Obesity‐Induced Metabolic Priming Exacerbates SARS‐CoV‐2 Inflammation

ABSTRACT Despite the early recognition that individuals living with obesity are more prone to develop adverse outcomes during COVID‐19, the mechanisms underlying these conditions are still unclear. During obesity, an accumulation of free fatty acids (FFAs) in the circulation promotes low‐grade inflammation. Here, we show that FFAs induce epigenetic reprogramming of monocytes, exacerbating their inflammatory profile after SARS‐CoV‐2 infection, a mechanism named metabolic‐primed immunity. Monocytes from people with obesity or primed with palmitate, a central component of circulating FFAs, presented elevated viral load and higher gene expression of IL‐6. Palmitate‐primed monocytes upregulate fatty acid oxidation and FFAs entry into the mitochondria. FFA‐derived acetyl‐CoA is then converted into citrate, exiting the mitochondria and is used to support H3K18 histone acetylation, which regulates IL‐6 accessibility. Ingestion of palm oil by lean and healthy individuals increased circulating FFAs levels and was sufficient to exacerbate the inflammatory profile of monocytes upon SARS‐CoV‐2 infection. Our findings demonstrate that obesity‐derived FFAs induce the metabolic priming of monocytes, which exacerbates the inflammatory response observed in people with severe COVID‐19.