Obesity-induced metabolic training exacerbates SARS-CoV-2 inflammation

Despite the early recognition that obese individuals are more prone to developadverse outcomes during COVID-19, the mechanisms underlying these conditions are still unclear. During obesity, there is an accumulation of free fatty acids (FFAs) in the circulation that promotes a state of 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-trained immunity. Monocytes from obese individuals or primed with palmitate presented elevated viral load and expression of IL1 and IL-6. Palmitate-primed monocytes upregulate fatty acid oxidation and FFA entry into the mitochondria. Instead of being used to feed the TCA cycle, acetyl-CoA is converted into citrate, which exits the mitochondria and is used to support histone acetylation. Also, the metabolic training of lean individuals induced by ingesting FFAs is sufficient to exacerbate the inflammatory profile of monocytes upon SARS-CoV-2 infection. Our findings demonstrate that obesity-derived FFAs induce the metabolic training of monocytes, which exacerbates inflammation observed in obese people with COVID-19.