zhuang, y. | Search bioRxiv

bioRxiv2020

Celastrol directly inhibits PFKM to induce weight loss and leptin sensitization

Despite the prevalence of obesity and related health consequences around the globe, effective treatments for inducing healthy weight loss are still lacking. Celastrol is a pentacyclic triterpene that was recently identified as a potent anti-obesity agent. Celastrol increases sensitivity to leptin, but the molecular target of celastrol is unknown. Therefore, the mechanisms by which this agent exerts its anti-obesity effect remain elusive. Using tissue-specific ABPP (activity-based protein profiling), we found that PFKM, a rate-limiting enzyme for glycolysis in skeletal muscle, is a direct target of celastrol. Celastrol inhibited PFKM enzymatic activity, and Pfkm knockout mice were resistant to a high fat diet, were hypersensitive to exogenous leptin, and were unresponsive to celastrol. PFKM inhibition led to activation of AMPK and inactivation of ACC in cultured myotubes and mouse skeletal muscle. Specific loss of AMPK in muscle significantly attenuated the anti-obesity effects of celastrol. Further, PFKM inhibition and subsequent activation of the AMPK/ACC signaling pathway reduced levels of free fatty acids by switching energy expenditure and consequently decreasing levels of SOCS1 expression, which are both required for leptin sensitization in 293t/hLepRb cells and mice. Finally, using a high throughput compound screen we identified an alternative PFKM inhibitor, 3-79, which exhibits a strong anti-obesity effect and non-covalent binding capacity. This compound is a promising agent for treating obesity in the clinic.

physiology↗

bioRxiv2019

The Signature Microbiota Driving Rumen Function Shifts in Goat Kids Introduced Solid Diet Regimes

The feeding regime of early supplementary solid diet improved rumen development and ruminant production. However, the signature microbiota linking dietary regimes to rumen function shifts and hosts are still unclear. We analyzed the rumen microbiome and functions affected by supplementation of solid diet using a combination of machine learning algorithms. The volatile fatty acids (i.e., acetate, propionate and butyrate) fermented by microbes increased significantly in the supplementary solid diet groups. The predominant genera altered significantly from unclassified Sphingobacteriaceae (non-supplementary group) to Prevotella (supplementary solid diet groups) RandomForest classification model revealed signature microbiota for solid diet that positively correlated with macronutrient intake, and linearly increased with volatile fatty acids production. The nutrient specific bacteria for carbohydrate and protein were also identified. According to FishTaco analysis, a set of intersecting core species contributed with rumen function shifts by solid diet. The core community structures consisted of specific signature microbiota and their symbiotic partners are manipulated by extra nutrients from concentrate and/or forage, and then produce more volatile fatty acids to promote rumen development and functions eventually host development. Our study provides mechanism of microbiome governing by solid diet and highlights the signatures microbiota for animal health and production.\n\nImportanceSmall ruminants are essential protein sources for human, so keeping them health and increasing their production are important. The microbial communities resided in rumen play key roles to convert fiber resources to human food. Moreover, rumen physiology experience huge changes after birth, and understanding its microbiome roles could provide insights for other species. Recently, our studies and others have shown that diet changed rumen microbial composition and goat performance. In this study, we identified core community structures that were affected by diet and associated to the rumen development and goat production. This outcome could potentially allow us to select specific microbiome to improve rumen physiology and functions, maintain host health and benefit animal production. Therefore, it gives a significant clue that core microbiome manipulation by feeding strategies can increase animal products. To our knowledge, we firstly used FishTaco for determination of link between signatures abundances and rumen function shifts.

microbiology↗