively consumed vegetable crops worldwide, which also contains many flavonoids, mainly naringenin chalcone. We investigated the effect of flavonoids, including naringenin chalcone, on the production of proinflammatory mediators in lipopolysaccharide (LPS)-stimulated macrophages and in the interaction between adipocytes and macrophages. Naringenin chalcone inhibited the production of TNF-alpha, MCP-1, and nitric oxide (NO) by LPS-stimulated RAW 264 macrophages in a dose-dependent manner. Coculture of 3T3-L1 adipocytes and RAW 264 macrophages markedly enhanced the production of TNF-alpha, MCP-1, and NO compared with the control cultures; however, treatment with naringenin chalcone dose-dependently inhibited the production of these proinflammatory mediators. These results indicate that naringenin chalcone exhibits anti-inflammatory properties by inhibiting the production of proinflammatory cytokines in the interaction between adipocytes and macrophages. Naringenin chalcone may be useful for ameliorating the inflammatory changes in obese adipose tissue.
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PMID:Inhibitory effect of naringenin chalcone on inflammatory changes in the interaction between adipocytes and macrophages. 1791 59

We describe the effect of MCP-1 deficiency in mice rendered hyperlipemic by the concomitant ablation of the LDL receptor. The MCP-1(-/-)LDLr(-/-) mice in comparison with LDLr(-/-) mice showed a decreased lipoprotein clearance, derangements in free fatty acids delivery and less glucose tolerance when fed a regular chow, and they showed a partial resistance to alterations in glucose and lipid metabolism induced by dietary fat and cholesterol. They also were less prone to the development of diet-induced obesity. Our results suggest that the role of MCP-1 in metabolism is relevant and that, although new hidden complexities are evident, the function of MCP-1/CCL2 extends far beyond the monocyte chemoattractant effect. Therefore, the regulatory mechanisms influenced by MCP-1 should be fully ascertained to understand the metabolic consequences of inflammation and before considering MCP-1 as a therapeutic target.
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PMID:Deficiency in monocyte chemoattractant protein-1 modifies lipid and glucose metabolism. 1792 May 86

We recently described a novel mouse model that combines resistance to lactogenic hormones with GH deficiency (GHD). The GHD/lactogen-resistant males develop obesity and insulin resistance with age. We hypothesized that altered production of pancreatic hormones and dysregulation of adipocytokine secretion and action contribute to the pathogenesis of their insulin resistance. Double-mutant males (age 12-16 months) had fasting hyperinsulinemia, hyperamylinemia, hyperleptinemia, and a decreased ratio of adiponectin to leptin. Adiponectin receptor 1 and 2 (AdipoR1 and R2) mRNA levels in liver and skeletal muscle were normal but hepatic insulin receptor mRNA was increased. Relative to double-mutant males, GHD males had lower levels of insulin, amylin, and leptin, higher levels of adiponectin, and higher expression of hepatic AdipoR1 and insulin receptor mRNAs. Lactogen-resistant mice had reduced hepatic adipoR2 mRNA. In response to stress the plasma concentrations of MCP-1 and IL-6 increased in double-mutant males but not GHD or lactogen-resistant males. Our findings suggest that the insulin resistance of GHD/lactogen-resistant males is accompanied by dysregulation of pancreatic hormone and adipocytokine secretion and receptor expression. Phenotypic differences between double-mutant and GHD males suggest that lactogens and GH exert differential but overlapping effects on fat deposition and adipocytokine secretion and action.
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PMID:Effects of lactogen resistance and GH deficiency on mouse metabolism: pancreatic hormones, adipocytokines, and expression of adiponectin and insulin receptors. 1797 45

The prevalence of obesity is rising dramatically in developed and developing countries. Obesity contributes to increased mortality from numerous causes, but the most important of these is cardiovascular death. The relationship between obesity and atherogenesis is multifactorial, including alterations in the composition and level of lipoproteins, changes in blood pressure, and changes in circulating coagulation and inflammatory factors. Mouse models can be useful for dissecting selected aspects of this complex relationship. One area in which these models can be of particular value is in investigating the effect of secretory products of adipose tissue on the vessel wall. Adipocytes and adipose tissue secrete numerous factors and their level of expression is altered in obese states. Adipose tissue and adipocytes produce adiponectin, resistin, leptin, and apolipoproteins (serum amyloid A and apoE); all of which can directly impact vessel wall homeostasis. Mouse models utilizing deletion or overexpression of many of these factors have demonstrated an important impact of these on vessel wall homeostasis. Subsequent to the development of obesity, factors secreted from adipose tissue have also been shown to have direct effect on liver production of systemic inflammatory factors. Mouse models have validated the importance of angiotensin II, TNFalpha, and MCP-1 for impacting vessel wall health in obese states. In summary, excess adipose tissue produces myriad changes in organismal homeostasis with potential impact on the vessel wall. The power of mouse genetics permits targeted mechanistic investigation for understanding how obesity accelerates atherosclerosis in a complex in vivo milieu.
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PMID:Adipose tissue and the vessel wall. 1804 97


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