Project description:Elevated branched chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets led to hyperphagia, obesity and reduced lifespan. These effects were not due to elevated BCAA per se or hepatic mTOR activation, but rather the shift in balance between dietary BCAAs and other AAs, notably tryptophan and threonine. Increasing the ratio of BCAAs to these AAs resulted in hyperphagia and was linked to central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averted the health costs of a high BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes were not due to intrinsic toxicity; rather, to hyperphagia driven by AA imbalance.
Project description:<p>Owing to its compositional and chemical complexity, much of the gut microbiota metabolome remains poorly characterized. Aromatic amino acids (AAAs) have a history of being privileged substrates for the biosynthesis of diverse bioactive metabolites and thus represent a potentially rich source of bioactive molecules within the microbiota metabolome. In this study, we leveraged 13C- and 2H-labeled aromatic amino acid and untargeted liquid chromatography-mass spectrometry (LC-MS) to profile AAA-derived metabolites produced by 80 phylogenetically diverse human gut bacterial isolates. Collectively, we found 93 unique LC-MS features, 28 of which, predominantly produced by Clostridioides difficile, were identified as N-acyl amino acids. C. difficile produced the highest levels of the AAA-derived precursors phenylacetic acid and phenylpropionic acid, exceeding all Bacteroidetes and Proteobacteria strains in our panel. C. difficile’s uniquely diverse N-acyl amino acids have the potential to serve biomarkers for C. difficile colonization and mediators of C. difficile-specific host interaction.</p>
Project description:Metabolic dysfunction-associated steatohepatitis (MASH), affects nearly one-third of the global population with limited pharmacotherapy approved, underscoring the urgent need for new therapeutic strategies. N-acyl amino acids (NAAs), comprising amino acids linked to long-chain fatty acid acyl groups, are gaining interest, yet their metabolic regulation in MASH remains elusive. Metabolomic profiling in mice and humans with MASH revealed a marked depletion of NAAs, particularly C18:1-Leu, which inversely correlated with disease severity. The bidirectional PM20D1 expression was suppressed in the livers of human and mice with MASH, as well as in lipid-loaded primary mouse hepatocytes and hepatic cell lines. Stable isotope tracing studies in mice with and without MASH confirmed reduced biosynthesis of C18:1-Leu. Genetically, hepatocyte-specific overexpression of PM20D1 or pharmacological treatment with exogenous C18:1-Leu significantly attenuated or reversed established MASH. Mechanistically, C18:1-Leu bound and activated peroxisome proliferator-activated receptor alpha (PPARα), enhancing fatty acid β-oxidation and suppressing the NF-κB/CCL2 axis, thereby reducing hepatic macrophage infiltration, inflammation, and fibrosis. These therapeutic effects were abolished in hepatocyte-specific PPARα- and CCL2-deficient mice, identifying C18:1-Leu as a promising metabolic therapy for MASH.
Project description:Postoperative insulin resistance refers to the phenomenon that the body’s glucose uptake stimulated by insulin is reduced due to stress effects such as trauma or the inhibitory effect of insulin on liver glucose output is weakened after surgery.
There is a clear link between postoperative insulin resistance and poor perioperative prognosis. Therefore, exploring interventions to reduce postoperative stress insulin resistance, stabilize postoperative blood glucose, and reduce postoperative complications are clinical problems that need to be solved urgently. In recent years, research on branched-chain amino acids and metabolic diseases has become a hot spot. Studies have found that in the rat model, preoperatively given a high branched-chain amino acid diet can inhibit postoperative insulin resistance and stabilize blood glucose levels. This research plan is to try to add branched-chain amino acids before surgery to observe the occurrence of postoperative insulin resistance in patients.