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Conti et al. J Cancer Metastasis Treat 2019;5:64 I http://dx.doi.org/10.20517/2394-4722.2019.015 Page 5 of 12

the dietary intake but also on the different rates of metabolic reaction that utilize FA as substrates.
Subsequent analysis of FA composition after LCD-induced weight loss and 6-month weight maintenance
showed a reduction in total SFA, palmitic and palmitoleic acid content that paralleled a concomitant
[37]
increase of stearic and oleic acids . Likewise a significant increase in some ω3 (i.e., eicosapentaenoic and
decosahexaenoic acids) and ω6 (i.e., linoleic, dihomo-γ-linolenic, arachidonic and docosatetraenoic acids)
PUFA was also observed. Furthermore, a specific role of MUFA in weight management and as predictors
of weight change was suggested. In fact lower baseline content of MUFA in SAT predicts a better weight
[37]
maintenance while lower oleic acid accumulation predicts lower weight decrease . Potentially beneficial
modifications in FA composition of SAT have also been observed in a Finnish study upon obesity surgery
- a procedure that leads to changes in gut anatomy and diet as well as to weight loss - in combination with
[38]
rapeseed oil- and fatty fish-enriched diet . The main findings were a decreased content in SFA, mainly
due to palmitic acid decrease, paralleling an increased accumulation of oleic acid in SAT. The metabolic
improvement observed after surgery has been attributed not only to weight loss but also to diet-induced
changes of endogenous lipid metabolism enzymes. In fact the increased activity of elongase 5 and delta 6
desaturase (D6D), as well as the decreased activity of SCD1 and D5D were strongly associated with weight
[38]
loss . Interestingly, with the exception of ω3 PUFA, comparable modifications in FA content were induced
[38]
by weight loss or lifestyle intervention without surgery .
DIETARY FATTY ACIDS AS MODULATORS OF ADIPOSE TISSUE INFLAMMATION
The primary event in the sequence leading to chronic inflammation in AT is metabolic dysfunction of
adipocytes, that promotes inflammation via the expression of inflammatory response genes. In spite of
the well-known capacity of FA to modulate inflammatory processes and of the observation that specific
FA profiles in the AT are associated with a pro-inflammatory condition, only few studies investigated the
effects of direct exposure of adipocytes rather than of other cell types within the stromovascular fraction, to
different FA on AT inflammation. Contrasting results were some time achieved likely reflecting differences
in AT microenvironment, as the stromovascular fraction of AT strongly contributes to shape inflammation
being a major source of immune mediators. Nevertheless, these studies shed light on the molecular
[4,6]
pathways triggered specifically in adipocytes underlying the pro- or anti-inflammatory effects of FA .
In vitro studies have reported that SFA stimulate an inflammatory response by the activation of Toll-like
receptor (TLR)/NF-κB pathways. Abdominal SAT and VAT adipocytes from obese subjects exposed to free
FA (i.e., oleic, linoleic, arachidonic, lauric and myristic acids or palmitic and stearic acid mixtures) show
an increased expression of pro-inflammatory cytokines (TNF-α, IL-6 and CCL2) [39,40] . Interestingly the
extent of SFA response does not differ greatly between AT explants and isolated adipocytes, highlighting
[40]
the capacity of the latter to mount an autonomous inflammatory response to environmental factors .
However, the reported activation of TLR pathways by dietary SFA (lauric and palmitic acids) was not
confirmed in other studies in SAT explants and adipocytes under different experimental conditions (i.e., FA
[41]
concentration or degree of endotoxin contamination) .
While SFA were found to stimulate pro-inflammatory responses, ω3 PUFA, in particular decosahexaenoic
and eicosapentaenoic acids, have been reported to exert an anti-inflammatory action in whole SAT and
VAT as well as in isolated adipocytes from obese subjects by down-regulating the expression of pro-
inflammatory mediators (IL-18, CASP-1, IL-1β, CX3CL1, CCL2, TNF-α and IL-6) [41-43] . Likewise, our
studies demonstrated that decosahexaenoic acid attenuates the VAT adipocyte inflammatory status by
reducing STAT3 activation and IL-6 secretion, and up-regulating adiponectin expression, regardless the
body weight [26,27] . Conversely, exposure of VAT adipocytes from lean and obese subjects to arachidonic
acid results in a significant up-regulation of phospho-STAT3 and concomitant down-regulation of PPARγ
expression as compared to the untreated paired individuals [26,27] . The observation that obesity-associated FA
profile of VAT parallels alterations of the immune cell repertoire in the tissue microenvironment suggests