The Fractalkine/CX3CR1 System Regulates β Cell Function and Insulin Secretion

Lee, Yun Sok; Morinaga, Hidetaka; Kim, Jane J.; Lagakos, William S.; Taylor, Susan S.; Keshwani, Malik M.; Perkins, Guy; Dong, Hui; Kayali, Ayse G.; Sweet, Ian R.; Olefsky, Jerrold M.

doi:10.1016/j.cell.2013.03.001

Cited by 133 publications

(143 citation statements)

References 44 publications

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“…Our results on diet-induced obesity in Cx3CR1 gfp mice differ from other reports on this model. For instance, Morris et al [26] and Lee et al [27] failed to detect differences in HFD induced body weight and adiposity in fractalkine receptor KO mice and controls. These discrepancies might be due to different fat composition (60% fat for Morris vs.…”

Section: Discussionmentioning

confidence: 99%

The fractalkine/Cx3CR1 system is implicated in the development of metabolic visceral adipose tissue inflammation in obesity

Polyák

Ferenczi

Dénes

et al. 2014

Brain, Behavior, and Immunity

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Diet-induced obesity and related peripheral and central inflammation are major risk factors for metabolic, neurological and psychiatric diseases. The chemokine fractalkine (Cx3CL1) and its receptor Cx3CR1 play a pivotal role in recruitment, infiltration and proinflammatory polarization of leukocytes and micoglial cells, however, the role of fractalkine signaling in the development of metabolic inflammation is not fully resolved. To address this issue, fractalkine receptor deficient (Cx3CR1 gfp/gfp) mice were exposed to normal or fat-enriched diet (FatED) for 10 weeks and physiological-, metabolic-and immune parameters were compared to those animals in which the fractalkine signaling is maintained by the presence of one functioning allele (Cx3CR1 +/gfp). Mice with intact fractalkine signaling develop obesity characterized by increased epididymal white fat depots and mild glucose intolerance, recruit leukocytes into the visceral adipose tissue and display increased expression of subset of pro-and anti-inflammatory cytokines when exposed to fat-enriched diet. By contrast, Cx3CR1-deficient (gfp/gfp) mice gain significantly less weight on fat-enriched diet and have smaller amount of white adipose tissue (WAT) in the visceral compartment than heterozygote controls. Furthermore, Cx3CR1 gfp/gfp mice fed a fat-enriched diet do not develop glucose intolerance, recruit proportionally less number of gfp-positive cells and express significantly less MCP-1, IL-1a and TNFa in the WAT than control animals with fat-enriched diet induced obesity. Furthermore, heterozygote obese, but not fractalkine receptor deficient mice express high levels of anti-inflammatory IL-10 and arginase1 markers in the visceral fat. The effect of fat-enriched diet on cytokine expression pattern was specific for the WAT, as we did not detect significant elevation of interleukin-1, tumor necrosis factor-alpha and monocyte chemoatracting protein (MCP-1) expression in the liver or in the hypothalamus in either genotype. These results highlight the importance of fractalkine signaling in recruitment and polarization of adipose tissue immune cells and identify fractalkine as a target to fight obesity-induced inflammatory complications.

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Section: Discussionmentioning

confidence: 99%

The fractalkine/Cx3CR1 system is implicated in the development of metabolic visceral adipose tissue inflammation in obesity

Polyák

Ferenczi

Dénes

et al. 2014

Brain, Behavior, and Immunity

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“…Other data have provided evidence that treatment of islets with CX3CL1 increased intracellular Ca 2+ and potentiated insulin secretion in both mouse and human islets. Moreover, expression of CX3CL1 in islets of mice was decreased by ageing and high-fat diet feeding/obesity [59]. Further studies are needed to understand how fractalkine affects pancreatic function.…”

Section: Myokines and Metabolic Regulationmentioning

confidence: 99%

Myokines in insulin resistance and type 2 diabetes

et al. 2014

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Skeletal muscle represents the largest organ of the body in non-obese individuals and is now considered to be an active endocrine organ releasing a host of so-called myokines. These myokines are part of a complex network that mediates communication between muscle, the liver, adipose tissue, the brain and other organs. Recent data suggest that myokines regulated by muscle contraction may play a key role in mediating the health-promoting effects of regular physical activity. Although hundreds of myokines have recently been described in proteomic studies, we currently have a rather limited knowledge of the specific role these myokines play in the prevention of insulin resistance, inflammation and associated metabolic dysfunction. Several myokines are known to have both local and endocrine functions, but in many cases the contribution of physical activity to the systemic level of these molecules remains as yet unexplored. Very recently, novel myokines such as irisin, which is thought to induce a white to brown shift in adipocytes, have gained considerable interest as potential therapeutic targets. In this review, we summarise the most recent findings on the role of myokines in the regulation of substrate metabolism and insulin sensitivity. We further explore the role of myokines in the regulation of inflammation and provide a critical assessment of irisin and other myokines regarding their potential as therapeutic targets.

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“…Recently, there has been renewed interest in the CX3CR1 gene with the discovery of its role in the pancreatic β-cell insulin secretory pathway (8). With their comprehensive studies using CX3CR1 KO mice islets, Lee et al (8) observed that attenuation of FKN/CX3CR1 system underlie beta cell dysfunction and insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

“…With their comprehensive studies using CX3CR1 KO mice islets, Lee et al (8) observed that attenuation of FKN/CX3CR1 system underlie beta cell dysfunction and insulin secretion. The 280M and 249I variants alter ligand-receptor binding affinity and are believed to influence an increased susceptibility to T2DM in the carrier.…”

Section: Discussionmentioning

confidence: 99%

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Nonsynonymous T280M gene variant of CX3CR1 in South Indian population is associated with reduced risk for vascular disease in patients with diabetes mellitus

Sumi¹,

Ramachandran²,

Vr³

et al. 2015

Curr Res Cardiol

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BaCKgRouNd: Vascular inflammation leading to coronary artery disease (CAD) is a major complication of type 2 diabetes mellitus (T2DM). The chemokine receptor CX3CR1 is a key regulator in vascular injuryrelated inflammation. oBjeCTIVe: The authors examined the T280M and V249I gene variants of the CX3CR1 gene in patients with T2DM, CAD and CAD associated with T2DM, to understand the effect of these polymorphisms on the disease phenotype. MeThodS: Whole blood samples were collected from 913 South Indian subjects comprising 160 patients with T2DM, 284 with T2DM and CAD, 198 with CAD and 271 healthy subjects. T280M and V249I variants of the CX3CR1 gene were genotyped in these study subjects using polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis and PCR-DNA sequencing. ReSulTS:Multivariate logistic regression analysis revealed that the frequencies of 280M and 249I alleles were higher in controls than in cases in both the CAD and T2DM groups. Adjusted odds of T280M according to logistic regression were significant in all disease groups compared withhealthy subjects. Both MM and II genotypes of T280M and V249I polymorphisms were found to have an atheroprotective role in CAD and T2DM. The association of these polymorphisms were then examined in patients with CAD who were also diagnosed with diabetes. The M allele of T280M polymorphism was associated with attenuated risk for CAD and T2DM. CoNCluSIoNS:The present study demonstrated a protective role of the T280M variant of CX3CR1 gene for vascular complication in patients with T2DM. This polymorphism may reduce the binding strength of the chemokine receptor, thus attenuating inflammation both in vascular wall and adipose tissue.

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The Fractalkine/CX3CR1 System Regulates β Cell Function and Insulin Secretion

Cited by 133 publications

References 44 publications

The fractalkine/Cx3CR1 system is implicated in the development of metabolic visceral adipose tissue inflammation in obesity

The fractalkine/Cx3CR1 system is implicated in the development of metabolic visceral adipose tissue inflammation in obesity

Myokines in insulin resistance and type 2 diabetes

Nonsynonymous T280M gene variant of CX3CR1 in South Indian population is associated with reduced risk for vascular disease in patients with diabetes mellitus

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