Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer.
Abstract Altered lipid metabolism is among the most prominent metabolic alterations in cancer. Enhanced synthesis or uptake of lipids contributes to rapid cancer cell growth and tumor formation. Lipids are a highly complex group of biomolecules that not only constitute the structural basis of biological membranes but also function as signaling molecules and an energy source. Here, we summarize recent evidence implicating altered lipid metabolism in different aspects of the cancer phenotype and discuss potential strategies by which targeting lipid metabolism could provide a therapeutic window for cancer treatment. ...
Source: Cell Metabolism - December 3, 2019 Category: Cytology Authors: Snaebjornsson MT, Janaki-Raman S, Schulze A Tags: Cell Metab Source Type: research

Sorting mtDNA Species-the Role of nDNA-mtDNA Co-evolution.
Abstract The segregation of heteroplasmic mtDNA species was thought to be mostly stochastic. However, recent findings, including a study by Latorre-Pellicer et al. (2019) published in this issue of Cell Metabolism, provide evidence that nuclear DNA and mitochondrial DNA interactions play an important role in the sorting process. PMID: 31801053 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - December 3, 2019 Category: Cytology Authors: Moraes CT Tags: Cell Metab Source Type: research

OPCs on a Diet: A Youthful Serving of Remyelination.
Abstract Remyelination declines in the aging central nervous system due to oligodendrocyte precursor cell (OPC) dysfunction. In the latest issue of Cell Stem Cell, Neumann et al. (2019) demonstrate that aged OPCs are amenable to functional rejuvenation by systemic interventions involving alternate-day fasting or treatment with the fasting mimetic metformin. PMID: 31801054 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - December 3, 2019 Category: Cytology Authors: White CW, Pratt K, Villeda SA Tags: Cell Metab Source Type: research

Human Tolerogenic Dendritic Cells Regulate Immune Responses through Lactate Synthesis.
, Josien R, Pecqueur C, Cuturi MC, Moreau A Abstract Cell therapy is a promising strategy for treating patients suffering from autoimmune or inflammatory diseases or receiving a transplant. Based on our preclinical studies, we have generated human autologous tolerogenic dendritic cells (ATDCs), which are being tested in a first-in-man clinical trial in kidney transplant recipients. Here, we report that ATDCs represent a unique subset of monocyte-derived cells based on phenotypic, transcriptomic, and metabolic analyses. ATDCs are characterized by their suppression of T cell proliferation and their expansion of...
Source: Cell Metabolism - December 3, 2019 Category: Cytology Authors: Marin E, Bouchet-Delbos L, Renoult O, Louvet C, Nerriere-Daguin V, Managh AJ, Even A, Giraud M, Vu Manh TP, Aguesse A, Bériou G, Chiffoleau E, Alliot-Licht B, Prieur X, Croyal M, Hutchinson JA, Obermajer N, Geissler EK, Vanhove B, Blancho G, Dalod M, Jos Tags: Cell Metab Source Type: research

Acyl-CoA-Binding Protein Is a Lipogenic Factor that Triggers Food Intake and Obesity.
, Pattou F, Raverdy V, Caiazzo R, Denis RGP, Boya P, Galluzzi L, Madeo F, Migrenne-Li S, Cruciani-Guglielmacci C, Tavernarakis N, López-Otín C, Magnan C, Kroemer G PMID: 31801056 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - December 3, 2019 Category: Cytology Authors: Bravo-San Pedro JM, Sica V, Martins I, Pol J, Loos F, Maiuri MC, Durand S, Bossut N, Aprahamian F, Anagnostopoulos G, Niso-Santano M, Aranda F, Ramírez-Pardo I, Lallement J, Denom J, Boedec E, Gorwood P, Ramoz N, Clément K, Pelloux V, Rohia A, Pattou F, Tags: Cell Metab Source Type: research

Fatty Liver Disease Caused by High-Alcohol-Producing Klebsiella pneumoniae.
PMID: 31801057 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - December 3, 2019 Category: Cytology Authors: Yuan J, Chen C, Cui J, Lu J, Yan C, Wei X, Zhao X, Li N, Li S, Xue G, Cheng W, Li B, Li H, Lin W, Tian C, Zhao J, Han J, An D, Zhang Q, Wei H, Zheng M, Ma X, Li W, Chen X, Zhang Z, Zeng H, Ying S, Wu J, Yang R, Liu D Tags: Cell Metab Source Type: research

Adipose Tissue B Cells Come of Age: The AABs of Fat Inflammation.
Abstract For nearly a decade, B cells residing locally within the adipose tissue have been linked to the control of metabolic homeostasis. In this issue, Camell et al. (2019) report an expansion of a unique age-associated B cell population in the visceral adipose tissue that regulates insulin resistance and adipose dysfunction during aging. PMID: 31801058 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - December 3, 2019 Category: Cytology Authors: Khan S, Tsai S, Winer DA Tags: Cell Metab Source Type: research

TMEM2 Modulates ER Stress in a Non-canonical Manner.
Abstract Cells utilize multiple mechanisms to support endoplasmic reticulum (ER) function. The unfolded protein response, UPRER, is engaged during proteotoxic challenges to either mitigate ER stress or promote apoptosis. In a CRISPR-based genetic screen, Schinzel et al. (2019) identified TMEM2 as a mediator of ER stress tolerance independent of the individual branches of the canonical UPRER and linked this path to nematode longevity. PMID: 31801059 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - December 3, 2019 Category: Cytology Authors: Goncalves RLS, Hotamisligil GS Tags: Cell Metab Source Type: research

Gut Microbiome Fermentation Determines the Efficacy of Exercise for Diabetes Prevention.
Abstract Exercise is an effective strategy for diabetes management but is limited by the phenomenon of exercise resistance (i.e., the lack of or the adverse response to exercise on metabolic health). Here, in 39 medication-naive men with prediabetes, we found that exercise-induced alterations in the gut microbiota correlated closely with improvements in glucose homeostasis and insulin sensitivity (clinicaltrials.gov entry NCT03240978). The microbiome of responders exhibited an enhanced capacity for biosynthesis of short-chain fatty acids and catabolism of branched-chain amino acids, whereas those of non-responders...
Source: Cell Metabolism - November 26, 2019 Category: Cytology Authors: Liu Y, Wang Y, Ni Y, Cheung CKY, Lam KSL, Wang Y, Xia Z, Ye D, Guo J, Tse MA, Panagiotou G, Xu A Tags: Cell Metab Source Type: research

Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4+ T Cell Pathogenicity and Suppresses Autoimmunity.
Abstract Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate to pyruvate during glycolysis. The PK isoform PKM2 has additional roles in regulation of gene transcription and protein phosphorylation. PKM2 has been shown to control macrophage metabolic remodeling in inflammation, but its role in T cell biology is poorly understood. Here, we report PKM2 upregulation, phosphorylation, and nuclear accumulation in murine and human CD4+ T cells following activation in vitro. Treatment of T cells with TEPP-46, an allosteric activator that induces PKM2 tetramerization and blocks its nucl...
Source: Cell Metabolism - November 20, 2019 Category: Cytology Authors: Angiari S, Runtsch MC, Sutton CE, Palsson-McDermott EM, Kelly B, Rana N, Kane H, Papadopoulou G, Pearce EL, Mills KHG, O'Neill LAJ Tags: Cell Metab Source Type: research

STAT3 Activation-Induced Fatty Acid Oxidation in CD8+ T Effector Cells Is Critical for Obesity-Promoted Breast Tumor Growth.
Abstract Although obesity is known to be critical for cancer development, how obesity negatively impacts antitumor immune responses remains largely unknown. Here, we show that increased fatty acid oxidation (FAO) driven by activated STAT3 in CD8+ T effector cells is critical for obesity-associated breast tumor progression. Ablating T cell Stat3 or treatment with an FAO inhibitor in obese mice spontaneously developing breast tumor reduces FAO, increases glycolysis and CD8+ T effector cell functions, leading to inhibition of breast tumor development. Moreover, PD-1 ligation in CD8+ T cells activates STAT3 ...
Source: Cell Metabolism - November 18, 2019 Category: Cytology Authors: Zhang C, Yue C, Herrmann A, Song J, Egelston C, Wang T, Zhang Z, Li W, Lee H, Aftabizadeh M, Li YJ, Lee PP, Forman S, Somlo G, Chu P, Kruper L, Mortimer J, Hoon DSB, Huang W, Priceman S, Yu H Tags: Cell Metab Source Type: research

Neutralization of Oxidized Phospholipids Ameliorates Non-alcoholic Steatohepatitis.
Abstract Oxidized phospholipids (OxPLs), which arise due to oxidative stress, are proinflammatory and proatherogenic, but their roles in non-alcoholic steatohepatitis (NASH) are unknown. Here, we show that OxPLs accumulate in human and mouse NASH. Using a transgenic mouse that expresses a functional single-chain variable fragment of E06, a natural antibody that neutralizes OxPLs, we demonstrate the causal role of OxPLs in NASH. Targeting OxPLs in hyperlipidemic Ldlr-/- mice improved multiple aspects of NASH, including steatosis, inflammation, fibrosis, hepatocyte death, and progression to hepatocellular carcinoma....
Source: Cell Metabolism - November 14, 2019 Category: Cytology Authors: Sun X, Seidman JS, Zhao P, Troutman TD, Spann NJ, Que X, Zhou F, Liao Z, Pasillas M, Yang X, Magida JA, Kisseleva T, Brenner DA, Downes M, Evans RM, Saltiel AR, Tsimikas S, Glass CK, Witztum JL Tags: Cell Metab Source Type: research

Selective Persulfide Detection Reveals Evolutionarily Conserved Antiaging Effects of S-Sulfhydration.
We report an age-associated decline in persulfidation that is conserved across evolutionary boundaries. Accordingly, dietary or pharmacological interventions to increase persulfidation associate with increased longevity and improved capacity to cope with stress stimuli. PMID: 31735592 [PubMed - as supplied by publisher] (Source: Cell Metabolism)
Source: Cell Metabolism - November 13, 2019 Category: Cytology Authors: Zivanovic J, Kouroussis E, Kohl JB, Adhikari B, Bursac B, Schott-Roux S, Petrovic D, Miljkovic JL, Thomas-Lopez D, Jung Y, Miler M, Mitchell S, Milosevic V, Gomes JE, Benhar M, Gonzales-Zorn B, Ivanovic-Burmazovic I, Torregrossa R, Mitchell JR, Whiteman M Tags: Cell Metab Source Type: research

Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis.
VD Abstract During aging, visceral adiposity is often associated with alterations in adipose tissue (AT) leukocytes, inflammation, and metabolic dysfunction. However, the contribution of AT B cells in immunometabolism during aging is unexplored. Here, we show that aging is associated with an expansion of a unique population of resident non-senescent aged adipose B cells (AABs) found in fat-associated lymphoid clusters (FALCs). AABs are transcriptionally distinct from splenic age-associated B cells (ABCs) and show greater expansion in female mice. Functionally, whole-body B cell depletion restores proper lipolysis...
Source: Cell Metabolism - November 13, 2019 Category: Cytology Authors: Camell CD, Günther P, Lee A, Goldberg EL, Spadaro O, Youm YH, Bartke A, Hubbard GB, Ikeno Y, Ruddle NH, Schultze J, Dixit VD Tags: Cell Metab Source Type: research

The Transsulfuration Pathway Makes, the Tumor Takes.
Abstract Cells can take up cysteine or synthesize it de novo from methionine, but synthesis alone does not meet the high demands of cancer cells to proliferate. In this issue, Zhu et al. (2019) identify the SAH:SAM ratio, indicative of the cellular methylation state, as limiting for effective cysteine synthesis and the growth of some tumors. PMID: 31693878 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - November 5, 2019 Category: Cytology Authors: Weber R, Birsoy K Tags: Cell Metab Source Type: research

The DAPA-HF Trial: A Momentous Victory in the War against Heart Failure.
Abstract In a randomized trial of patients with heart failure and reduced ejection fraction, the SGLT2 inhibitor dapagliflozin markedly reduced mortality and worsening heart failure (McMurray et al., 2019). Remarkably, these benefits seemed to be similar in people with and without diabetes. These data usher in a new paradigm in the treatment of heart failure. PMID: 31693879 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - November 5, 2019 Category: Cytology Authors: Bhatt DL, Verma S, Braunwald E Tags: Cell Metab Source Type: research

The Crosstalk between Hepatocytes, Hepatic Macrophages, and Hepatic Stellate Cells Facilitates Alcoholic Liver Disease.
Abstract Choi et al. (2019) explored the pathogenesis of alcohol-induced de novo lipogenesis in mice with ALD to reveal a novel mechanism of cannabinoid 1 receptor (CB1R)-SREB1-dependent triglyceride synthesis that requires crosstalk between hepatocytes and HSCs. Using genetic and pharmacological inhibition of the key components of the xCT-glutamate→mGluR5-2-AG→CB1R-SREBP1-FASN paracrine communication system, Choi et al. identified potential new targets for drugs for ALD. PMID: 31693880 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - November 5, 2019 Category: Cytology Authors: Kisseleva T, Brenner DA Tags: Cell Metab Source Type: research

A Gut Check Explains Improved Glucose Metabolism after Surgery.
tou F Abstract Biliopancreatic diversion (BPD) surgery leads to more frequent diabetes remission than Roux-en-Y gastric bypass (RYGB). In this issue, Harris et al. (2019) compare each surgery after careful matching for percentage weight loss and find the gut as a major site of difference between the effects of the two surgeries. PMID: 31693881 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - November 5, 2019 Category: Cytology Authors: Laferrère B, Pattou F Tags: Cell Metab Source Type: research

Adipocyte Hypoxia-Inducible Factor 2 α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism.
This study highlights adipocyte HIF-2α as a putative drug target against atherosclerosis. PMID: 31668872 [PubMed - as supplied by publisher] (Source: Cell Metabolism)
Source: Cell Metabolism - October 23, 2019 Category: Cytology Authors: Zhang X, Zhang Y, Wang P, Zhang SY, Dong Y, Zeng G, Yan Y, Sun L, Wu Q, Liu H, Liu B, Kong W, Wang X, Jiang C Tags: Cell Metab Source Type: research

Proteomics-Based Comparative Mapping of the Secretomes of Human Brown and White Adipocytes Reveals EPDR1 as a Novel Batokine.
In conclusion, we report substantial differences between the secretomes of brown and white human adipocytes and identify novel candidate batokines that can be important regulators of human metabolism. PMID: 31668873 [PubMed - as supplied by publisher] (Source: Cell Metabolism)
Source: Cell Metabolism - October 18, 2019 Category: Cytology Authors: Deshmukh AS, Peijs L, Beaudry JL, Jespersen NZ, Nielsen CH, Ma T, Brunner AD, Larsen TJ, Bayarri-Olmos R, Prabhakar BS, Helgstrand C, Severinsen MCK, Holst B, Kjaer A, Tang-Christensen M, Sanfridson A, Garred P, Privé GG, Pedersen BK, Gerhart-Hines Z, Ni Tags: Cell Metab Source Type: research

Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease.
Abstract Mild reduction in food intake was recently shown to slow polycystic kidney disease (PKD) progression in mouse models, but whether the effect was due to solely reduced calories or some other aspect of the diet has been unclear. We now show that the benefit is due to the induction of ketosis. Time-restricted feeding, without caloric reduction, strongly inhibits mTOR signaling, proliferation, and fibrosis in the affected kidneys in a PKD rat model. A ketogenic diet had a similar effect and led to regression of renal cystic burden. Acute fasting in rat, mouse, and feline models of PKD results in rapid reducti...
Source: Cell Metabolism - October 15, 2019 Category: Cytology Authors: Torres JA, Kruger SL, Broderick C, Amarlkhagva T, Agrawal S, Dodam JR, Mrug M, Lyons LA, Weimbs T Tags: Cell Metab Source Type: research

The Long Noncoding RNA Paupar Modulates PAX6 Regulatory Activities to Promote Alpha Cell Development and Function.
In this study, comparative transcriptome analyses between embryonic mouse pancreas and adult mouse islets identified several pancreatic lncRNAs that lie in close proximity to essential pancreatic transcription factors, including the Pax6-associated lncRNA Paupar. We demonstrate that Paupar is enriched in glucagon-producing α cells where it promotes the alternative splicing of Pax6 to an isoform required for activation of essential α cell genes. Consistently, deletion of Paupar in mice resulted in dysregulation of PAX6 α cell target genes and corresponding α cell dysfunction, including blunted glucag...
Source: Cell Metabolism - October 9, 2019 Category: Cytology Authors: Singer RA, Arnes L, Cui Y, Wang J, Gao Y, Guney MA, Burnum-Johnson KE, Rabadan R, Ansong C, Orr G, Sussel L Tags: Cell Metab Source Type: research

A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer.
Abstract Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like α-smooth muscle actin (ACTA2). Allosteric regulation is considered to be an innovative strategy to discover a highly selective and potent inhibitor targeting PGAM1. Here, we identified a novel PGAM1 allosteric inhibitor, HKB99, via structure-based optimization. HKB99 acted to allosterically block conformational change of PGAM1 during catalytic process and PGAM1-ACTA2 interaction. HKB99 suppressed tumor growth and metastasis and overcame...
Source: Cell Metabolism - October 3, 2019 Category: Cytology Authors: Huang K, Liang Q, Zhou Y, Jiang LL, Gu WM, Luo MY, Tang YB, Wang Y, Lu W, Huang M, Zhang SZ, Zhuang GL, Dai Q, Shen QC, Zhang J, Lei HM, Zhu L, Ye DY, Chen HZ, Zhou L, Shen Y Tags: Cell Metab Source Type: research

Transsulfuration Activity Can Support Cell Growth upon Extracellular Cysteine Limitation.
CB Abstract Cysteine acts both as a building unit for protein translation and as the limiting substrate for glutathione synthesis to support the cellular antioxidant system. In addition to transporter-mediated uptake, cellular cysteine can also be synthesized from methionine through the transsulfuration pathway. Here, we investigate the regulation of transsulfuration and its role in sustaining cell proliferation upon extracellular cysteine limitation, a condition reported to occur in human tumors as they grow in size. We observed constitutive expression of transsulfuration enzymes in a subset of cancer cell lines...
Source: Cell Metabolism - October 3, 2019 Category: Cytology Authors: Zhu J, Berisa M, Schwörer S, Qin W, Cross JR, Thompson CB Tags: Cell Metab Source Type: research

Regulation of Mother-to-Offspring Transmission of mtDNA Heteroplasmy.
Ruíz-Cabello J, Enríquez JA Abstract mtDNA is present in multiple copies in each cell derived from the expansions of those in the oocyte. Heteroplasmy, more than one mtDNA variant, may be generated by mutagenesis, paternal mtDNA leakage, and novel medical technologies aiming to prevent inheritance of mtDNA-linked diseases. Heteroplasmy phenotypic impact remains poorly understood. Mouse studies led to contradictory models of random drift or haplotype selection for mother-to-offspring transmission of mtDNA heteroplasmy. Here, we show that mtDNA heteroplasmy affects embryo metabolism, cell fitness, and ...
Source: Cell Metabolism - October 3, 2019 Category: Cytology Authors: Latorre-Pellicer A, Lechuga-Vieco AV, Johnston IG, Hämäläinen RH, Pellico J, Justo-Méndez R, Fernández-Toro JM, Clavería C, Guaras A, Sierra R, Llop J, Torres M, Criado LM, Suomalainen A, Jones NS, Ruíz-Cabello J, Enríquez JA Tags: Cell Metab Source Type: research

Auto-Regulation of Leptin Neurobiology.
Abstract The clinical use of the hormone leptin, a key regulator of food intake, to treat the most common instances of obesity has so far failed. In this issue, Zhao et al. (2019) report that, paradoxically, reducing leptin levels in obese mice increases their sensitivity to the concentrations that remain, and leads to reductions in weight gain, thus suggesting why these earlier trials may have failed and possibly a new approach to treating obesity. PMID: 31577926 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - October 1, 2019 Category: Cytology Authors: LeDuc CA, Leibel RL Tags: Cell Metab Source Type: research

Don't Trust Your Gut: When Gut Microbiota Disrupt Fertility.
Abstract Emerging evidence indicates that the composition of the gut microbiome might affect metabolic homeostasis as well as reproductive fitness in women. In Nature Medicine, a new study by Qi et al. (2019), provides exciting insights into how gut microbiota dysbiosis may drive development of polycystic ovary syndrome (PCOS) and insulin resistance. PMID: 31577927 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - October 1, 2019 Category: Cytology Authors: Silva MSB, Giacobini P Tags: Cell Metab Source Type: research

Polysaccharide Protection: How Bacteroides thetaiotaomicron Survives an Antibiotic Attack.
Abstract Microbial metabolism in the gut is important for host immunity, digestion, and the modification of drugs, but it may be especially important for gut health during antibiotic treatments. In this issue, Cabral et al. (2019) study the taxonomic and metabolic responses to antibiotics and identify a diet-modulated tolerance of Bacteroides thetaiotaomicron. PMID: 31577928 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - October 1, 2019 Category: Cytology Authors: Jogia W, Maurice CF Tags: Cell Metab Source Type: research

Bone Marrow: An Immunometabolic Refuge during Energy Depletion.
Abstract An integrated immunometabolic response during negative energy balance is required for host survival. Three new papers by Jordan et al. (2019), Nagai et al. (2019), and Collins et al. (2019) report that monocytes, naive B cells, and memory CD8 T cells use bone marrow as a haven to tide off periods of metabolic adversity to maintain immune-responsiveness. PMID: 31577929 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - October 1, 2019 Category: Cytology Authors: Goldberg EL, Dixit VD Tags: Cell Metab Source Type: research

United They Stand, Divided They Fall.
Abstract Cancer cells that leave their natural environment during metastatic spread must adapt to numerous stresses to survive. In this issue, Labuschagne et al. (2019) highlight one adaptive mechanism to overcome these stresses that involves cell clustering, which induces a hypoxic environment and metabolic rewiring to buffer oxidative stress. PMID: 31577930 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - October 1, 2019 Category: Cytology Authors: Harris IS, Brugge JS Tags: Cell Metab Source Type: research

Substrates of PHD.
Abstract The discovery of prolyl hydroxylase domain proteins (PHDs) as key enzymes in the hypoxia inducible factor (HIF) pathway has been followed by reports of a multitude of non-HIF substrates of PHD. Reporting in eLife, Cockman et al. (2019) find a surprising lack of detectable PHD activity toward any of them. PMID: 31577931 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - October 1, 2019 Category: Cytology Authors: Lee FS Tags: Cell Metab Source Type: research

Breathe: Your Mitochondria Will Do the Rest … If They Are Healthy!
Breathe: Your Mitochondria Will Do the Rest… If They Are Healthy! Cell Metab. 2019 Oct 01;30(4):628-629 Authors: Viscomi C, Zeviani M Abstract Dysfunctions of the mitochondrial electron transport chain cause severe, currently untreatable, diseases in humans. A new study by Jain et al. (2019) reports increased oxygen levels in the brain of complex-I-deficient mice. Reducing the O2 levels by hypoxia, carbon monoxide, or anemia, improved the clinical phenotype and prolonged the lifespan of the mouse model. PMID: 31577932 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - October 1, 2019 Category: Cytology Authors: Viscomi C, Zeviani M Tags: Cell Metab Source Type: research

NAD+ in Brain Aging and Neurodegenerative Disorders.
Abstract NAD+ is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD+-dependent enzymes are involved in synaptic plasticity and neuronal stress resistance. Here, we review emerging findings that reveal key roles for NAD+ and related metabolites in the adaptation of neurons to a wide range of physiological stressors and in counteracting processes in neurodegenerative diseases, such as those occurring in Alzheimer's, Parkinson's, and Huntington diseases, and amyotrophic lateral sclerosis. Advances in underst...
Source: Cell Metabolism - October 1, 2019 Category: Cytology Authors: Lautrup S, Sinclair DA, Mattson MP, Fang EF Tags: Cell Metab Source Type: research

Dietary Sugars Alter Hepatic Fatty Acid Oxidation via Transcriptional and Post-translational Modifications of Mitochondrial Proteins.
Abstract Dietary sugars, fructose and glucose, promote hepatic de novo lipogenesis and modify the effects of a high-fat diet (HFD) on the development of insulin resistance. Here, we show that fructose and glucose supplementation of an HFD exert divergent effects on hepatic mitochondrial function and fatty acid oxidation. This is mediated via three different nodes of regulation, including differential effects on malonyl-CoA levels, effects on mitochondrial size/protein abundance, and acetylation of mitochondrial proteins. HFD- and HFD plus fructose-fed mice have decreased CTP1a activity, the rate-limiting enzyme of...
Source: Cell Metabolism - October 1, 2019 Category: Cytology Authors: Softic S, Meyer JG, Wang GX, Gupta MK, Batista TM, Lauritzen HPMM, Fujisaka S, Serra D, Herrero L, Willoughby J, Fitzgerald K, Ilkayeva O, Newgard CB, Gibson BW, Schilling B, Cohen DE, Kahn CR Tags: Cell Metab Source Type: research

Hyperpolarized MRI of Human Prostate Cancer Reveals Increased Lactate with Tumor Grade Driven by Monocarboxylate Transporter 1.
Abstract Metabolic imaging using hyperpolarized magnetic resonance can increase the sensitivity of MRI, though its ability to inform on relevant changes to biochemistry in humans remains unclear. In this work, we image pyruvate metabolism in patients, assessing the reproducibility of delivery and conversion in the setting of primary prostate cancer. We show that the time to max of pyruvate does not vary significantly within patients undergoing two separate injections or across patients. Furthermore, we show that lactate increases with Gleason grade. RNA sequencing data demonstrate a significant increase in the pre...
Source: Cell Metabolism - September 24, 2019 Category: Cytology Authors: Granlund KL, Tee SS, Vargas HA, Lyashchenko SK, Reznik E, Fine S, Laudone V, Eastham JA, Touijer KA, Reuter VE, Gonen M, Sosa RE, Nicholson D, Guo YW, Chen AP, Tropp J, Robb F, Hricak H, Keshari KR Tags: Cell Metab Source Type: research

Miro1 Marks Parkinson's Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson's Models.
Abstract The identification of molecular targets and pharmacodynamic markers for Parkinson's disease (PD) will empower more effective clinical management and experimental therapies. Miro1 is localized on the mitochondrial surface and mediates mitochondrial motility. Miro1 is removed from depolarized mitochondria to facilitate their clearance via mitophagy. Here, we explore the clinical utility of Miro1 for detecting PD and for gauging potential treatments. We measure the Miro1 response to mitochondrial depolarization using biochemical assays in skin fibroblasts from a broad spectrum of PD patients and discover tha...
Source: Cell Metabolism - September 23, 2019 Category: Cytology Authors: Hsieh CH, Li L, Vanhauwaert R, Nguyen KT, Davis MD, Bu G, Wszolek ZK, Wang X Tags: Cell Metab Source Type: research

Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction.
Abstract The gut-microbe-derived metabolite trimethylamine N-oxide (TMAO) is increased by insulin resistance and associated with several sequelae of metabolic syndrome in humans, including cardiovascular, renal, and neurodegenerative disease. The mechanism by which TMAO promotes disease is unclear. We now reveal the endoplasmic reticulum stress kinase PERK (EIF2AK3) as a receptor for TMAO: TMAO binds to PERK at physiologically relevant concentrations; selectively activates the PERK branch of the unfolded protein response; and induces the transcription factor FoxO1, a key driver of metabolic disease, in a PERK...
Source: Cell Metabolism - September 17, 2019 Category: Cytology Authors: Chen S, Henderson A, Petriello M, Romano KA, Gearing M, Miao J, Schell M, Sandoval-EspinolaEspinola WJ, Tao J, Sha B, Graham M, Crooke R, Kleinridders A, Balskus EP, Rey FE, Morris A, Biddinger SB Tags: Cell Metab Source Type: research

Fatty Liver Disease Caused by High-Alcohol-Producing Klebsiella pneumoniae.
Abstract The underlying etiology of nonalcoholic fatty liver disease (NAFLD) is believed to be quite varied. Changes in the gut microbiota have been investigated and are believed to contribute to at least some cases of the disease, though a causal relationship remains unclear. Here, we show that high-alcohol-producing Klebsiella pneumoniae (HiAlc Kpn) is associated with up to 60% of individuals with NAFLD in a Chinese cohort. Transfer of clinical isolates of HiAlc Kpn by oral gavage into mice induced NAFLD. Likewise, fecal microbiota transplant (FMT) into mice using a HiAlc-Kpn-strain-containing microbiota isolate...
Source: Cell Metabolism - September 12, 2019 Category: Cytology Authors: Yuan J, Chen C, Cui J, Lu J, Yan C, Wei X, Zhao X, Li N, Li S, Xue G, Cheng W, Li B, Li H, Lin W, Tian C, Zhao J, Han J, An D, Zhang Q, Wei H, Zheng M, Ma X, Li W, Chen X, Zhang Z, Zeng H, Ying S, Wu J, Yang R, Liu D Tags: Cell Metab Source Type: research

Microbial Metabolism Modulates Antibiotic Susceptibility within the Murine Gut Microbiome.
Abstract Although antibiotics disturb the structure of the gut microbiota, factors that modulate these perturbations are poorly understood. Bacterial metabolism is an important regulator of susceptibility in vitro and likely plays a large role within the host. We applied a metagenomic and metatranscriptomic approach to link antibiotic-induced taxonomic and transcriptional responses within the murine microbiome. We found that antibiotics significantly alter the expression of key metabolic pathways at the whole-community and single-species levels. Notably, Bacteroides thetaiotaomicron, which blooms in response ...
Source: Cell Metabolism - September 11, 2019 Category: Cytology Authors: Cabral DJ, Penumutchu S, Reinhart EM, Zhang C, Korry BJ, Wurster JI, Nilson R, Guang A, Sano WH, Rowan-Nash AD, Li H, Belenky P Tags: Cell Metab Source Type: research

Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions.
We report that in mitochondrial myopathy, ISRmt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISRmt (ATF5, mitochondrial one-carbon cycle, FGF21, and GDF15). The local progression to 2nd metabolic ISRmt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondrial unfolded protein response marks the 3rd ISRmt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and mo...
Source: Cell Metabolism - September 9, 2019 Category: Cytology Authors: Forsström S, Jackson CB, Carroll CJ, Kuronen M, Pirinen E, Pradhan S, Marmyleva A, Auranen M, Kleine IM, Khan NA, Roivainen A, Marjamäki P, Liljenbäck H, Wang L, Battersby BJ, Richter U, Velagapudi V, Nikkanen J, Euro L, Suomalainen A Tags: Cell Metab Source Type: research

Mediation of the Acute Stress Response by the Skeleton.
Abstract We hypothesized that bone evolved, in part, to enhance the ability of bony vertebrates to escape danger in the wild. In support of this notion, we show here that a bone-derived signal is necessary to develop an acute stress response (ASR). Indeed, exposure to various types of stressors in mice, rats (rodents), and humans leads to a rapid and selective surge of circulating bioactive osteocalcin because stressors favor the uptake by osteoblasts of glutamate, which prevents inactivation of osteocalcin prior to its secretion. Osteocalcin permits manifestations of the ASR to unfold by signaling in post-synapti...
Source: Cell Metabolism - September 4, 2019 Category: Cytology Authors: Berger JM, Singh P, Khrimian L, Morgan DA, Chowdhury S, Arteaga-Solis E, Horvath TL, Domingos AI, Marsland AL, Kumal Yadav V, Rahmouni K, Gao XB, Karsenty G Tags: Cell Metab Source Type: research

Microglia Metabolic Breakdown Drives Alzheimer's Pathology.
Abstract Altered metabolic function is common in stressed immune cells, but alteration in brain microglia during neurodegeneration is not understood. In this issue, Baik et al. (2019) provide insight into microglial metabolism. They demonstrate a switch from oxidative phosphorylation to glycolysis following interaction with amyloid beta acutely, and breakdown in both pathways chronically. PMID: 31484050 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - September 3, 2019 Category: Cytology Authors: Bennett FC, Liddelow SA Tags: Cell Metab Source Type: research

Membrane Lipid Remodeling Takes Center Stage in Growth Factor Receptor-Driven Cancer Development.
Abstract Enhanced growth factor signaling is a hallmark of cancer, allowing cancer cells to thrive in a challenging environment. In this issue of Cell Metabolism, Bi et al. (2019) identify LPCAT1, a key membrane lipid remodeling enzyme, as a central link between genetically driven growth factor receptor expression, signaling, and tumor growth, highlighting lipid remodeling as a therapeutic target in cancer. PMID: 31484051 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - September 3, 2019 Category: Cytology Authors: Swinnen JV, Dehairs J, Talebi A Tags: Cell Metab Source Type: research

Host-Pathogen Relationship Advice: Fat Protects against a Broken Heart.
Abstract During infection, disease tolerance promotes host health without killing the pathogen. In a recent issue of Cell, Luan et al. (2019) identify GDF15 as a central regulator of disease tolerance of bacterial and viral challenges, while preventing cardiac damage, by mediating downstream cross-organ communication via the sympathetic and metabolic systems. PMID: 31484052 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - September 3, 2019 Category: Cytology Authors: McCarville JL, Ayres JS Tags: Cell Metab Source Type: research

Alternate-Day Fasting Gets a Safe Bill of Health.
Abstract Various forms of fasting improve health and longevity in preclinical models. However, safety, outcomes, and the molecular changes underpinning human fasting are unclear. Stekovic et al. (2019) report improved markers of health for up to 6 months and associated metabolic changes among healthy adults who followed alternate-day fasting. PMID: 31484053 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - September 3, 2019 Category: Cytology Authors: Heilbronn LK, Panda S Tags: Cell Metab Source Type: research

Hallmarks of Endothelial Cell Metabolism in Health and Disease.
Abstract In 2009, it was postulated that endothelial cells (ECs) would only be able to execute the orders of growth factors if these cells would accordingly adapt their metabolism. Ten years later, it has become clear that ECs, often differently from other cell types, rely on distinct metabolic pathways to survive and form new blood vessels; that manipulation of EC metabolic pathways alone (even without changing angiogenic signaling) suffices to alter vessel sprouting; and that perturbations of these metabolic pathways can underlie excess formation of new blood vessels (angiogenesis) in cancer and ocular diseases....
Source: Cell Metabolism - September 3, 2019 Category: Cytology Authors: Li X, Sun X, Carmeliet P Tags: Cell Metab Source Type: research

Mechanisms and Implications of Metabolic Heterogeneity in Cancer.
Abstract Tumors display reprogrammed metabolic activities that promote cancer progression. We currently possess a limited understanding of the processes governing tumor metabolism in vivo and of the most efficient approaches to identify metabolic vulnerabilities susceptible to therapeutic targeting. While much of the literature focuses on stereotyped, cell-autonomous pathways like glycolysis, recent work emphasizes heterogeneity and flexibility of metabolism between tumors and even within distinct regions of solid tumors. Metabolic heterogeneity is important because it influences therapeutic vulnerabilit...
Source: Cell Metabolism - September 3, 2019 Category: Cytology Authors: Kim J, DeBerardinis RJ Tags: Cell Metab Source Type: research

Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease.
PMID: 31484056 [PubMed - in process] (Source: Cell Metabolism)
Source: Cell Metabolism - September 3, 2019 Category: Cytology Authors: Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A, Dulai PS, Caussy C, Bettencourt R, Highlander SK, Jones MB, Sirlin CB, Schnabl B, Brinkac L, Schork N, Chen CH, Brenner DA, Biggs W, Yooseph S, Venter JC, Nelson KE Tags: Cell Metab Source Type: research

Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis.
Abstract Fibrosis is the final common pathway leading to end-stage renal failure. By analyzing the kidneys of patients and animal models with fibrosis, we observed a significant mitochondrial defect, including the loss of the mitochondrial transcription factor A (TFAM) in kidney tubule cells. Here, we generated mice with tubule-specific deletion of TFAM (Ksp-Cre/Tfamflox/flox). While these mice developed severe mitochondrial loss and energetic deficit by 6 weeks of age, kidney fibrosis, immune cell infiltration, and progressive azotemia causing death were only observed around 12 weeks of age. In renal ce...
Source: Cell Metabolism - August 27, 2019 Category: Cytology Authors: Chung KW, Dhillon P, Huang S, Sheng X, Shrestha R, Qiu C, Kaufman BA, Park J, Pei L, Baur J, Palmer M, Susztak K Tags: Cell Metab Source Type: research

SGLT2 Inhibition with Empagliflozin Increases Circulating Provascular Progenitor Cells in People with Type 2 Diabetes Mellitus.
Abstract Hess et al. quantified circulating aldehyde dehydrogenase-expressing (ALDHhi) cell subsets in people with T2DM given either empagliflozin (EMPA) or placebo. EMPA treatment increased circulating pro-angiogenic CD133+ progenitor cells, decreased pro-inflammatory ALDHhi granulocyte precursors, and increased ALDHhi monocytes with M2 polarization. EMPA treatment improved T2DM-associated "regenerative cell depletion" contributing to enhanced vascular health. PMID: 31477497 [PubMed - as supplied by publisher] (Source: Cell Metabolism)
Source: Cell Metabolism - August 27, 2019 Category: Cytology Authors: Hess DA, Terenzi DC, Trac JZ, Quan A, Mason T, Al-Omran M, Bhatt DL, Dhingra N, Rotstein OD, Leiter LA, Zinman B, Sabongui S, Yan AT, Teoh H, Mazer CD, Connelly KA, Verma S Tags: Cell Metab Source Type: research