Delineating organ phosphoproteomic landscapes and deregulated metabolic associated signaling under dietary intervention

Mammalian organs are biochemically optimized for their unique physiological roles through tightly regulated, phosphorylation-dependent intracellular signaling, impacting human health. Overconsumption of prevalent high-fat, high-fructose, high-cholesterol (HFHFHC) diet often leads to obesity and metabolic syndrome in organs, which typically stems from dysregulated phosphorylation events in signaling pathways. To better understand the influence of HFHFHC diet intake on organs in living organisms, we established a comprehensive mouse organ-specific phosphoproteome atlas quantified across 11 mouse organs and tissues. The atlas harbors 34,551 Class I phosphosites from 6,306 phosphoproteins, inclusive of 5,364 novel phosphosites that were not reported in previous mouse phosphoproteome libraries. Through deep phosphoproteome analysis, we profiled different phosphorylation patterns in metabolic and non-metabolic organs related to their physiological functions and the deregulated signaling pathways under HFHFHC dietary conditions. Tyrosine phosphorylation is a rapid and rare protein modification controlled by kinase and phosphatase. We built up a receptor-type protein tyrosine phosphatase κ (PTPRK) knockout mouse model to investigate the regulatory mechanism of phosphatase in metabolic reprogramming. With these, we found most signaling interference is caused by HFHFHC diet-induced reactive oxygen species (ROS), and mTOR/AMPK signaling was enriched in most organs indicating a pro-survival signal in early adulthood mice. This rich dataset is complementary to the current phosphoproteome online resource. More importantly, we elucidated the influence of diet predispositions in organisms in early adulthood and comprehended molecular mechanisms underlying metabolic disease signaling pathways under dietary intervention.