114 7 Prospective
those individuals with a normal BMI might possess a higher body fat proportion.
Compared with people with a normal body fat composition, those persons with
VAT have a nearly fourfold risk of prediabetes, and nearly twice as likely to have
high blood pressure or heart disease (Levine and Levine 2011 ). As to BAT and
WAT, while adults have much WAT, new born babies have much BAT. Obese indi-
viduals have more WAT than do lean individuals.
Is low-grade inflammation originated from obesity? There are much discrep-
ant opinions regarding the origin and cause of obesity-induced inflammation.
Some authors thought that inflammation might be derived from the activated mac-
rophages within the adipose tissue (Weisberg et al. 2003 ), some authors suggested
that increased adipocyte O 2 consumption would trigger HIF-1α, causing inflam-
mation and insulin resistance in obesity (Lee et al. 2014 ), and other authors sup-
posed that hypoxia-induced heme oxygenase-1 (HO-1) might drive the chronic
inflammation and insulin resistance (Jais et al. 2014 ). However, it was also
believed that macrophage activation induces proinflammatory cytokines, which
can in turn activate iNOS to produce NO and drive hypoxia via HIF-1α.
A logical relationship is inflammation cause hypoxia, hypoxia results in reduced
energy expenditure, and reduced energy expenditure leads to obesity. Indeed, BAT
is usually “whitening” due to decreased mitochondria and compromised angio-
genesis (Shimizu et al. 2014 ). So it can be anticipated that anti-inflammation and
antihypoxia are generally effective for weight reduction. It was found that chronic
blockade of iNOS by l-NMMA reduces adiposity and improves insulin resistance
in HFD-induced obese mice (Tsuchiya et al. 2007 ). Through anti-inflammation,
salisylate as a degraded product of aspirin was found to reduce circulating lipids
in obese rats and to improve insulin sensitivity (Yuan et al. 2001 ). Like metformin,
aspirin was shown to able to treat type II diabetes as an activator of AMPK (Hawley
et al. 2012 ). Nitroaspirin was suggested to have therapeutic potential for NAFLD
(Ibrahim et al. 2011 ). Overexpression of or supplementation with EPO induces
reduced blood glucose levels and body mass in mice (Katz et al. 2010 ). Similarly,
it was also noticed that EPO treatment can inhibit WAT inflammation, normalized
insulin sensitivity, and reduced glucose intolerance in mice (Alnaali et al. 2014 ).
What are the primary and cardinal reasons triggering adipose, muscular, and
systemic inflammations? Such issues are debating in either noninfectious origin or
infectious origin. Nevertheless, some scientists seem to insist a dual origin pattern,
by which the free fatty acids (FFA) and LPS can equally activate proinflammatory
cytokines and induce insulin resistance (Heinrichsdorff and Olefsky 2012 ). Although
some authors supposed FFA-mediated inflammation in obesity, they are unable to
reasonably explain how can FFA do this. While the interaction of LPS with Toll-
like receptor 4 (TLR4) via CD14 has been confirmed, an interaction of FFA with
TLR4 is illy elucidated for a long time. Eventually, the liver secretory protein Fetuin
A (FetA) was found to function as an adapter between FFA and TLR4, by which the
triple interaction of FFA with TLR4 via FetA has been established (Pal et al. 2012 ).
Nevertheless, it remains awaiting for answering why short-chain fatty acids (SCFAs)
prevent rather than promote obesity (Blaut 2014 ), and how can FetA distinguish and
selectively bind to saturated FFA but not unsaturated FFA.