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Employing the method of differential display of expressed genes (by analysis of
8800 gene products utilizing cDNA probes) in paired samples of
subcutaneous and visceral fat donated from 2 female volunteers, the
investigators identified an adipokine that is synthesized primarily
by visceral fat and termed this molecule “visfatin.” They
subsequently found that the visfatin had been previously identified
as “pre-B cell colony-enhancing factor” (PBEF). This is
secreted by the liver, bone marrow, and muscle, is a growth factor
for early stage B lymphocytes, and down-regulates apoptosis of
neutrophils. The investigators demonstrated that: 1) expression of
PBEF/visfatin increased during adipocyte differentiation in vitro
with increased secretion of this protein into medium; 2) plasma
concentrations of visfatin correlated with the volume of visceral fat
in humans and mice but not the quantity of subcutaneous fat; 3)
plasma levels of visfatin increased as the amount of fat accumulated
in a mouse model of obesity; and 4) visfatin values rose rapidly in
mice ingesting a high-fat diet. Subsequently, the authors observed
that intravenous administration of visfatin led to a dose-dependent
decline in glucose concentrations without affecting insulin values in
intact and diabetic mice. Complete knock-out of the visfatin gene was
lethal. In heterozygotic (visfatin+/-) animals, basal
plasma glucose values were elevated, glucose tolerance was impaired,
while there was no difference in size or insulin levels. In vitro,
visfatin had several insulin-like actions including: enhancement of
glucose uptake, suppression of glucose release, accumulation of
triglycerides, and induction of gene markers of adipocyte
differentiation (PPAR γ, fatty acid synthase, adiponectin, and so forth). The investigators
also showed that visfatin bound to the insulin receptor and induced
its autophosphorylation, as well as phosphorylation of a number of
downstream products consistent with induction of the insulin/insulin
receptor signal transduction pathway. Most interestingly, they
demonstrated that visfatin did not bind to the same segment of the
insulin receptor as insulin (extracellular α subunit),
although the binding site on the insulin receptor to which visfatin
adheres was not identified. The authors concluded that visfatin has
insulin-like effects and may be of physiological significance in the
regulation of glucose homeostasis.
Fukuhara A, Matsuda M, Nishizawa M, et al. Visfatin: A protein secreted
by visceral fat that mimics the effects of insulin. Science.
2005;307:426-430.
Editor’s
Comment: This exciting discovery adds yet another factor to the
many that regulate glucose and lipid homeostasis and to the list of
adipocyte products that includes leptin, adiponectin, resistin,
tumor-necrosis factor-α, and
interleukin-6.1 Although visfatin has many insulin-like
qualities, its serum concentrations are lower than those of insulin
and do not change acutely after eating. Inasmuch as visfatin is
primarily secreted as the quantity of visceral fat increases, it may
serve as a (less than optimal) compensatory mechanism for the
deleterious effects of increased visceral adiposity. It is of
interest that visfatin, like other non-peptidal small molecules, such
as modified benzoquinones, can cross the plasma membrane and interact
with and activate the insulin receptor tyrosine kinase.2
These agents are active orally in animal models of type 2 diabetes
mellitus; they increase insulin sensitivity and also exert other
central and peripheral effects.
Allen W. Root, MD
Reference - (linked to  )
- Hug
C, Lodish HF. Science. 2005;307:36-37.
- Strowski
MZ, Li Z, Szalkowsk D, et al. Endocrinology. 2004;145:5259-5268.
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Current GGH - Vol. 24 No. 1
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