Relationship Between Cerebrospinal Fluid Visfatin (PBEF/Nampt) Levels and Adiposity in Humans

Hallschmid, Manfred; Randeva, Harpal S.; Tan, Bee K.; Kern, Werner; Lehnert, Hendrik

doi:10.2337/db08-1176

Cited by 65 publications

(41 citation statements)

References 27 publications

(34 reference statements)

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“…PBEF is detectable in serum and synovial fluid (1,6), and the levels of PBEF have been found to be increased in patients with rheumatoid arthritis, in whom it is clinically correlated with the Disease Activity Score in 28 joints and elevated C-reactive protein level (1,2,6). Other groups have detected PBEF in a variety of bodily fluids (35,(38)(39)(40)(41), and the levels appear to be correlated with inflammation (35,39,40). This suggests that infiltrating leukocytes and/or stromal cells at sites of inflammation actively secrete PBEF.…”

Section: Discussionmentioning

confidence: 93%

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

Evans

Williams

Hayes

et al. 2011

Arthritis & Rheumatism

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Objective. To assess the ability of pre-B cell colony-enhancing factor (PBEF) to regulate inflammation and degradative processes in inflammatory arthritis, using the small molecule inhibitor APO866 in human fibroblasts in vitro and in murine collageninduced arthritis (CIA).Methods. Enzyme-linked immunosorbent assays were used to examine regulation of expression of metalloproteinases and chemokines in human fibroblasts. The role of PBEF was further examined using APO866 in mice with CIA, with effects on disease activity assessed using radiography, histology, in vivo imaging, and quantitative polymerase chain reaction (qPCR).Results. In vitro activation of human fibroblasts with PBEF promoted expression of matrix metalloproteinase 3 (MMP-3), CCL2, and CXCL8, an effect inhibited by APO866. In mice with CIA, early intervention with APO866 inhibited synovial inflammation, including chemokine-directed leukocyte infiltration, and reduced a systemic marker of inflammation, serum hyaluronic acid. APO866 blockade led to reduced expression of MMP-3 and MMP-13 in joint extracts and to a reduction in a systemic marker of cartilage erosion, serum cartilage oligomeric matrix protein. Radiologic images revealed that APO866 protected against bone erosion, while qPCR demonstrated inhibition of RANKL expression. In mice with established disease, APO866 reduced synovial inflammation and cartilage destruction, and halted bone erosion. In addition, APO866 reduced the activity of MMP-3, CCL2, and RANKL in vivo, and inhibited production of CCL2 and RANKL in synovial explants from arthritic mice, a result that was reversed with nicotinamide mononucleotide.Conclusion. These findings confirm PBEF to be an important regulator of inflammation, cartilage catabolism, and bone erosion, and highlight APO866 as a promising therapeutic agent for targeting PBEF activity in inflammatory arthritis.Pre-B cell colony-enhancing factor (PBEF) represents an inflammatory mediator that exerts enzymatic activities and is highly expressed within the synovial tissue and plasma of patients with rheumatoid arthritis (1,2). In this respect, PBEF acts as a nicotinamide phosphoribosyltransferase (referred to as NAMPT) that controls NAD biosynthesis by catalyzing nicotinamide with 5-phosphoribosyl-1-pyrophosphate (3-5). Conversely, exogenous PBEF is also described as an adipocytokine (referred to as visfatin), and can regulate cellular processes via activation of transcriptional events through NF-B, phosphatidylinositol 3-kinase, and MAP kinase (6-8). Several groups have shown that PBEF interacts with the insulin receptor (8-10); however, this notion remains controversial (11,12), and it may be that PBEF signals through an alternative signaling route. It is also unlikely that this signaling effect is attributable to the endotoxin that may be present in PBEF preparations, since coincubation with polymixin B shows no abrogation of PBEF signaling (6,10,13).In vitro activation of signaling pathways by PBEF has been shown to regulate the expression of metalloproteinases...

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Section: Discussionmentioning

confidence: 93%

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

Evans

Williams

Hayes

et al. 2011

Arthritis & Rheumatism

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“…Endothelial cells of brain microvessels in obese fa/fa rats exhibit reduced insulin binding [31] that has been shown to result in reduced internalisation of the insulin-insulin receptor complex in rat brain endothelial cells, suggesting that the reduced CSF:plasma insulin ratio reflects impaired transendothelial insulin transport across the BBB in obesity [4]. Comparable results have been obtained for the CSF:plasma ratio of leptin [32] and also of visfatin (also known as pre-B-cell colonyenhancing factor and nicotinamide phosphoribosyltransferase), a peptide produced by adipose tissue as well as other organs with as yet largely unknown physiological effects [33]. These findings support the notion that reduced BBB transport of neuropeptidergic messengers involved in energy homeostasis is an important feature of obesity.…”

Section: Central Nervous Insulin Resistancementioning

confidence: 96%

Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?

Hallschmid

Schultes

2009

Diabetologia

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Research on functions and signalling pathways of insulin has traditionally focused on peripheral tissues such as muscle, fat and liver, while the brain was commonly believed to be insensitive to the effects of this hormone secreted by pancreatic beta cells. However, since the discovery some 30 years ago that insulin receptors are ubiquitously found in the central nervous system, an evergrowing research effort has conclusively shown that circulating insulin accesses the brain, which itself does not synthesise insulin, and exerts pivotal functions in central nervous networks. As an adiposity signal reflecting the amount of body fat, insulin provides direct negative feedback to hypothalamic nuclei that control whole-body energy and glucose homeostasis. Moreover, insulin affects distinct cognitive processes, e.g. by triggering the formation of psychological memory contents. Accordingly, metabolic and cognitive disorders such as obesity, type 2 diabetes mellitus and Alzheimer's disease are associated with resistance of central nervous structures to the effects of insulin, which may derive from genetic polymorphisms as well as from long-term exposure to excess amounts of circulating insulin due to peripheral insulin resistance. Thus, overcoming central nervous insulin resistance, e.g. by pharmacological interventions, appears to be an attractive strategy in the treatment and prevention of these disorders. Enhancement of central nervous insulin signalling by administration of intranasal insulin, insulin analogues and insulin sensitisers in basic research approaches has yielded encouraging results that bode well for the successful translation of these effects into future clinical practice.

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“…Visfatin is also a ratelimiting enzyme for the biosynthesis of NAD, an electron carrier that enables the body to produce ATP. Visfatin functions in various biological processes, such as obesity and metabolism (Sethi & Vidal-Puig 2005, Revollo et al 2007, Hallschmid et al 2009, Laudes et al 2010, immunology and inflammation (Moschen et al 2007,circadian clock (Yang et al 2007, Nakahata et al 2009, Ramsey et al 2009, are related to NAD production. Interestingly, as its name implies, visfatin has been characterized as a new adipokine that is mainly expressed in and secreted from visceral fat rather than subcutaneous fat.…”

Section: Introductionmentioning

confidence: 99%

Visfatin, a novel adipokine, stimulates glucose uptake through the Ca2+-dependent AMPK–p38 MAPK pathway in C2C12 skeletal muscle cells

Lee¹,

Kim²,

Lee³

et al. 2015

Journal of Molecular Endocrinology

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Visfatin is a novel adipocytokine produced by visceral fat. In the present study, visfatin increased AMP-activated protein kinase (AMPK) phosphorylation in mouse C2C12 skeletal muscle cells. It also increased phosphorylation of the insulin receptor, whose knockdown blocked visfatin-induced AMPK phosphorylation and glucose uptake. Visfatin stimulated glucose uptake in differentiated skeletal muscle cells. However, inhibition of AMPKa2 with an inhibitor or with knockdown of AMPKa2 using siRNA blocked visfatin-induced glucose uptake, which indicates that visfatin stimulates glucose uptake through the AMPKa2 pathway. Visfatin increased the intracellular Ca 2C concentration. STO-609, a calmodulindependent protein kinase kinase inhibitor, blocked visfatin-induced AMPK phosphorylation and glucose uptake. Visfatin-mediated activation of p38 MAPK was AMPKa2-dependent. Furthermore, both inhibition and knockdown of p38 MAPK blocked visfatin-induced glucose uptake. Visfatin increased glucose transporter type 4 (GLUT4) mRNA and protein levels. In addition, visfatin stimulated the translocation of GLUT4 to the plasma membrane, and this effect was suppressed by AMPKa2 inhibition. The present results indicate that visfatin plays an important role in glucose metabolism via the Ca 2C -mediated AMPK-p38 MAPK pathway.

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Relationship Between Cerebrospinal Fluid Visfatin (PBEF/Nampt) Levels and Adiposity in Humans

Cited by 65 publications

References 27 publications

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?

Visfatin, a novel adipokine, stimulates glucose uptake through the Ca2+-dependent AMPK–p38 MAPK pathway in C2C12 skeletal muscle cells

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