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

An increase in fat mass associated with obesity results from recruitment and differentiation of adipocyte progenitor cells. The precise origin of these cells is unknown, although accumulating evidence suggests that circulating stem cells can differentiate into cells of mesenchymal lineage. It is currently unclear whether a progenitor adipocyte population exists in circulation. One potential candidate is the fibrocyte, which may represent a common progenitor cell for several mesenchymal lineages. We demonstrate that these circulating progenitors become adipocytes when cultured under adipogenic conditions, with intracellular lipids accumulation and up-regulation of proteins specific for adipocyte differentiation, including leptin, PPARgamma, and FABP4. cDNA microarray analysis revealed gene clusters that were differentially regulated during adipogenesis of fibrocytes, which were similar to visceral and subcutaneous adipose tissue preadipocyte-to-adipocyte differentiation. Moreover, these progenitors engrafted and formed human adipose tissue following injection into SCID mice. Although fibrocytes express an array of chemokine receptors, we observed an up-regulation of CCR2 expression following fibrocytes differentiation into adipocytes, which was associated with increased chemotactic response to CCL2. This paradigm supports the notion that elevated CCL2 levels in visceral adipose tissue associated with Metabolic Syndrome is a chemotactic niche, whereby fibrocytes can home to and differentiate into adipocytes to perpetuate its tissue formation.
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PMID:Characterization of human fibrocytes as circulating adipocyte progenitors and the formation of human adipose tissue in SCID mice. 1618 61

The C-C motif chemokine receptor-2 (CCR2) regulates monocyte and macrophage recruitment and is necessary for macrophage-dependent inflammatory responses and the development of atherosclerosis. Although adipose tissue expression and circulating concentrations of CCL2 (also known as MCP1), a high-affinity ligand for CCR2, are elevated in obesity, the role of CCR2 in metabolic disorders, including insulin resistance, hepatic steatosis, and inflammation associated with obesity, has not been studied. To determine what role CCR2 plays in the development of metabolic phenotypes, we studied the effects of Ccr2 genotype on the development of obesity and its associated phenotypes. Genetic deficiency in Ccr2 reduced food intake and attenuated the development of obesity in mice fed a high-fat diet. In obese mice matched for adiposity, Ccr2 deficiency reduced macrophage content and the inflammatory profile of adipose tissue, increased adiponectin expression, ameliorated hepatic steatosis, and improved systemic glucose homeostasis and insulin sensitivity. In mice with established obesity, short-term treatment with a pharmacological antagonist of CCR2 lowered macrophage content of adipose tissue and improved insulin sensitivity without significantly altering body mass or improving hepatic steatosis. These data suggest that CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic insulin resistance and plays a role in the maintenance of adipose tissue macrophages and insulin resistance once obesity and its metabolic consequences are established.
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PMID:CCR2 modulates inflammatory and metabolic effects of high-fat feeding. 1639 2

Macrophage recruitment to adipose tissue in obesity contributes to enhanced adipose tissue inflammatory activity and thus may underlie obesity-associated metabolic dysfunction. Obese adipose tissue exhibits increases in CC chemokine ligand 2 (CCL2, or monocyte chemoattractant protein-1), an important macrophage-recruiting factor. We therefore hypothesized that elevated CCL2 may contribute to obesity-associated adipose tissue macrophage recruitment. Male 6-week-old CCL2(-/-) and wild-type mice (n = 11-14 per group) were fed standard and high-fat diets until 34 weeks of age. At 12-16 and 25-29 weeks of age, blood was collected for plasma glucose and hormone measurements, and glucose tolerance and insulin tolerance tests were performed. Adipose tissue was collected at 34 weeks for analysis of macrophage infiltration. Surprisingly, CCL2(-/-) mice on high-fat diet showed no reductions in adipose tissue macrophages. CCL2(-/-) mice on standard and high-fat diet were also glucose intolerant and had mildly increased plasma glucose and decreased serum adiponectin levels compared with wild-type mice. On high-fat diet, CCL2(-/-) mice also gained slightly more weight and were hyperinsulinemic compared with wild-type mice. Because macrophage levels were unchanged in CCL2(-/-) mice, the phenotype appears to be caused by lack of CCL2 itself. The fact that metabolic function was altered in CCL2(-/-) mice, despite no changes in adipose tissue macrophage levels, suggests that CCL2 has effects on metabolism that are independent of its macrophage-recruiting capabilities. Importantly, we conclude that CCL2 is not critical for adipose tissue macrophage recruitment. The dominant factor for recruiting macrophages in adipose tissue during obesity therefore remains to be identified.
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PMID:Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. 1747 19

The mucopolysaccharidosis (MPS) type VII mouse was originally described as the adipose storage deficiency mouse because of its extreme lean phenotype of unknown etiology. Here, we show that adipose storage deficiency and lower leptin levels are common to five different lysosomal storage diseases (LSDs): MPSI, MPSIIIB, MPSVII, Niemann-Pick type A/B, and infantile neuronal ceroid lipofuscinosis. Elevated circulating pro-inflammatory proteins (VCAM1 and MCP1) were found in multiple LSDs. Multiple anti-inflammatory strategies (dexamethasone, MCP1 deficiency, M3 expression) failed to alter adiposity in LSD animals. All of the models had normal or greater caloric intake and lower to normal metabolic rate, fasting plasma glucose, non-esterified fatty acids, cholesterol, and triglycerides. Triglycerides were lower in the livers of MPSI mice, and the trend was lower in the muscle. Lipid absorption and processing in MPSI mice were indistinguishable from those in normal mice following oral gavage of olive oil. The increased lean mass of MPSI and MPSIIIB mice suggests a shift in adipose triglycerides to lysosomal storage. In agreement, MPSI livers had a similar total caloric content but reduced caloric density, indicating a shift in energy from lipids to proteins/carbohydrates (lysosomal storage). Enzyme replacement therapy normalized the caloric density within 48 h without reducing total caloric content. This was due to an increase in lipids. Recycling of stored material is likely reduced or nonexistent. Therefore, to maintain homeostasis, energy is likely diverted to synthesis at the expense of typical energy storage depots. Thus, these diseases will serve as important tools in studying the role of lysosome function in metabolism and obesity.
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PMID:Lysosomal dysfunction results in altered energy balance. 1791 Nov 6

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

Obesity is associated with a complex systemic inflammatory reaction that has been associated with the development of atherosclerosis and insulin resistance. Obesity also induces macrophage accumulation in adipose tissue. Macrophages produce many of the pro inflammatory molecules released by adipose tissue and have been implicated in the development of obesity-induced adipose tissue inflammation. Monocyte chemoattractant proteins (MCPs) and their receptors play key roles in the development of inflammatory responses and are crucial for the recruitment of immune cells towards inflammation sites. Adipose tissue expression of at least 1 MCP, C-C motif chemokine ligand-2 (CCL2 or MCP1), increases in proportion to adiposity. The C-C motif chemokine receptor-2 (CCR2) regulates monocyte and macrophage recruitment and is necessary for macrophage-dependent inflammatory responses and the development of atherosclerosis. Because CCR2 regulates monocyte and macrophage chemotaxis and local inflammatory responses, it has been hypothesized that monocyte chemoattractant molecules acting through CCR2 might regulate obesity-induced inflammation in adipose tissue. Our study focuses on the molecular and genetic mechanisms that recruit and retain macrophages in adipose tissue.
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PMID:[Macrophages, inflammation, adipose tissue, obesity and insulin resistance]. 1826 82

Monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) secreted by adipocytes is a member of the CC chemokine family and plays a pivotal role in the inflammatory process. A polymorphism, the -2518 A/G of MCP-1 gene, has been associated with type 2 diabetes, type 1 diabetes, parameters of insulin resistance and obesity. Therefore, we investigated the effects of MCP-1 single nucleotide polymorphisms (SNPs) on the susceptibility to type 2 diabetes or insulin resistance in the Japanese population. We also assessed the correlation between serum MCP-1 concentration and other clinical characteristics in Japanese type 2 diabetic subjects. The serum MCP-1 concentration was significantly correlated with HOMA-IR and the visceral fat area, but not with BMI. Although there was no association between this SNP and type 2 diabetes, the -2518A/G polymorphism was associated with the serum MCP-1 concentration. In subgroup analysis, Japanese obese diabetic -2518AA carriers had a higher MCP-1 concentration and increased insulin resistance than obese diabetic -2518G carriers. These data indicated that the MCP-1 polymorphism was associated with insulin resistance in Japanese obese diabetic subjects and that MCP-1 was implicated in the pathogenesis of insulin resistance, especially associated with obesity, in humans.
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PMID:Association of serum MCP-1 concentration and MCP-1 polymorphism with insulin resistance in Japanese individuals with obese type 2 diabetes. 1876 29

Infection with Trypanosoma cruzi, the etiologic agent of Chagas disease is accompanied by an intense inflammatory reaction. Our laboratory group has identified adipose tissue as one of the major sites of inflammation during disease progression. Because adipose tissue is composed of many cell types, we were interested in investigating whether the adipocyte per se was a source of inflammatory mediators in this infection. Cultured adipocytes were infected with the Tulahuen strain of T. cruzi for 48-96 h. Immunoblot and quantitative PCR (qPCR) analyses demonstrated an increase in the expression of proinflammatory cytokines and chemokines, including interleukin (IL)-1 beta, interferon-gamma, tumor necrosis factor-alpha, CCL2, CCL5, and CXCL10 as well as an increase in the expression of Toll-like receptors-2 and 9 and activation of the notch pathway. Interestingly, caveolin-1 expression was reduced while cyclin D1 and extracellular signal-regulated kinase (ERK) expression was increased. The expression of PI3kinase and the activation of AKT (phosphorylated AKT) were increased suggesting that infection may induce components of the insulin/IGF-1 receptor cascade. There was an infection-associated decrease in adiponectin and peroxisome proliferator-activated receptor-gamma (PPAR-gamma). These data provide a mechanism for the increase in the inflammatory phenotype that occurs in T. cruzi-infected adipocytes. Overall, these data implicate the adipocyte as an important target of T. cruzi, and one which contributes significantly to the inflammatory response observed in Chagas disease.
Obesity (Silver Spring) 2008 Sep
PMID:Trypanosoma cruzi infection of cultured adipocytes results in an inflammatory phenotype. 1918 25

The recent increase in the prevalence of obesity has significant contribution to development of atherosclerosis and consequent cardiovascular disease. Obesity especially visceral obesity causes insulin resistance and is associated with dyslipidemia, impaired glucose metabolism, and hypertension, all of which exacerbate atherosclerosis. One plausible mechanism proposed recently is that factors known as adipocytokines, produced by adipose tissue in obesity can directly impact the atherogenic environment of the vessel wall by regulating gene expression and function in endothelial, arterial smooth muscle, and macrophage cells. These include TNFalpha, leptin, adiponectin, resistin, MCP1 and PAIl as well as free fatty acids. Reduction of visceral fat mass leads to amelioration of these risk factors and potentially prevents cardiovascular events.
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PMID:[Obesity and atherosclerosis]. 1920 8

Diet-mediated changes in transcriptional programs that promote the early differentiation of the mammary gland may lead to reduced breast cancer risk. The disparity in adult breast cancer incidence between Asian women and Western counterparts is attributed partly to high soy food intake. Here, we conducted genome-wide profiling of mammary tissues of weanling rats exposed to soy protein isolate (SPI) or control casein (CAS) via maternal diet to evaluate the contribution of early exposure on mammary gene expression. Of the identified 18 up- and 39 downregulated genes with SPI relative to CAS, a subset was associated with lipid metabolic pathways, consistent with reduced mammary adipocyte size and suggesting stromal adipocyte-specific genomic changes. Female offspring of rats fed SPI tended to have fewer terminal end buds (P = 0.06) and had significantly lower body weight and abdominal fat mass. To demonstrate the functional consequence of SPI-mediated adipocyte metabolic changes on neighboring mammary epithelium, the expression of in vivo regulated genes in 3T3-L1 adipocytes treated with soy isoflavone genistein and effects of the resultant conditioned medium (CM) on the differentiation of HC11 mammary epithelial cells were evaluated by quantitative RT-PCR and/or Western immunoblots. In differentiated 3T3-L1, genistein decreased fatty acid synthase and stearoyl-CoA desaturase and increased hydroxysteroid 11-beta dehydrogenase 1 expression. CM from genistein-treated adipocytes had higher adiponectin levels and augmented prolactin-induced, glucocorticoid-regulated beta-casein levels. These findings suggest that soy-associated components, by targeting mammary adipocytes, alter paracrine signaling to enhance mammary epithelial differentiation, with important implications for the prevention of breast cancer associated with obesity and obesity-related diseases.
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PMID:Early soy exposure via maternal diet regulates rat mammary epithelial differentiation by paracrine signaling from stromal adipocytes. 1932 80


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