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Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection. 酮体生成促进对铜绿假单胞菌肺部感染的耐受性。
Pub Date : 2023-10-03 DOI: 10.1016/j.cmet.2023.09.001
Kira L Tomlinson, Ying-Tsun Chen, Alex Junker, AndreaCarola Urso, Tania Wong Fok Lung, Danielle Ahn, Casey E Hofstaedter, Swikrity U Baskota, Robert K Ernst, Alice Prince, Sebastián A Riquelme

Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response; however, most hosts become tolerant to the bacterial burden, developing chronic infection. Using a murine model of pneumonia, we demonstrate that this shift from inflammation to disease tolerance is promoted by ketogenesis. In response to pulmonary infection, ketone bodies are generated in the liver and circulate to the lungs where they impose selection for P. aeruginosa strains unable to display surface lipopolysaccharide (LPS). Such keto-adapted LPS strains fail to activate glycolysis and tissue-damaging cytokines and, instead, facilitate mitochondrial catabolism of fats and oxidative phosphorylation (OXPHOS), which maintains airway homeostasis. Within the lung, P. aeruginosa exploits the host immunometabolite itaconate to further stimulate ketogenesis. This environment enables host-P. aeruginosa coexistence, supporting both pathoadaptive changes in the bacteria and the maintenance of respiratory integrity via OXPHOS.

铜绿假单胞菌是肺部感染的常见原因。作为革兰氏阴性病原体,它可以引发活跃且极具破坏性的炎症反应;然而,大多数宿主对细菌负荷具有耐受性,发展为慢性感染。使用小鼠肺炎模型,我们证明了生酮促进了从炎症到疾病耐受的转变。作为对肺部感染的反应,酮体在肝脏中产生并循环到肺部,在那里它们对不能显示表面脂多糖(LPS)的铜绿假单胞菌菌株进行选择。这种酮适应的LPS菌株不能激活糖酵解和破坏组织的细胞因子,反而促进脂肪的线粒体分解代谢和氧化磷酸化(OXPHOS),从而维持气道稳态。在肺部,铜绿假单胞菌利用宿主免疫代谢产物衣康酸盐进一步刺激生酮。此环境启用host-P。铜绿假单胞菌共存,支持细菌的病理适应性变化和通过OXPHOS维持呼吸完整性。
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引用次数: 0
She didn't start the fire: Mammary duct epithelial cells suppress adipocyte thermogenesis. 她没有引起火灾:乳腺管上皮细胞抑制脂肪细胞的产热。
Pub Date : 2023-10-03 DOI: 10.1016/j.cmet.2023.09.007
David Merrick

Male and female mice display highly divergent responses to cold-induced thermogenic beiging of subcutaneous adipose tissues. Recently in Nature, Patel et al. showed that mammary duct epithelial cells respond to cold-induced sympathetic activity, triggering the secretion of lipocalin 2 (LCN2) to inhibit thermogenic differentiation of adjacent mammary adipocytes.

雄性和雌性小鼠对冷诱导的皮下脂肪组织的产热beiging表现出高度不同的反应。最近在《自然》杂志上,Patel等人。显示乳腺管上皮细胞对冷诱导的交感神经活动作出反应,触发脂质运载蛋白2(LCN2)的分泌以抑制邻近乳腺脂肪细胞的产热分化。
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引用次数: 0
Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion. 使用抗体-酶融合靶向拉福拉病中的致病性拉福拉体。
Pub Date : 2019-10-01 Epub Date: 2019-07-25 DOI: 10.1016/j.cmet.2019.07.002
M Kathryn Brewer, Annette Uittenbogaard, Grant L Austin, Dyann M Segvich, Anna DePaoli-Roach, Peter J Roach, John J McCarthy, Zoe R Simmons, Jason A Brandon, Zhengqiu Zhou, Jill Zeller, Lyndsay E A Young, Ramon C Sun, James R Pauly, Nadine M Aziz, Bradley L Hodges, Tracy R McKnight, Dustin D Armstrong, Matthew S Gentry

Lafora disease (LD) is a fatal childhood epilepsy caused by recessive mutations in either the EPM2A or EPM2B gene. A hallmark of LD is the intracellular accumulation of insoluble polysaccharide deposits known as Lafora bodies (LBs) in the brain and other tissues. In LD mouse models, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Therefore, LBs have become a therapeutic target for ameliorating LD. Herein, we demonstrate that human pancreatic α-amylase degrades LBs. We fused this amylase to a cell-penetrating antibody fragment, and this antibody-enzyme fusion (VAL-0417) degrades LBs in vitro and dramatically reduces LB loads in vivo in Epm2a-/- mice. Using metabolomics and multivariate analysis, we demonstrate that VAL-0417 treatment of Epm2a-/- mice reverses the metabolic phenotype to a wild-type profile. VAL-0417 is a promising drug for the treatment of LD and a putative precision therapy platform for intractable epilepsy.

拉福拉病(LD)是一种致命的儿童癫痫,由EPM2A或EPM2B基因的隐性突变引起。LD的一个标志是不溶性多糖沉积物在大脑和其他组织中的细胞内积聚,称为拉福拉体(LB)。在LD小鼠模型中,糖原合成的遗传减少消除了LB的形成并挽救了神经表型。因此,LBs已成为改善LD的治疗靶点。在此,我们证明了人类胰腺α-淀粉酶降解LB。我们将这种淀粉酶与穿透细胞的抗体片段融合,这种抗体-酶融合(VAL-0417)在体外降解LB,并显著降低Epm2a-/-小鼠体内的LB负荷。使用代谢组学和多变量分析,我们证明VAL-0417对Epm2a-/-小鼠的治疗将代谢表型逆转为野生型。VAL-0417是一种很有前途的LD治疗药物,也是一种公认的难治性癫痫精确治疗平台。
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引用次数: 0
Thermoneutral Housing Accelerates Metabolic Inflammation to Potentiate Atherosclerosis but Not Insulin Resistance. 中温住房会加速代谢炎症,从而加剧动脉粥样硬化,但不会加剧胰岛素抵抗。
Pub Date : 2016-01-12 Epub Date: 2015-11-05 DOI: 10.1016/j.cmet.2015.10.003
Xiao Yu Tian, Kirthana Ganeshan, Cynthia Hong, Khoa D Nguyen, Yifu Qiu, Jason Kim, Rajendra K Tangirala, Peter Tontonoz, Peter Tonotonoz, Ajay Chawla

Chronic, low-grade inflammation triggered by excess intake of dietary lipids has been proposed to contribute to the pathogenesis of metabolic disorders, such as obesity, insulin resistance, type 2 diabetes, and atherosclerosis. Although considerable evidence supports a causal association between inflammation and metabolic diseases, most tests of this link have been performed in cold-stressed mice that are housed below their thermoneutral zone. We report here that thermoneutral housing of mice has a profound effect on the development of metabolic inflammation, insulin resistance, and atherosclerosis. Mice housed at thermoneutrality develop metabolic inflammation in adipose tissue and in the vasculature at an accelerated rate. Unexpectedly, this increased inflammatory response contributes to the progression of atherosclerosis but not insulin resistance. These findings not only suggest that metabolic inflammation can be uncoupled from obesity-associated insulin resistance, but also point to how thermal stress might limit our ability to faithfully model human diseases in mice.

饮食中摄入过量脂质引发的慢性低度炎症被认为是肥胖、胰岛素抵抗、2 型糖尿病和动脉粥样硬化等代谢性疾病的发病机理之一。尽管有大量证据支持炎症与代谢性疾病之间存在因果关系,但对这种联系的大多数测试都是在冷应激小鼠中进行的,这些小鼠的饲养条件低于它们的中温区。我们在此报告,中温带饲养小鼠对代谢性炎症、胰岛素抵抗和动脉粥样硬化的发展有深远影响。在中温区饲养的小鼠会加速脂肪组织和血管中代谢炎症的发展。令人意想不到的是,这种炎症反应的增加导致了动脉粥样硬化的发展,而不是胰岛素抵抗。这些发现不仅表明代谢性炎症可以与肥胖相关的胰岛素抵抗脱钩,而且还指出热应激可能会限制我们用小鼠忠实模拟人类疾病的能力。
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引用次数: 0
Impairment of central leptin-mediated PI3K signaling manifested as hepatic steatosis independent of hyperphagia and obesity. 中枢瘦素介导的 PI3K 信号转导受损表现为肝脂肪变性,与多食和肥胖无关。
Pub Date : 2011-12-07 DOI: 10.1016/j.cmet.2011.11.001
James P Warne, Farzad Alemi, Alison S Reed, Jillian M Varonin, Helen Chan, Merisa L Piper, Mark E Mullin, Martin G Myers, Carlos U Corvera, Allison W Xu

Hepatic steatosis is generally thought to develop via peripheral mechanisms associated with obesity. We show that chronic central infusion of leptin suppresses hepatic lipogenic gene expression and reduces triglyceride content via stimulation of hepatic sympathetic activity. This leptin function is independent of feeding and body weight but requires phosphatidylinositol 3-kinase (PI3K) signaling. Attenuation of leptin-induced PI3K signaling, brought about by transgenic expression of phosphatase and tensin homolog (PTEN) in leptin receptor neurons, leads to decreased hepatic sympathetic tone and increased triglyceride levels without affecting adiposity or hepatic insulin signaling. Central leptin's effects on hepatic norepinephrine levels and triglyceride content are blunted in these mutant mice. Simultaneous downregulation of PI3K and signal transducer and activator of transcription-3 (Stat3) in leptin receptor neurons does not exacerbate obesity but causes more severe hepatic steatosis. Together, our results indicate that central cellular leptin resistance in PI3K signaling manifests as hepatic steatosis without causing obesity.

肝脏脂肪变性通常被认为是通过与肥胖相关的外周机制发展而来的。我们的研究表明,长期中枢输注瘦素可抑制肝脏脂肪生成基因的表达,并通过刺激肝脏交感神经的活性降低甘油三酯的含量。瘦素的这种功能与进食和体重无关,但需要磷脂酰肌醇 3- 激酶(PI3K)信号传导。通过在瘦素受体神经元中转基因表达磷酸酶和天丝蛋白同源物(PTEN)来减弱瘦素诱导的 PI3K 信号传导,会导致肝交感神经张力降低和甘油三酯水平升高,而不会影响脂肪或肝胰岛素信号传导。在这些突变小鼠体内,中枢瘦素对肝脏去甲肾上腺素水平和甘油三酯含量的影响被削弱。同时下调瘦素受体神经元中的 PI3K 和信号转导和转录激活因子-3(Stat3)不会加剧肥胖,但会导致更严重的肝脂肪变性。我们的研究结果表明,PI3K 信号传导中枢细胞瘦素抗性表现为肝脂肪变性,但不会导致肥胖。
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引用次数: 0
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Cell metabolism
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