Department of Cell Physiology and Metabolism, Centre Médical Universitaire, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Diabetes Centre, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
Genomic Research Lab, Division of Infectious Diseases, Geneva University Hospitals, 1211 Geneva, Switzerland.
Cell Metab. 2018 Dec 4;28(6):907-921.e7. doi: 10.1016/j.cmet.2018.08.005. Epub 2018 Aug 30.
Caloric restriction (CR) stimulates development of functional beige fat and extends healthy lifespan. Here we show that compositional and functional changes in the gut microbiota contribute to a number of CR-induced metabolic improvements and promote fat browning. Mechanistically, these effects are linked to a lower expression of the key bacterial enzymes necessary for the lipid A biosynthesis, a critical lipopolysaccharide (LPS) building component. The decreased LPS dictates the tone of the innate immune response during CR, leading to increased eosinophil infiltration and anti-inflammatory macrophage polarization in fat of the CR animals. Genetic and pharmacological suppression of the LPS-TLR4 pathway or transplantation with Tlr4 bone-marrow-derived hematopoietic cells increases beige fat development and ameliorates diet-induced fatty liver, while Tlr4 or microbiota-depleted mice are resistant to further CR-stimulated metabolic alterations. These data reveal signals critical for our understanding of the microbiota-fat signaling axis during CR and provide potential new anti-obesity therapeutics.
热量限制（CR）可刺激功能性米色脂肪的发育并延长健康寿命。在这里，我们表明，肠道微生物组的组成和功能变化有助于许多 CR 诱导的代谢改善，并促进脂肪褐变。从机制上讲，这些作用与关键细菌酶的表达降低有关，这些酶对于脂质 A 生物合成是必需的，脂质 A 是关键的脂多糖（LPS）组成部分。较低的 LPS 决定了 CR 期间先天免疫反应的基调，导致 CR 动物脂肪中嗜酸性粒细胞浸润和抗炎性巨噬细胞极化增加。LPS-TLR4 途径的遗传和药物抑制或用 Tlr4 骨髓来源的造血细胞移植可增加米色脂肪的发育并改善饮食诱导的脂肪肝，而 Tlr4 或缺乏微生物的小鼠则抵抗进一步的 CR 刺激的代谢改变。这些数据揭示了我们理解 CR 期间微生物-脂肪信号轴的关键信号，并为潜在的新型抗肥胖治疗提供了依据。
