Oxidative stress is a hallmark of
metabolic disease, though the mechanisms that define this link are not fully understood. Irreversible modification of
proteins by reactive
lipid aldehydes (protein carbonylation) is a major consequence of oxidative stress in adipose tissue and the substrates and specificity of this modification are largely unexplored. Here we show that
histones are avidly modified by
4-hydroxynonenal (4-HNE) in vitro and in vivo. Carbonylation of
histones by 4-HNE increased with age in male flies and visceral fat depots of mice and was potentiated in genetic (ob/ob) and high-fat feeding models of
obesity. Proteomic evaluation of in vitro 4-HNE- modified
histones led to the identification of both Michael and
Schiff base adducts. In contrast, mapping of sites in vivo from obese mice exclusively revealed Michael adducts. In total, we identified 11 sites of 4-hydroxy
hexenal (4-HHE) and 10 sites of 4-HNE
histone modification in visceral adipose tissue. In summary, these results characterize adipose
histone carbonylation as a redox-linked epigenomic mark associated with
metabolic disease and aging.