115Interestingly, a previous finding delineated that the disruption of FatA expres-
sion renders animals more susceptible to endotoxemia, whereas the supplementa-
tion of FetA confers protection against lethal endotoxemia (Li et al. 2011 ). This
result implies that elevation of FetA might be due to LPS accumulation in obesity
because FetA can competitively bind to TLR4 with LPS. In fact, it seems that the
LPS-originated inflammation theory has evoked much enthusiasms in recent years.
Ding et al. ( 2010 ) indicated that intestinal inflammation precedes and correlates
with HFD-induced obesity, adiposity and insulin resistance. They suggested that
HFD interact with gut microbiota to trigger the expression of TNF-α and NF-κB.
The absence of gut microbiota in germ-free mice blunts the upregulation of pri-
mary inflammatory indicators. A relevance of HFD to gut dysbiosis was revealed
as that HFD increases the ratio of Firmicutes to Bacteriodetes, and induces the
overgrowth of Enterobecteriaceae, which exacerbates inflammation and obesity
in mice via the TLR4 signaling pathway (Kim et al. 2012 ). A recent work indi-
cated that adipocyte inflammation is essential for healthy adipose tissue expansion
and remodeling, in which visceral fat is deposited for effectively filtering the gut-
derived LPS (Asterholm et al. 2014 ). This finding seems imply an association of
gut bacterial dysbiosis with visceral adipose storage.
Recently, we investigated the effects of different dosages of LPS on the expres-
sion levels of proinflammatory cytokines in mice fed with HFD. Surprisingly, we
found that low-dose (0.25 mg/kg) LPS enhances the low-grade inflammation in
the visceral tissue, whereas high-dose (1.2 mg/kg) LPS does not induce or even
suppresses inflammation in the peripheral tissue. For example, intramuscular
injection of HFD-induced mice with 1.2 mg/kg LPS extremely downregulates pro-
inflammatory cytokines in the skeletal muscle. In contrast, intraperitoneal injection
of HFD-induced mice with 0.25 mg/kg LPS mildly upregulates proinflammatory
cytokines for only 2–3 folds.
Accordingly, we also noticed that the serum NO and 3NT levels that represents
the extent of iNOS activation by proinflammatory cytokines are gradually declined
during high-dose LPS injection. In contrast, low-dose LPS can mimic the gastroin-
testinal infection by G− bacteria that produce and leak LPS into the blood stream.
It could be concluded that low-grade inflammation is originated from low-dose
LPS, but we are currently unknown why high-dose LPS exerts an immunosup-
pressive effect. We found that ART, DNP, and NG exert weight-reducing effects
through anti-inflammation and mitochondrial biogenesis. For example, ART, DNP,
and NG were found to downregulate iNOS and downstream genes, and upregulate
eNOS and downstream genes, suggesting activated eNOS/inactivated iNOS might
be a pivotal switch for weight loss.
I propose here a novel hypothesis of healthy/unhealthy obesity based on
the comparison of low-grade inflammation, insulin resistance, SAT/VAT, and
BAT/WAT (Fig. 7.2).
Healthy obesity was assumed to be germ-free (without LPS leakage) or G+
bacteria-induced adiposity with a high BMI but without VAT and insulin resist-
ance, whereas unhealthy obesity was supposed to be G− bacteria-induced adipos-
ity with high BMI, VAT and low-grade inflammation, probably exhibiting insulin
7.2 Low-Grade Inflammation as an Essential Consequence of Obesity?