Impaired Neutrophil Mechanoregulation by Fluid Flow: A Potential Contributing Factor for Microvascular Dysfunction in Obesity - The Mechanobiology of Obesity and Related Diseases - page 197

years, however, researchers have also found evidence that implicates obesity as an
inflammatory disease.
2.1 Obesity and Chronic Inflammation
Obese individuals express increased levels of C-reactive protein (CRP) [ 14 ]. In
addition to acting as an inflammatory marker, CRP has been associated with
increased risk for development of cardiovascular diseases [ 15 , 16 ]. One of the
earliest studies to link obesity with an inflammatory phenotype was that of
Hotamisligil et al. [ 17 ] who reported tumor necrosis factor-a (TNFa)tobe
systemically upregulated in obese mice. Since then, a large number of additional
pro-inflammatory cytokines, including interleukins (IL) -6 and -8, have been found
circulating within the bloodstream of obese individuals [ 18 , 19 ].
Secretion of these cytokines is believed to occur through the actions of adipose
tissue. Once viewed as simply an energy reservoir, adipose tissue has been shown
to have secretory capabilities [ 20 ] for several pro-inflammatory cytokines (e.g.,
IL-6, TNFa) that may activate leukocytes in the bloodstream [ 21 ]. In this fashion,
adipose tissue has been viewed as capable of driving an inflammatory state within
the body. In fact, higher levels of adipose tissues in the body appear to correspond
with increased cytokine secretion, such as TNFa [ 22 ]. Production of excessive
TNFa induces the activation of many types of leukocytes, such as neutrophils,
contributing to a chronic inflammatory state [ 23 ]. In addition to release from
adipose tissues, elevations in the number of macrophages within these tissues are
believed to contribute to the enhanced secretion of pro-inflammatory agonists [ 24 ].
Release of these substances is believed to result in sustained leukocyte activation
in blood due to continuous stimulation of inflammatory processes or by an
inhibitory effect on the resolution stage of inflammation [ 10 , 25 ].
Not surprisingly, obese individuals also display elevated leukocyte counts in the
bloodstream that are characteristic of an inflamed phenotype [ 26 ]. Furthermore,
these leukocytes exhibit an enhanced state of activation [ 27 , 28 ]. For example,
blood plasma from obese men contained elevated levels of myeloperoxidase
activity, indicative of enhanced neutrophil activation [ 29 ]. Additional leukocytes
implicated in adipose tissue-related inflammation include the T cells, macro-
phages, dendritic cells, natural killer cells, and mast cells [ 30 , 31 ].
The downstream effects of obesity include microvascular dysfunction, which
has been linked to elevated levels of pro-inflammatory cytokines present within
obese individuals [ 32 , 33 ]. For example, elevated levels of TNFa promote endo-
thelial damage due to oxidative stress that, in turn, impairs vasomotor control of
blood flow [ 34 ]. TNFa is also known to upregulate the expression of adhesion
molecules along the endothelium [ 35 ], which may further contribute to micro-
vascular dysfunction by promoting leukocyte adhesion in the microvasculature.