# Branched chain amino acids prime metabolic inflammation

## TL;DR

The study shows that branched chain amino acids (BCAA) can enhance inflammation in response to stressors, linking them to age-related diseases.

## Contribution

The study identifies BCAA as a novel immune priming factor that augments inflammatory responses in metabolic contexts.

## Key findings

- BCAA are the top correlate of CRP surge during human fasting.
- BCAA potentiate endotoxin responses and inflammatory programs in mice.
- BCAA reprogram chromatin in murine liver and increase cytokine levels.

## Abstract

Sterile inflammation is associated with a broad range of metabolic stressors including both dietary excess and prolonged fasting. In a 10-day human fasting study, we previously identified a surge in the circulating inflammatory biomarker, C-reactive protein (CRP), which we leveraged in the current study to identify novel metabolic inflammatory correlates. With a variety of longitudinal metabolic variables as input, including metabolomics, we identified branched chain amino acids (BCAA) as the top candidate inflammatory correlate. We then used in vitro myeloid/macrophage culture and in vivo murine models to test BCAA as a determinant of inflammatory signaling. Short-term exposure to BCAA alone had modest effects on a variety of immune readouts; however, when coupled with a second stimulus, such as exposure to endotoxin or when administered to diet-induced obese mice, members of the JAK/STAT/cytokine signaling pathways were augmented on the transcriptional level by concurrent BCAA administration in multiple tissues, including visceral adipose and liver. The modifying effect of BCAA on inflammatory stressors translated into increased levels of circulating inflammatory cytokines. Collectively, these data position BCAA as an immune priming factor, a potential mechanism underlying the well-established association between circulating BCAA and diverse diseases of aging.

•CRP surge with human fasting used to screen for candidate immuno-metabolic drivers.•Branched chain amino acids identified as top CRP correlate with human fasting.•Branched chain amino acids reprogram chromatin landscape in murine liver.•Branched chain amino acids potentiate endotoxin responses in mice.•Branched chain amino acids augment inflammatory programs in obese mice.

CRP surge with human fasting used to screen for candidate immuno-metabolic drivers.

Branched chain amino acids identified as top CRP correlate with human fasting.

Branched chain amino acids reprogram chromatin landscape in murine liver.

Branched chain amino acids potentiate endotoxin responses in mice.

Branched chain amino acids augment inflammatory programs in obese mice.