Title

 

Authors

R. Zaninetti¹, R. Rahimian², A. Amoruso³, P. Marzullo⁴, P.L. Canonico¹, S. Brunelleschi³, L. Fresu³, A.A. Genazzani<sup>1

1</sup> DiSCAFF, Università degli Studi del Piemonte Orientale A. Avogadro, Novara, Italy
² Dept. of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
³ Dept. of Medical Sciences, School of Medicine, Università degli Studi del Piemonte Orientale A. Avogadro, Novara, Italy
⁴ Dept. of Clinical and Molecular Medicine, Università del Piemonte Orientale A. Avogadro, Novara, Italy; Laboratory of Molecular Biology, I.R.C.C.S. Istituto Auxologico Italiano, Piancavallo (VB), Italy

 

Abstract

Nicotinamide phoshoribosyltransferase (NAMPT) is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide. NAMPT is also known as pre-B cell colony enhancing factor (PBEF), as a cytokine that can promote the maturation of B cell precursors and inhibit neutrophil apoptosis and was later re-identified as a “new visceral fat-derived hormone” named visfatin. It has been known for a long time that visfatin is an inflammatory mediator and in recent years more direct evidence has come to light. NAMPT inhibitors have been recently shown to reduce inflammation in models of collagen-induced arthritis and endotoxemia, an effect linked to a decrease in cellular NAD levels, as well as a decrease in TNF-α and IL-6. Furthermore, this effect has also been linked in part to a decreased activity of sirtuins (NAD-dependent deacetylases).Recently, it has been shown that, in a T-lymphocyte autoimmune disorder model (experimental autoimmune encephalomyelitis), NAMPT inhibitors are able to reduce demyelination, neurological damage and clinical manifestations of the disease. In this instance, the effect was linked to sirtuin and PARP inhibition, as well as to a secondary decrease of TNF-α and interferon-γ .
Over the last decade, much evidence has emerged that obesity is closely linked to systemic inflammation and increasing risk of developing cardiometabolic and degenerative diseases. Monocytes represent immune effector cells, equipped with chemokine receptors and adhesion receptors that mediate migration from blood to tissues during infection; they produce inflammatory cytokines and take up cells and toxic molecules; they can also differentiate into inflammatory dendritic cells or macrophages during inflammation and possibly, less efficiently, in the steady state. Compared with adipose tissue of lean individuals, adipose tissue of the obese expresses increased amounts of proinflammatory proteins such as TNF-α, IL-6, iNOS, TGF-β1, C-reactive protein. Adipose tissue macrophage numbers increase in obesity and participate in this inflammatory pathways. It has been reported that macrophages from visceral white adipose tissue expressed higher levels of visfatin than did mature adipocytes, moreover visfatin has been reported to be strongly expressed within lipid-loaded macrophages in atherosclerotic lesions and some reports also suggest a positive correlation between plasma levels of visfatin and visceral adiposity.
The aim of our study has been to evaluate ex-vivo visfatin expression in monocyte/macrophages in severe obesity at baseline and after six months of diet therapy. The objective of the study has focused on the correlation of severe obesity and insulin resistance with NAD levels, the assessment of the expression of visfatin in plasma and monocyte/macrophages and the investigation of whether visfatin concentrations are related to changes in body weight. The results and possible implications will be discussed.