Mechanisms of obesity-associated insulin resistance: many choices on the menu

doi:10.1101/GAD.1550907

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Mechanisms of obesity-associated insulin resistance: many choices on the menu

Journal Article•DOI•

Mechanisms of obesity-associated insulin resistance: many choices on the menu

Mohammed Qatanani¹, Mitchell A. Lazar•Institutions (1)

University of Pennsylvania¹

15 Jun 2007-Genes & Development (Genes Dev)-Vol. 21, Iss: 12, pp 1443-1455

TL;DR: Obesity-associated insulin resistance is a major risk factor for type 2 diabetes and cardiovascular disease and understanding the biology of these systems will inform the search for interventions that specifically prevent or treat insulin resistance and its associated pathologies.

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Abstract: Obesity-associated insulin resistance is a major risk factor for type 2 diabetes and cardiovascular disease. In the past decade, a large number of endocrine, inflammatory, neural, and cell-intrinsic pathways have been shown to be dysregulated in obesity. Although it is possible that one of these factors plays a dominant role, many of these factors are interdependent, and it is likely that their dynamic interplay underlies the pathophysiology of insulin resistance. Understanding the biology of these systems will inform the search for interventions that specifically prevent or treat insulin resistance and its associated pathologies.

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Journal Article•DOI•

Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes

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Adilson L. Guilherme¹, Joseph V. Virbasius¹, Vishwajeet Puri¹, Michael P. Czech¹•Institutions (1)

University of Massachusetts Medical School¹

01 May 2008-Nature Reviews Molecular Cell Biology

TL;DR: It is postulate that this variability in the severity of insulin resistance varies greatly among obese people might reflect differences in levels of lipid-droplet proteins that promote the sequestration of fatty acids within adipocytes in the form of triglycerides, thereby lowering exposure of skeletal muscle to the inhibitory effects of fatty acid.

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Abstract: Acquired resistance to the action of insulin to stimulate glucose transport in skeletal muscle is associated with obesity and promotes the development of type 2 diabetes. In skeletal muscle, insulin resistance can result from high levels of circulating fatty acids that disrupt insulin signalling pathways. However, the severity of insulin resistance varies greatly among obese people. Here we postulate that this variability might reflect differences in levels of lipid-droplet proteins that promote the sequestration of fatty acids within adipocytes in the form of triglycerides, thereby lowering exposure of skeletal muscle to the inhibitory effects of fatty acids.

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1,980 citations

Journal Article•DOI•

Macrophage-mediated inflammation in metabolic disease

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Ajay Chawla¹, Khoa D. Nguyen², Khoa D. Nguyen¹, Y. P. Sharon Goh¹, Y. P. Sharon Goh² - Show less +1 more•Institutions (2)

University of California, San Francisco¹, Stanford University²

10 Oct 2011-Nature Reviews Immunology

TL;DR: This work focuses on the pathogenic and protective functions of classically and alternatively activated macrophages, respectively, in experimental models of obesity and metabolic disease, in order to clarify the role of these cells in metabolic homeostasis.

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Abstract: Metabolism and immunity are two fundamental systems of metazoans. The presence of immune cells, such as macrophages, in metabolic tissues suggests dynamic, ongoing crosstalk between these two regulatory systems. Here, we discuss how changes in the recruitment and activation of macrophages contribute to metabolic homeostasis. In particular, we focus our discussion on the pathogenic and protective functions of classically and alternatively activated macrophages, respectively, in experimental models of obesity and metabolic disease.

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1,137 citations

Cites background from "Mechanisms of obesity-associated in..."

...In general, several cell-extrinsic and -intrinsic mechanisms have been identified that exhibit a cause-and-effect relationship between weight gain and peripheral insulin resistanc...
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Journal Article•DOI•

Chronic Inflammation in Obesity and the Metabolic Syndrome

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Rosário Monteiro¹, Isabel Azevedo¹•Institutions (1)

University of Porto¹

14 Jul 2010-Mediators of Inflammation

TL;DR: The difficulty in the management of obesity/metabolic syndrome is linked to their multifactorial nature where environmental, genetic and psychosocial factors interact through complex networks.

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Abstract: The increasing incidence of obesity and the metabolic syndrome is disturbing. The activation of inflammatory pathways, used normally as host defence, reminds the seriousness of this condition. There is probably more than one cause for activation of inflammation. Apparently, metabolic overload evokes stress reactions, such as oxidative, inflammatory, organelle and cell hypertrophy, generating vicious cycles. Adipocyte hypertrophy, through physical reasons, facilitates cell rupture, what will evoke an inflammatory reaction. Inability of adipose tissue development to engulf incoming fat leads to deposition in other organs, mainly in the liver, with consequences on insulin resistance. The oxidative stress which accompanies feeding, particularly when there is excessive ingestion of fat and/or other macronutrients without concomitant ingestion of antioxidant-rich foods/beverages, may contribute to inflammation attributed to obesity. Moreover, data on the interaction of microbiota with food and obesity brought new hypothesis for the obesity/fat diet relationship with inflammation. Beyond these, other phenomena, for instance psychological and/or circadian rhythm disturbances, may likewise contribute to oxidative/inflammatory status. The difficulty in the management of obesity/metabolic syndrome is linked to their multifactorial nature where environmental, genetic and psychosocial factors interact through complex networks.

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877 citations

Cites background from "Mechanisms of obesity-associated in..."

...Thus, it was discovered that saturated fatty acids activate both TLR2 and TLR4 and, instead, unsaturated fatty acids inhibit TLR-mediated signalling and gene expression [16]....
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...Examples include fatty acyl CoA, diacylglycerol, which activate PKC serine kinases, and ceramide, which can undergo phosphorylation to ceramide1-phosphate and promote inflammation or originate secondary metabolites with the same effect....
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...PKC has also been shown to constitute an important interface between metabolic deregulation, inflammation, and insulin resistance....
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...TLR4 has been found in murine preadipocytes 3T3-L1 and both TLR2 and TLR4 have been shown to be present and functional in human subcutaneous adipocytes [16]....
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...The apoptosis of inflammatory cells is a nonphlogistic physiological process of removing dead cells and is essential for the resolution of inflammation [16] with the added advantage that after engulfing these apoptotic cells, macrophages acquire a phenotype conductive to resolution, releasing anti-inflammatory signals such as interleukin-(IL-) 10 and transforming growth factor β (TGFβ) [29]....
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Journal Article•DOI•

Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota.

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Chih-Jung Chang¹, Chuan-Sheng Lin¹, Chia-Chen Lu², Jan Martel¹, Yun-Fei Ko³, David M. Ojcius¹, Shun-Fu Tseng¹, Tsung-Ru Wu¹, Yi-Yuan Margaret Chen¹, John D. Young³, Hsin-Chih Lai¹ - Show less +7 more•Institutions (3)

Chang Gung University¹, Fu Jen Catholic University², Ming Chi University of Technology³

23 Jun 2015-Nature Communications

TL;DR: The results indicate that G. lucidum and its high molecular weight polysaccharides may be used as prebiotic agents to prevent gut dysbiosis and obesity-related metabolic disorders in obese individuals.

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Abstract: Obesity is associated with low-grade chronic inflammation and intestinal dysbiosis. Ganoderma lucidum is a medicinal mushroom used in traditional Chinese medicine with putative anti-diabetic effects. Here, we show that a water extract of Ganoderma lucidum mycelium (WEGL) reduces body weight, inflammation and insulin resistance in mice fed a high-fat diet (HFD). Our data indicate that WEGL not only reverses HFD-induced gut dysbiosis-as indicated by the decreased Firmicutes-to-Bacteroidetes ratios and endotoxin-bearing Proteobacteria levels-but also maintains intestinal barrier integrity and reduces metabolic endotoxemia. The anti-obesity and microbiota-modulating effects are transmissible via horizontal faeces transfer from WEGL-treated mice to HFD-fed mice. We further show that high molecular weight polysaccharides (>300 kDa) isolated from the WEGL extract produce similar anti-obesity and microbiota-modulating effects. Our results indicate that G. lucidum and its high molecular weight polysaccharides may be used as prebiotic agents to prevent gut dysbiosis and obesity-related metabolic disorders in obese individuals.

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867 citations

Journal Article•DOI•

Alternative (M2) activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance

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Justin I. Odegaard¹, Roberto R. Ricardo-Gonzalez¹, Alex Red Eagle¹, Divya Vats¹, Christine R. Morel¹, Matthew H. Goforth¹, Vidya Subramanian², Lata Mukundan¹, Anthony W. Ferrante², Ajay Chawla¹ - Show less +6 more•Institutions (2)

Stanford University¹, Columbia University²

04 Jun 2008-Cell Metabolism

TL;DR: It is shown that in response to the Th2 cytokine interleukin-4 (IL-4), peroxisome proliferator-activated receptor delta (PPARdelta) directs expression of the alternative phenotype in Kupffer cells and adipose tissue macrophages of lean mice, suggesting an unexpected beneficial role for alternatively activated K upffer cells in metabolic syndrome and type 2 diabetes.

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788 citations

Cites background from "Mechanisms of obesity-associated in..."

...The infiltration and activation of macrophages in metabolic tissues are key events in the pathogenesis of diet-induced obesity and insulin resistance (Qatanani and Lazar, 2007)....
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References

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Journal Article•DOI•

Positional cloning of the mouse obese gene and its human homologue

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Yiying Zhang¹, Ricardo Proenca¹, Ricardo Proenca², Margherita Maffei², Marisa Barone¹, Marisa Barone², Lori Leopold², Lori Leopold¹, Jeffrey M. Friedman², Jeffrey M. Friedman¹ - Show less +6 more•Institutions (2)

Howard Hughes Medical Institute¹, Rockefeller University²

01 Dec 1994-Nature

TL;DR: The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.

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Abstract: The mechanisms that balance food intake and energy expenditure determine who will be obese and who will be lean. One of the molecules that regulates energy balance in the mouse is the obese (ob) gene. Mutation of ob results in profound obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.

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12,394 citations

"Mechanisms of obesity-associated in..." refers background in this paper

...The discovery of leptin by Friedman and colleagues in 1994 (Zhang et al. 1994) ushered in an era of receptivity to the notion that adipose tissue is an endocrine organ, and that increased adipose mass in obesity could lead to pathological changes in adipocyte hormones (adipokines) that regulate insulin sensitivity....
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Journal Article•DOI•

Obesity is associated with macrophage accumulation in adipose tissue

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Stuart P. Weisberg¹, Daniel McCann, Manisha Desai, Michael Rosenbaum, Rudolph L. Leibel, Anthony W. Ferrante - Show less +2 more•Institutions (1)

Columbia University¹

15 Dec 2003-Journal of Clinical Investigation

TL;DR: Transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob) found that the expression of 1,304 transcripts correlated significantly with body mass.

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Abstract: Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications. To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob). We found that the expression of 1,304 transcripts correlated significantly with body mass. Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass. Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass. Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68. Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1op/op) mice suggest that these F4/80+ cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages. Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-alpha expression and significant amounts of iNOS and IL-6 expression. Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.

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8,902 citations

"Mechanisms of obesity-associated in..." refers background in this paper

...Recent studies suggest that macrophages are the major source of TNF in adipose tissue (Weisberg et al. 2003)....
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...Furthermore, obesity is characterized by macrophage accumulation in white adipose tissue, which has added another dimension to our understanding of the development of adipose tissue inflammation in obesity (Weisberg et al. 2003; Xu et al. 2003)....
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...Systemic chronic inflammation has been proposed to have an important role in the pathogenesis of obesityrelated insulin resistance (Hotamisligil et al. 1995; Weisberg et al. 2003; Xu et al. 2003; Wellen and Hotamisligil 2005)....
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Journal Article•DOI•

PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes

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Vamsi K. Mootha¹, Cecilia M. Lindgren¹, Cecilia M. Lindgren², Karl-Fredrik Eriksson², Aravind Subramanian¹, Smita Sihag¹, J. Lehar¹, Pere Puigserver³, Emma Carlsson², Martin Ridderstråle², Esa Laurila², Nicholas E. Houstis¹, Mark J. Daly¹, Nick Patterson¹, Jill P. Mesirov¹, Todd R. Golub¹, Todd R. Golub³, Pablo Tamayo¹, Bruce M. Spiegelman³, Eric S. Lander¹, Joel N. Hirschhorn¹, Joel N. Hirschhorn⁴, Joel N. Hirschhorn³, David Altshuler, Leif Groop² - Show less +21 more•Institutions (4)

Massachusetts Institute of Technology¹, Lund University², Harvard University³, Boston Children's Hospital⁴

01 Jul 2003-Nature Genetics

TL;DR: An analytical strategy is introduced, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes, which identifies a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle.

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Abstract: DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.

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7,997 citations

"Mechanisms of obesity-associated in..." refers background in this paper

...Thus, a better understanding of the molecular mechanisms underlying insulin resistance will be required to combat the epidemics of T2DM and cardiovascular disease that are fueled by obesity-associated insulin resistance....
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...Other studies have revealed similar decreases in mitochondrial activity and increases in intramyocellular fat content in young insulin-resistant offspring of parents with T2DM, a group that has a strong tendency to develop diabetes later in life (Petersen et al. 2004)....
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...Plasma PAI-1 levels are elevated in obesity and insulin resistance and predict future risk for T2DM (Mertens and Van Gaal 2002; Juhan-Vague et al. 2003)....
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...In humans, circulating TNF levels are increased in obese nondiabetic and T2DM individuals, but the correlation between insulin resistance and plasma TNF levels is relatively weak (Hotamisligil et al. 1995; Nilsson et al. 1998; Zinman et al. 1999; Miyazaki et al. 2003)....
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...Plasma IL-6 concentrations predict the development of T2DM (Vozarova et al. 2001), and peripheral administration of IL-6 induces hyperlipidemia, hyperglycemia, and insulin resistance in rodents and humans (Stith and Luo 1994; Tsigos et al. 1997; Petersen et al. 2005)....
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Journal Article•DOI•

Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance

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Gökhan S. Hotamisligil¹, Narinder S. Shargill¹, Bruce M. Spiegelman¹•Institutions (1)

Harvard University¹

01 Jan 1993-Science

TL;DR: A role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity is indicated.

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Abstract: Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

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7,347 citations

"Mechanisms of obesity-associated in..." refers background in this paper

...TNF was the first cytokine to be implicated in the pathogenesis of obesity and insulin resistance (Hotamisligil et al. 1993)....
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...Adipose tissue expression of TNF is increased in obese rodents and humans and positively correlated with adiposity and insulin resistance (Hotamisligil et al. 1993; Fernandez-Real and Ricart 2003; Hotamisligil 2003; Ruan and Lodish 2003)....
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...Treatment with neutralizing soluble TNF receptors improves insulin sensitivity in rodent obesity (Hotamisligil et al. 1993; Cheung et al. 1998)....
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Journal Article•DOI•

Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.

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Haiyan Xu¹, Glenn Barnes, Qing Yang, Guo Tan, Daseng Yang, Chieh J. Chou, Jason Sole, Andrew Nichols, Jeffrey S. Ross, Louis A. Tartaglia, Hong Chen - Show less +7 more•Institutions (1)

Millennium Pharmaceuticals¹

15 Dec 2003-Journal of Clinical Investigation

TL;DR: It is proposed that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue, and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance.

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Abstract: Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance However, the underlying molecular pathways are largely unknown In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO) The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue

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6,165 citations

"Mechanisms of obesity-associated in..." refers background in this paper

...Furthermore, obesity is characterized by macrophage accumulation in white adipose tissue, which has added another dimension to our understanding of the development of adipose tissue inflammation in obesity (Weisberg et al. 2003; Xu et al. 2003)....
[...]
...In addition, TZDs have antiinflammatory effects including transrepression of TNF production by macrophages and decreased macrophage infiltration of adipose tissue (Xu et al. 2003; Di Gregorio et al. 2005; Pascual et al. 2005)....
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...Systemic chronic inflammation has been proposed to have an important role in the pathogenesis of obesityrelated insulin resistance (Hotamisligil et al. 1995; Weisberg et al. 2003; Xu et al. 2003; Wellen and Hotamisligil 2005)....
[...]