Abstract :
[en] Obesity is a worldwide epidemic now recognized as a low-grade inflammatory disease, favouring the
development of metabolic diseases and cancers. It is characterised by an expansion of the adipose tissue,
accompanied by a release of fatty acids from dead adipocytes. Immunity is modified in this enlarged tissue,
with macrophage enrichment (up to 50% increased) and a general shift towards pro-inflammatory immune
cells. These changes get systemic with time, as we can see higher rates of circulating free fatty acids as well
as circulating immune cells favouring the general low-grade inflammatory state. In this work, we tried to
better understand the role of free fatty acids-induced changes in macrophages. We also attempted to bring a
finer characterization of innate immune changes befitting obesity and glucose intolerance.
Stearate, a saturated fatty acid, is able to reshape the transcriptome of human monocyte derived
macrophages (MDM), in opposition to oleate, its unsaturated counterpart. Gene set enrichment analysis of the stearate-induced transcriptome highlights metabolic pathways such as glycolysis and fatty acid
metabolism. Increase of glycolysis is confirmed by lactate assay, and seems to be mediated by mTORC1
pathway. Phospholipidomic profiling of stearate-treated MDM shows an increase of saturated phospholipids, which is characteristic of de novo lipogenesis. Seeing these changes in vitro, we asked ourselves if
they were also observed with obesity and glucose intolerance. Phospholipidomic profiling of peripheral
blood mononuclear cells underlines an increase of saturated and monounsaturated phospholipids with obesity, but more specifically with glucose intolerance. Flow cytometry experiments indicate higher amount of
circulating inflammatory monocyte subtypes with obese glucose intolerant patients. Monocytes also uptake
higher amounts of glucose with obesity, which might mirror a glycolytic change. Metabolic variation of
immune cells is usually linked to activity alteration. No differences of monocyte phagocytosis are observed,
whereas CCL2 and IL8 secretion vary for obese patients. In this work, we also studied variations for circulating NK cells. CD56bright NK cells levels increase with obesity and glucose tolerance where CD56dim
NK cells decrease. CD56bright NK cells phenotype differs with obesity and glucose tolerance and these
cells show variations of their activating receptors expression. NK cells from obese patients are less cytotoxic
against cancer cells, which is not observed with glucose intolerant patients. These cells ability to secrete
cytokines also decreases with obesity, showing a global restraining of NK cells with this disease.
Altogether, our results indicate that saturated fatty acids induce a metabolic switch in human MDM,
with increased glycolysis and fatty acid metabolism. Signs of metabolic changes are also observed in circulating immune cells, which show phenotype and activity variations with obesity and / or glucose intolerance.
