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  • AMPK: Sensing Glucose as well as Cellular Energy Status
    Cell Metab. (IF 18.164) Pub Date : 2017-11-16
    Sheng-Cai Lin, D. Grahame Hardie

    Mammalian AMPK is known to be activated by falling cellular energy status, signaled by rising AMP/ATP and ADP/ATP ratios. We review recent information about how this occurs but also discuss new studies suggesting that AMPK is able to sense glucose availability independently of changes in adenine nucleotides. The glycolytic intermediate fructose-1,6-bisphosphate (FBP) is sensed by aldolase, which binds to the v-ATPase on the lysosomal surface. In the absence of FBP, interactions between aldolase and the v-ATPase are altered, allowing formation of an AXIN-based AMPK-activation complex containing the v-ATPase, Ragulator, AXIN, LKB1, and AMPK, causing increased Thr172 phosphorylation and AMPK activation. This nutrient-sensing mechanism activates AMPK but also primes it for further activation if cellular energy status subsequently falls. Glucose sensing at the lysosome, in which AMPK and other components of the activation complex act antagonistically with another key nutrient sensor, mTORC1, may have been one of the ancestral roles of AMPK.

    更新日期:2017-11-19
  • Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis
    Cell Metab. (IF 18.164) Pub Date : 2017-11-16
    Joan Sanchez-Gurmaches, Yuefeng Tang, Naja Zenius Jespersen, Martina Wallace, Camila Martinez Calejman, Sharvari Gujja, Huawei Li, Yvonne J.K. Edwards, Christian Wolfrum, Christian M. Metallo, Søren Nielsen, Camilla Scheele, David A. Guertin

    Brown adipose tissue (BAT) is a therapeutic target for metabolic diseases; thus, understanding its metabolic circuitry is clinically important. Many studies of BAT compare rodents mildly cold to those severely cold. Here, we compared BAT remodeling between thermoneutral and mild-cold-adapted mice, conditions more relevant to humans. Although BAT is renowned for catabolic β-oxidative capacity, we find paradoxically that the anabolicde novolipogenesis (DNL) genes encoding ACLY, ACSS2, ACC, and FASN were among the most upregulated by mild cold and that, in humans, DNL correlates withUcp1expression. The regulation and function of adipocyte DNL and its association with thermogenesis are not understood. We provide evidence suggesting that AKT2 drives DNL in adipocytes by stimulating ChREBPβ transcriptional activity and that cold induces the AKT2-ChREBP pathway in BAT to optimize fuel storage and thermogenesis. These data provide insight into adipocyte DNL regulation and function and illustrate the metabolic flexibility of thermogenesis.

    更新日期:2017-11-19
  • AMPK: Sensing Glucose as well as Cellular Energy Status
    Cell Metab. (IF 18.164) Pub Date : 2017-11-16
    Sheng-Cai Lin, D. Grahame Hardie
    更新日期:2017-11-19
  • Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis
    Cell Metab. (IF 18.164) Pub Date : 2017-11-16
    Joan Sanchez-Gurmaches, Yuefeng Tang, Naja Zenius Jespersen, Martina Wallace, Camila Martinez Calejman, Sharvari Gujja, Huawei Li, Yvonne J.K. Edwards, Christian Wolfrum, Christian M. Metallo, Søren Nielsen, Camilla Scheele, David A. Guertin
    更新日期:2017-11-19
  • CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response
    Cell Metab. (IF 18.164) Pub Date : 2017-11-09
    Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Megan W. Wyatt, Payal Dhar, Shanmugam Paneer Selvam, Jianing Fu, Jinyu Zhang, Hung Nguyen, Inhong Kang, Kyle Toth, Mazen Al-Homrani, Mahvash Husain, Gyda Beeson, Lauren Ball, Kristi Helke, Shahid Husain, Elizabeth Garrett-Mayer, Gary Hardiman, Meenal Mehrotra, Michael I. Nishimura, Craig C. Beeson, Melanie Gubbels Bupp, Jennifer Wu, Besim Ogretmen, Chrystal M. Paulos, Jeffery Rathmell, Xue-Zhong Yu, Shikhar Mehrotra

    Heightened effector function and prolonged persistence, the key attributes of Th1 and Th17 cells, respectively, are key features of potent anti-tumor T cells. Here, we establishedex vivoculture conditions to generate hybrid Th1/17 cells, which persisted long-termin vivowhile maintaining their effector function. Using transcriptomics and metabolic profiling approaches, we showed that the enhanced anti-tumor property of Th1/17 cells was dependent on the increased NAD+-dependent activity of the histone deacetylase Sirt1. Pharmacological or genetic inhibition of Sirt1 activity impaired the anti-tumor potential of Th1/17 cells. Importantly, T cells with reduced surface expression of the NADase CD38 exhibited intrinsically higher NAD+, enhanced oxidative phosphorylation, higher glutaminolysis, and altered mitochondrial dynamics that vastly improved tumor control. Lastly, blocking CD38 expression improved tumor control even when using Th0 anti-tumor T cells. Thus, strategies targeting the CD38-NAD+axis could increase the efficacy of anti-tumor adoptive T cell therapy.

    更新日期:2017-11-10
  • Advances in Hypoxia-Inducible Factor Biology
    Cell Metab. (IF 18.164) Pub Date : 2017-11-09
    Hani Choudhry, Adrian L. Harris

    Hypoxia-inducible factor (HIF), a central regulator for detecting and adapting to cellular oxygen levels, transcriptionally activates genes modulating oxygen homeostasis and metabolic activation. Beyond this, HIF influences many other processes. Hypoxia, in part through HIF-dependent mechanisms, influences epigenetic factors, including DNA methylation and histone acetylation, which modulate hypoxia-responsive gene expression in cells. Hypoxia profoundly affects expression of many noncoding RNAs classes that have clinicopathological implications in cancer. HIF can regulate noncoding RNAs production, while, conversely, noncoding RNAs can modulate HIF expression. There is recent evidence for crosstalk between circadian rhythms and hypoxia-induced signaling, suggesting involvement of molecular clocks in adaptation to fluxes in nutrient and oxygen sensing. HIF induces increased production of cellular vesicles facilitating intercellular communication at a distance—for example, promoting angiogenesis in hypoxic tumors. Understanding the complex networks underlying cellular and genomic regulation in response to hypoxia via HIF may identify novel and specific therapeutic targets.

    更新日期:2017-11-10
  • Mechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes
    Cell Metab. (IF 18.164) Pub Date : 2017-11-09
    Rachel J. Perry, Liang Peng, Gary W. Cline, Yongliang Wang, Aviva Rabin-Court, Joongyu D. Song, Dongyan Zhang, Xian-Man Zhang, Yuichi Nozaki, Sylvie Dufour, Kitt Falk Petersen, Gerald I. Shulman

    Caloric restriction rapidly reverses type 2 diabetes (T2D), but the mechanism(s) of this reversal are poorly understood. Here we show that 3 days of a very-low-calorie diet (VLCD, one-quarter their typical intake) lowered plasma glucose and insulin concentrations in a rat model of T2D without altering body weight. The lower plasma glucose was associated with a 30% reduction in hepatic glucose production resulting from suppression of both gluconeogenesis from pyruvate carboxylase (VPC), explained by a reduction in hepatic acetyl-CoA content, and net hepatic glycogenolysis. In addition, VLCD resulted in reductions in hepatic triglyceride and diacylglycerol content and PKCɛ translocation, associated with improved hepatic insulin sensitivity. Taken together, these data show that there are pleotropic mechanisms by which VLCD reverses hyperglycemia in a rat model of T2D, including reduced DAG-PKCɛ-induced hepatic insulin resistance, reduced hepatic glycogenolysis, and reduced hepatic acetyl-CoA content, PC flux, and gluconeogenesis.

    更新日期:2017-11-10
  • CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response
    Cell Metab. (IF 18.164) Pub Date : 2017-11-09
    Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Megan W. Wyatt, Payal Dhar, Shanmugam Paneer Selvam, Jianing Fu, Jinyu Zhang, Hung Nguyen, Inhong Kang, Kyle Toth, Mazen Al-Homrani, Mahvash Husain, Gyda Beeson, Lauren Ball, Kristi Helke, Shahid Husain, Elizabeth Garrett-Mayer, Gary Hardiman, Meenal Mehrotra, Michael I. Nishimura, Craig C. Beeson, Melanie Gubbels Bupp, Jennifer Wu, Besim Ogretmen, Chrystal M. Paulos, Jeffery Rathmell, Xue-Zhong Yu, Shikhar Mehrotra
    更新日期:2017-11-10
  • Advances in Hypoxia-Inducible Factor Biology
    Cell Metab. (IF 18.164) Pub Date : 2017-11-09
    Hani Choudhry, Adrian $L̫VxnLE$L̫Vxn
    更新日期:2017-11-10
  • Mechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes
    Cell Metab. (IF 18.164) Pub Date : 2017-11-09
    Rachel J. Perry, Liang Peng, Gary W. Cline, Yongliang Wang, Aviva Rabin-Court, Joongyu D. Song, Dongyan Zhang, Xian-Man Zhang, Yuichi Nozaki, Sylvie Dufour, Kitt Falk Petersen, Gerald I. Shulman
    更新日期:2017-11-10
  • NFIL-trating the Host Circadian Rhythm—Microbes Fine-Tune the Epithelial Clock
    Cell Metab. (IF 18.164) Pub Date : 2017-11-07
    Christoph A. Thaiss, Samuel P. Nobs, Eran Elinav
    更新日期:2017-11-07
  • Resistance Is Futile: Targeting Mitochondrial Energetics and Metabolism to Overcome Drug Resistance in Cancer Treatment
    Cell Metab. (IF 18.164) Pub Date : 2017-11-07
    Claudie Bosc, Mary A. Selak, Jean-Emmanuel Sarry
    更新日期:2017-11-07
  • What Ignites UCP1?
    Cell Metab. (IF 18.164) Pub Date : 2017-11-07
    Barbara Cannon, Jan Nedergaard
    更新日期:2017-11-07
  • Glial Cell Evolution: The Origins of a Lipid Store
    Cell Metab. (IF 18.164) Pub Date : 2017-11-07
    Klaus-Armin Nave, Iva D. Tzvetanova, Stefanie Schirmeier
    更新日期:2017-11-07
  • Dealing with Consequences of Irreproducibility and Modifying the Published Literature: Retractions versus Revisions
    Cell Metab. (IF 18.164) Pub Date : 2017-11-07
    David J. Glass, Jeffrey S. Flier

    One of the barriers to revising the literature when new data are produced, demonstrating the lack of reproducibility of particular published findings, is the stigma associated with the current tools available, most notably the use of retractions. We suggest an additional tool: revisions, which could be linked to prior manuscripts by the original authors and by others (upon peer review). We hope new approaches such as the ability to revise prior reports will help to keep the literature up-to-date and representative of the most complete understanding of an issue.

    更新日期:2017-11-07
  • Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota
    Cell Metab. (IF 18.164) Pub Date : 2017-11-07
    Guolin Li, Cen Xie, Siyu Lu, Robert G. Nichols, Yuan Tian, Licen Li, Daxeshkumar Patel, Yinyan Ma, Chad N. Brocker, Tingting Yan, Kristopher W. Krausz, Rong Xiang, Oksana Gavrilova, Andrew D. Patterson, Frank J. Gonzalez

    (Cell Metabolism 26, 672–685; October 3, 2017)

    更新日期:2017-11-07
  • 17β-Estradiol Directly Lowers Mitochondrial Membrane Microviscosity and Improves Bioenergetic Function in Skeletal Muscle
    Cell Metab. (IF 18.164) Pub Date : 2017-11-02
    Maria J. Torres, Kim A. Kew, Terence E. Ryan, Edward Ross Pennington, Chien-Te Lin, Katherine A. Buddo, Amy M. Fix, Cheryl A. Smith, Laura A. Gilliam, Sira Karvinen, Dawn A. Lowe, Espen E. Spangenburg, Tonya N. Zeczycki, Saame Raza Shaikh, P. Darrell Neufer

    Menopause results in a progressive decline in 17β-estradiol (E2) levels, increased adiposity, decreased insulin sensitivity, and a higher risk for type 2 diabetes. Estrogen therapies can help reverse these effects, but the mechanism(s) by which E2 modulates susceptibility to metabolic disease is not well understood. In young C57BL/6N mice, short-term ovariectomy decreased—whereas E2 therapy restored—mitochondrial respiratory function, cellular redox state (GSH/GSSG), and insulin sensitivity in skeletal muscle. E2 was detected by liquid chromatography-mass spectrometry in mitochondrial membranes and varied according to whole-body E2 status independently of ERα. Loss of E2 increased mitochondrial membrane microviscosity and H2O2emitting potential, whereas E2 administrationin vivoandin vitrorestored membrane E2 content, microviscosity, complex I and I + III activities, H2O2emitting potential, and submaximal OXPHOS responsiveness. These findings demonstrate that E2 directly modulates membrane biophysical properties and bioenergetic function in mitochondria, offering a direct mechanism by which E2 status broadly influences energy homeostasis.

    更新日期:2017-11-02
  • Artemether Does Not Turn α Cells into β Cells
    Cell Metab. (IF 18.164) Pub Date : 2017-11-02
    Talitha van der Meulen, Sharon Lee, Els Noordeloos, Cynthia J. Donaldson, Michael W. Adams, Glyn M. Noguchi, Alex M. Mawla, Mark O. Huising

    Pancreatic α cells retain considerable plasticity and can, under the right circumstances, transdifferentiate into functionally mature β cells. In search of a targetable mechanistic basis, a recent paper suggested that the widely used anti-malaria drug artemether suppresses the α cell transcription factor Arx to promote transdifferentiation into β cells. However, key initial experiments in this paper were carried out in islet cell lines, and most subsequent validation experiments implied transdifferentiation without direct demonstration of α to β cell conversion. Indeed, we find no evidence that artemether promotes transdifferentiation of primary α cells into β cells. Moreover, artemether reducesIns2expression in primary β cells >100-fold, suppresses glucose uptake, and abrogates β cell calcium responses and insulin secretion in response to glucose. Our observations suggest that artemether induces general islet endocrine cell dedifferentiation and call into question the utility of artemisinins to promote α to β cell transdifferentiation in treating diabetes.

    更新日期:2017-11-02
  • 17β-Estradiol Directly Lowers Mitochondrial Membrane Microviscosity and Improves Bioenergetic Function in Skeletal Muscle
    Cell Metab. (IF 18.164) Pub Date : 2017-11-02
    Maria J. Torres, Kim A. Kew, Terence E. Ryan, Edward Ross Pennington, Chien-Te Lin, Katherine A. Buddo, Amy M. Fix, Cheryl A. Smith, Laura A. Gilliam, Sira Karvinen, Dawn A. Lowe, Espen E. Spangenburg, Tonya N. Zeczycki, Saame Raza Shaikh, P. Darrell Neufer
    更新日期:2017-11-02
  • Artemether Does Not Turn α Cells into β Cells
    Cell Metab. (IF 18.164) Pub Date : 2017-11-02
    Talitha van der Meulen, Sharon Lee, Els Noordeloos, Cynthia J. Donaldson, Michael W. Adams, Glyn M. Noguchi, Alex M. Mawla, Mark O. Huising
    更新日期:2017-11-02
  • Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling
    Cell Metab. (IF 18.164) Pub Date : 2017-10-26
    Heather J. Weir, Pallas Yao, Frank K. Huynh, Caroline C. Escoubas, Renata L. Goncalves, Kristopher Burkewitz, Raymond Laboy, Matthew D. Hirschey, William B. Mair

    Mitochondrial network remodeling between fused and fragmented states facilitates mitophagy, interaction with other organelles, and metabolic flexibility. Aging is associated with a loss of mitochondrial network homeostasis, but cellular processes causally linking these changes to organismal senescence remain unclear. Here, we show that AMP-activated protein kinase (AMPK) and dietary restriction (DR) promote longevity inC. elegansvia maintaining mitochondrial network homeostasis and functional coordination with peroxisomes to increase fatty acid oxidation (FAO). Inhibiting fusion or fission specifically blocks AMPK- and DR-mediated longevity. Strikingly, however, preserving mitochondrial network homeostasis during aging by co-inhibition of fusion and fission is sufficient itself to increase lifespan, while dynamic network remodeling is required for intermittent fasting-mediated longevity. Finally, we show that increasing lifespan via maintaining mitochondrial network homeostasis requires FAO and peroxisomal function. Together, these data demonstrate that mechanisms that promote mitochondrial homeostasis and plasticity can be targeted to promote healthy aging.

    更新日期:2017-10-27
  • Abrogating Mitochondrial Dynamics in Mouse Hearts Accelerates Mitochondrial Senescence
    Cell Metab. (IF 18.164) Pub Date : 2017-10-26
    Moshi Song, Antonietta Franco, Julie A. Fleischer, Lihong Zhang, Gerald W. Dorn

    Mitochondrial fusion and fission are critical to heart health; genetically interrupting either is rapidly lethal. To understand whether it is loss of, or the imbalance between, fusion and fission that underlies observed cardiac phenotypes, we engineered mice in which Mfn-mediated fusion and Drp1-mediated fission could be concomitantly abolished. Compared to fusion-defective Mfn1/Mfn2 cardiac knockout or fission-defective Drp1 cardiac knockout mice, Mfn1/Mfn2/Drp1 cardiac triple-knockout mice survived longer and manifested a unique pathological form of cardiac hypertrophy. Over time, however, combined abrogation of fission and fusion provoked massive progressive mitochondrial accumulation that severely distorted cardiomyocyte sarcomeric architecture. Mitochondrial biogenesis was not responsible for mitochondrial superabundance, whereas mitophagy was suppressed despite impaired mitochondrial proteostasis. Similar but milder defects were observed in aged hearts. Thus, cardiomyopathies linked to dynamic imbalance between fission and fusion are temporarily mitigated by forced mitochondrial adynamism at the cost of compromising mitochondrial quantity control and accelerating mitochondrial senescence.

    更新日期:2017-10-27
  • Overlapping Brain Circuits for Homeostatic and Hedonic Feeding
    Cell Metab. (IF 18.164) Pub Date : 2017-10-26
    Mark A. Rossi, Garret D. Stuber

    Central regulation of food intake is a key mechanism contributing to energy homeostasis. Many neural circuits that are thought to orchestrate feeding behavior overlap with the brain’s reward circuitry both anatomically and functionally. Manipulation of numerous neural pathways can simultaneously influence food intake and reward. Two key systems underlying these processes—those controlling homeostatic and hedonic feeding—are often treated as independent. Homeostatic feeding is necessary for basic metabolic processes and survival, while hedonic feeding is driven by sensory perception or pleasure. Despite this distinction, their functional and anatomical overlap implies considerable interaction that is often overlooked. Here, we argue that the neurocircuits controlling homeostatic feeding and hedonic feeding are not completely dissociable given the current data and urge researchers to assess behaviors extending beyond food intake in investigations of the neural control of feeding.

    更新日期:2017-10-27
  • System-wide Benefits of Intermeal Fasting by Autophagy
    Cell Metab. (IF 18.164) Pub Date : 2017-10-26
    Nuria Martinez-Lopez, Elena Tarabra, Miriam Toledo, Marina Garcia-Macia, Srabani Sahu, Luisa Coletto, Ana Batista-Gonzalez, Nir Barzilai, Jeffrey E. Pessin, Gary J. Schwartz, Sander Kersten, Rajat Singh

    Autophagy failure is associated with metabolic insufficiency. Although caloric restriction (CR) extends healthspan, its adherence in humans is poor. We established an isocaloric twice-a-day (ITAD) feeding model wherein ITAD-fed mice consume the same food amount asad libitumcontrols but at two short windows early and late in the diurnal cycle. We hypothesized that ITAD feeding will provide two intervals of intermeal fasting per circadian period and induce autophagy. We show that ITAD feeding modifies circadian autophagy and glucose/lipid metabolism that correlate with feeding-driven changes in circulating insulin. ITAD feeding decreases adiposity and, unlike CR, enhances muscle mass. ITAD feeding drives energy expenditure, lowers lipid levels, suppresses gluconeogenesis, and prevents age/obesity-associated metabolic defects. Using liver-, adipose-, myogenic-, and proopiomelanocortin neuron-specific autophagy-null mice, we mapped the contribution of tissue-specific autophagy to system-wide benefits of ITAD feeding. Our studies suggest that consuming two meals a day without CR could prevent the metabolic syndrome.

    更新日期:2017-10-27
  • Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling
    Cell Metab. (IF 18.164) Pub Date : 2017-10-26
    Heather J. Weir, Pallas Yao, Frank K. Huynh, Caroline C. Escoubas, Renata L. Goncalves, Kristopher Burkewitz, Raymond Laboy, Matthew D. Hirschey, William B. Mair
    更新日期:2017-10-27
  • Abrogating Mitochondrial Dynamics in Mouse Hearts Accelerates Mitochondrial Senescence
    Cell Metab. (IF 18.164) Pub Date : 2017-10-26
    Moshi Song, Antonietta Franco, Julie A. Fleischer, Lihong Zhang, Gerald W. Dorn
    更新日期:2017-10-27
  • Overlapping Brain Circuits for Homeostatic and Hedonic Feeding
    Cell Metab. (IF 18.164) Pub Date : 2017-10-26
    Mark A. Rossi, Garret D. Stuber
    更新日期:2017-10-27
  • System-wide Benefits of Intermeal Fasting by Autophagy
    Cell Metab. (IF 18.164) Pub Date : 2017-10-26
    Nuria Martinez-Lopez, Elena Tarabra, Miriam Toledo, Marina Garcia-Macia, Srabani Sahu, Luisa Coletto, Ana Batista-Gonzalez, Nir Barzilai, Jeffrey E. Pessin, Gary J. Schwartz, Sander Kersten, Rajat Singh
    更新日期:2017-10-27
  • In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors
    Cell Metab. (IF 18.164) Pub Date : 2017-10-19
    Lucia Salamanca-Cardona, Hardik Shah, Alex J. Poot, Fabian M. Correa, Valentina Di Gialleonardo, Hui Lui, Vesselin Z. Miloushev, Kristin L. Granlund, Sui S. Tee, Justin R. Cross, Craig B. Thompson, Kayvan R. Keshari

    The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers, where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to accessin vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and IDH2, we report that 2-HG can be rapidly generated from glutaminein vitro. Then, using hyperpolarized magnetic resonance imaging (HP-MRI), we demonstrate thatin vivoHP [1-13C] glutamine can be used to non-invasively measure glutamine-derived HP 2-HG production. This can be readily modulated utilizing a selective IDH1 inhibitor, opening the door to targeting glutamine-derived 2-HG therapeutically. Rapid rates of HP 2-HG generationin vivofurther demonstrate that, in a context-dependent manner, glutamine can be a primary carbon source for 2-HG production in mutant IDH tumors.

    更新日期:2017-10-19
  • CANTOS Ushers in a New Calculus of Inflammasome Targeting for Vascular Protection—and Maybe More
    Cell Metab. (IF 18.164) Pub Date : 2017-10-19
    Subodh Verma, Lawrence A. Leiter, Deepak L. Bhatt

    Despite overwhelming basic science linking inflammation to the pathobiology of atherothrombosis, the specific clinical evidence indicating cardiovascular benefits from anti-inflammatory pharmacotherapy has been lacking. The CANTOS trial ( Ridker et al., 2017a ) now provides the first largescale proof of concept that inflammasome targeting can reduce cardiovascular events—and, surprisingly, lung cancer.

    更新日期:2017-10-19
  • Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway
    Cell Metab. (IF 18.164) Pub Date : 2017-10-19
    Paige V. Bauer, Frank A. Duca, T.M. Zaved Waise, Brittany A. Rasmussen, Mona A. Abraham, Helen J. Dranse, Akshita Puri, Catherine A. O’Brien, Tony K.T. Lam

    The gut microbiota alters energy homeostasis. In parallel, metformin regulates upper small intestinal sodium glucose cotransporter-1 (SGLT1), but whether changes of the microbiota or SGLT1-dependent pathways in the upper small intestine mediate metformin action is unknown. Here we report that upper small intestinal glucose sensing triggers an SGLT1-dependent pathway to lower glucose production in rodents. High-fat diet (HFD) feeding reduces glucose sensing and SGLT1 expression in the upper small intestine. Upper small intestinal metformin treatment restores SGLT1 expression and glucose sensing while shifting the upper small intestinal microbiota partly by increasing the abundance ofLactobacillus. Transplantation of upper small intestinal microbiota from metformin-treated HFD rats to the upper small intestine of untreated HFD rats also increases the upper small intestinal abundance ofLactobacillusand glucose sensing via an upregulation of SGLT1 expression. Thus, we demonstrate that metformin alters upper small intestinal microbiota and impacts a glucose-SGLT1-sensing glucoregulatory pathway.

    更新日期:2017-10-19
  • Acetyl-CoA Carboxylase 1-Dependent Protein Acetylation Controls Breast Cancer Metastasis and Recurrence
    Cell Metab. (IF 18.164) Pub Date : 2017-10-19
    Marcos Rios Garcia, Brigitte Steinbauer, Kshitij Srivastava, Mahak Singhal, Frits Mattijssen, Adriano Maida, Sven Christian, Holger Hess-Stumpp, Hellmut G. Augustin, Karin Müller-Decker, Peter P. Nawroth, Stephan Herzig, Mauricio Berriel Diaz

    Breast tumor recurrence and metastasis represent the main causes of cancer-related death in women, and treatments are still lacking. Here, we define the lipogenic enzyme acetyl-CoA carboxylase (ACC) 1 as a key player in breast cancer metastasis. ACC1 phosphorylation was increased in invading cells both in murine and human breast cancer, serving as a point of convergence for leptin and transforming growth factor (TGF) β signaling. ACC1 phosphorylation was mediated by TGFβ-activated kinase (TAK) 1, and ACC1 inhibition was indispensable for the elevation of cellular acetyl-CoA, the subsequent increase in Smad2 transcription factor acetylation and activation, and ultimately epithelial-mesenchymal transition and metastasis induction. ACC1 deficiency worsened tumor recurrence upon primary tumor resection in mice, and ACC1 phosphorylation levels correlated with metastatic potential in breast and lung cancer patients. Given the demonstrated effectiveness of anti-leptin receptor antibody treatment in halting ACC1-dependent tumor invasiveness, our work defines a “metabolocentric” approach in metastatic breast cancer therapy.

    更新日期:2017-10-19
  • Molecular Mechanisms Linking Exercise to Cancer Prevention and Treatment
    Cell Metab. (IF 18.164) Pub Date : 2017-10-19
    Pernille Hojman, Julie Gehl, Jesper F. Christensen, Bente K. Pedersen

    The benefits of exercise training for cancer patients are becoming increasingly evident. Physical exercise has been shown to reduce cancer incidence and inhibit tumor growth. Here we provide the status of the current molecular understanding of the effect of exercise on cancer. We propose that exercise has a role in controlling cancer progression through a direct effect on tumor-intrinsic factors, interplay with whole-body exercise effects, alleviation of cancer-related adverse events, and improvement of anti-cancer treatment efficacy. These findings have wide-ranging societal implications, as this understanding may lead to changes in cancer treatment strategies.

    更新日期:2017-10-19
  • In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors
    Cell Metab. (IF 18.164) Pub Date : 2017-10-19
    Lucia Salamanca-Cardona, Hardik Shah, Alex J. Poot, Fabian M. Correa, Valentina Di Gialleonardo, Hui Lui, Vesselin Z. Miloushev, Kristin L. Granlund, Sui S. Tee, Justin R. Cross, Craig B. Thompson, Kayvan R. Keshari
    更新日期:2017-10-19
  • CANTOS Ushers in a New Calculus of Inflammasome Targeting for Vascular Protection—and Maybe More
    Cell Metab. (IF 18.164) Pub Date : 2017-10-19
    Subodh Verma, Lawrence A. Leiter, Deepak L. Bhatt
    更新日期:2017-10-19
  • Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway
    Cell Metab. (IF 18.164) Pub Date : 2017-10-19
    Paige V. Bauer, Frank A. Duca, T.M. Zaved Waise, Brittany A. Rasmussen, Mona A. Abraham, Helen J. Dranse, Akshita Puri, Catherine A. O’Brien, Tony K.T. Lam
    更新日期:2017-10-19
  • Acetyl-CoA Carboxylase 1-Dependent Protein Acetylation Controls Breast Cancer Metastasis and Recurrence
    Cell Metab. (IF 18.164) Pub Date : 2017-10-19
    Marcos Rios Garcia, Brigitte Steinbauer, Kshitij Srivastava, Mahak Singhal, Frits Mattijssen, Adriano Maida, Sven Christian, Holger Hess-Stumpp, Hellmut G. Augustin, Karin Müller-Decker, Peter P. Nawroth, Stephan Herzig, Mauricio Berriel Diaz
    更新日期:2017-10-19
  • Molecular Mechanisms Linking Exercise to Cancer Prevention and Treatment
    Cell Metab. (IF 18.164) Pub Date : 2017-10-19
    Pernille Hojman, Julie Gehl, Jesper F. Christensen, Bente K. Pedersen
    更新日期:2017-10-19
  • PGC-1α Promotes Breast Cancer Metastasis and Confers Bioenergetic Flexibility against Metabolic Drugs
    Cell Metab. (IF 18.164) Pub Date : 2017-10-05
    Sylvia Andrzejewski, Eva Klimcakova, Radia M. Johnson, Sébastien Tabariès, Matthew G. Annis, Shawn McGuirk, Jason J. Northey, Valérie Chénard, Urshila Sriram, David J. Papadopoli, Peter M. Siegel, Julie St-Pierre

    Metabolic adaptations play a key role in fueling tumor growth. However, less is known regarding the metabolic changes that promote cancer progression to metastatic disease. Herein, we reveal that breast cancer cells that preferentially metastasize to the lung or bone display relatively high expression of PGC-1α compared with those that metastasize to the liver. PGC-1α promotes breast cancer cell migration and invasionin vitroand augments lung metastasisin vivo. Pro-metastatic capabilities of PGC-1α are linked to enhanced global bioenergetic capacity, facilitating the ability to cope with bioenergetic disruptors like biguanides. Indeed, biguanides fail to mitigate the PGC-1α-dependent lung metastatic phenotype and PGC-1α confers resistance to stepwise increases in metformin concentration. Overall, our results reveal that PGC-1α stimulates bioenergetic potential, which promotes breast cancer metastasis and facilitates adaptation to metabolic drugs.

    更新日期:2017-10-05
  • FGF19, FGF21, and an FGFR1/β-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia
    Cell Metab. (IF 18.164) Pub Date : 2017-10-05
    Tian Lan, Donald A. Morgan, Kamal Rahmouni, Junichiro Sonoda, Xiaorong Fu, Shawn C. Burgess, William L. Holland, Steven A. Kliewer, David J. Mangelsdorf

    Despite the different physiologic functions of FGF19 and FGF21 as hormonal regulators of fed and fasted metabolism, their pharmacologic administration causes similar increases in energy expenditure, weight loss, and enhanced insulin sensitivity in obese animals. Here, in genetic loss-of-function studies of the shared co-receptor β-Klotho, we show that these pharmacologic effects are mediated through a common, tissue-specific pathway. Surprisingly, FGF19 and FGF21 actions in liver and adipose tissue are not required for their longer-term weight loss and glycemic effects. In contrast, β-Klotho in neurons is essential for both FGF19 and FGF21 to cause weight loss and lower glucose and insulin levels. We further show an FGF21 mimetic antibody that activates the FGF receptor 1/β-Klotho complex also requires neuronal β-Klotho for its metabolic effects. These studies highlight the importance of the nervous system in mediating the beneficial weight loss and glycemic effects of endocrine FGF drugs.

    更新日期:2017-10-05
  • Cold-Induced Thermogenesis Depends on ATGL-Mediated Lipolysis in Cardiac Muscle, but Not Brown Adipose Tissue
    Cell Metab. (IF 18.164) Pub Date : 2017-10-05
    Renate Schreiber, Clemens Diwoky, Gabriele Schoiswohl, Ursula Feiler, Nuttaporn Wongsiriroj, Mahmoud Abdellatif, Dagmar Kolb, Joris Hoeks, Erin E. Kershaw, Simon Sedej, Patrick Schrauwen, Guenter Haemmerle, Rudolf Zechner

    Fatty acids (FAs) activate and fuel UCP1-mediated non-shivering thermogenesis (NST) in brown adipose tissue (BAT). Release of FAs from intracellular fat stores by adipose triglyceride lipase (ATGL) is considered a key step in NST. Accordingly, the severe cold intolerance of global ATGL knockout (AKO) mice has been attributed to defective BAT lipolysis. Here we show that this conclusion is incorrect. We demonstrate that although the BAT-specific loss of ATGL impairs BAT lipolysis and alters BAT morphology, it does not compromise the β3-adrenergic thermogenic response or cold-induced NST. Instead, NST depends on nutrient supply or lipolysis in white adipose tissue during fasting, suggesting that circulating energy substrates are sufficient to fuel NST. Cold intolerance in AKO mice is not caused by BAT dysfunction as previously suspected but by severe cardiomyopathy. We conclude that functional NST requires adequate substrate supply and cardiac function, but does not depend on ATGL-mediated lipolysis in BAT.

    更新日期:2017-10-05
  • Citrobacter rodentium Subverts ATP Flux and Cholesterol Homeostasis in Intestinal Epithelial Cells In Vivo
    Cell Metab. (IF 18.164) Pub Date : 2017-10-05
    Cedric N. Berger, Valerie F. Crepin, Theodoros I. Roumeliotis, James C. Wright, Danielle Carson, Meirav Pevsner-Fischer, R. Christopher D. Furniss, Gordon Dougan, Mally Bachash, Lu Yu, Abigail Clements, James W. Collins, Eran Elinav, Gerald J. Larrouy-Maumus, Jyoti S. Choudhary, Gad Frankel

    The intestinal epithelial cells (IECs) that line the gut form a robust line of defense against ingested pathogens. We investigated the impact of infection with the enteric pathogenCitrobacter rodentiumon mouse IEC metabolism using global proteomic and targeted metabolomics and lipidomics. The major signatures of the infection were upregulation of the sugar transporter Sglt4, aerobic glycolysis, and production of phosphocreatine, which mobilizes cytosolic energy. In contrast, biogenesis of mitochondrial cardiolipins, essential for ATP production, was inhibited, which coincided with increased levels of mucosal O2and a reduction in colon-associated anaerobic commensals. In addition, IECs responded to infection by activating Srebp2 and the cholesterol biosynthetic pathway. Unexpectedly, infected IECs also upregulated the cholesterol efflux proteins AbcA1, AbcG8, and ApoA1, resulting in higher levels of fecal cholesterol and a bloom ofProteobacteria. These results suggest thatC. rodentiummanipulates host metabolism to evade innate immune responses and establish a favorable gut ecosystem.

    更新日期:2017-10-05
  • Lipolysis in Brown Adipocytes Is Not Essential for Cold-Induced Thermogenesis in Mice
    Cell Metab. (IF 18.164) Pub Date : 2017-10-05
    Hyunsu Shin, Yinyan Ma, Tatyana Chanturiya, Qiang Cao, Youlin Wang, Anil K.G. Kadegowda, Rachel Jackson, Dominic Rumore, Bingzhong Xue, Hang Shi, Oksana Gavrilova, Liqing Yu

    Lipid droplet (LD) lipolysis in brown adipose tissue (BAT) is generally considered to be required for cold-induced nonshivering thermogenesis. Here, we show that mice lacking BAT Comparative Gene Identification-58 (CGI-58), a lipolytic activator essential for the stimulated LD lipolysis, have normal thermogenic capacity and are not cold sensitive. Relative to littermate controls, these animals had higher body temperatures when they were provided food during cold exposure. The increase in body temperature in the fed, cold-exposed knockout mice was associated with increased energy expenditure and with increased sympathetic innervation and browning of white adipose tissue (WAT). Mice lacking CGI-58 in both BAT and WAT were cold sensitive, but only in the fasted state. Thus, LD lipolysis in BAT is not essential for cold-induced nonshivering thermogenesisin vivo. Rather, CGI-58-dependent LD lipolysis in BAT regulates WAT thermogenesis, and our data uncover an essential role of WAT lipolysis in fueling thermogenesis during fasting.

    更新日期:2017-10-05
  • ATF4-Induced Metabolic Reprograming Is a Synthetic Vulnerability of the p62-Deficient Tumor Stroma
    Cell Metab. (IF 18.164) Pub Date : 2017-10-05
    Juan F. Linares, Thekla Cordes, Angeles Duran, Miguel Reina-Campos, Tania Valencia, Christopher S. Ahn, Elias A. Castilla, Jorge Moscat, Christian M. Metallo, Maria T. Diaz-Meco

    Tumors undergo nutrient stress and need to reprogram their metabolism to survive. The stroma may play a critical role in this process by providing nutrients to support the epithelial compartment of the tumor. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation by the direct control of ATF4 stability through its p62-mediated polyubiquitination. ATF4 upregulation by p62 deficiency in the stroma activates glucose carbon flux through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine generation as a source of nitrogen for stroma and tumor epithelial proliferation. Thus, p62 directly targets nuclear transcription factors to control metabolic reprogramming in the microenvironment and repress tumorigenesis, and identifies ATF4 as a synthetic vulnerability in p62-deficient tumor stroma.

    更新日期:2017-10-05
  • PGC-1α Promotes Breast Cancer Metastasis and Confers Bioenergetic Flexibility against Metabolic Drugs
    Cell Metab. (IF 18.164) Pub Date : 2017-10-05
    Sylvia Andrzejewski, Eva Klimcakova, Radia M. Johnson, Sébastien Tabariès, Matthew G. Annis, Shawn McGuirk, Jason J. Northey, Valérie Chénard, Urshila Sriram, David J. Papadopoli, Peter M. Siegel, Julie St-Pierre
    更新日期:2017-10-05
  • FGF19, FGF21, and an FGFR1/β-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia
    Cell Metab. (IF 18.164) Pub Date : 2017-10-05
    Tian Lan, Donald A. Morgan, Kamal Rahmouni, Junichiro Sonoda, Xiaorong Fu, Shawn C. Burgess, William L. Holland, Steven A. Kliewer, David J. Mangelsdorf
    更新日期:2017-10-05
  • Cold-Induced Thermogenesis Depends on ATGL-Mediated Lipolysis in Cardiac Muscle, but Not Brown Adipose Tissue
    Cell Metab. (IF 18.164) Pub Date : 2017-10-05
    Renate Schreiber, Clemens Diwoky, Gabriele Schoiswohl, Ursula Feiler, Nuttaporn Wongsiriroj, Mahmoud Abdellatif, Dagmar Kolb, Joris Hoeks, Erin E. Kershaw, Simon Sedej, Patrick Schrauwen, Guenter Haemmerle, Rudolf Zechner
    更新日期:2017-10-05
  • Citrobacter rodentium Subverts ATP Flux and Cholesterol Homeostasis in Intestinal Epithelial Cells In Vivo
    Cell Metab. (IF 18.164) Pub Date : 2017-10-05
    Cedric N. Berger, Valerie F. Crepin, Theodoros I. Roumeliotis, James C. Wright, Danielle Carson, Meirav Pevsner-Fischer, R. Christopher D. Furniss, Gordon Dougan, Mally Bachash, Lu Yu, Abigail Clements, James W. Collins, Eran Elinav, Gerald J. Larrouy-Maumus, Jyoti S. Choudhary, Gad Frankel
    更新日期:2017-10-05
  • $L̫VxnLE$L̫Vxn
  • Lipolysis in Brown Adipocytes Is Not Essential for Cold-Induced Thermogenesis in Mice
    Cell Metab. (IF 18.164) Pub Date : 2017-10-05
    Hyunsu Shin, Yinyan Ma, Tatyana Chanturiya, Qiang Cao, Youlin Wang, Anil K.G. Kadegowda, Rachel Jackson, Dominic Rumore, Bingzhong Xue, Hang Shi, Oksana Gavrilova, Liqing Yu
    更新日期:2017-10-05
  • ATF4-Induced Metabolic Reprograming Is a Synthetic Vulnerability of the p62-Deficient Tumor Stroma
    Cell Metab. (IF 18.164) Pub Date : 2017-10-05
    Juan F. Linares, Thekla Cordes, Angeles Duran, Miguel Reina-Campos, Tania Valencia, Christopher S. Ahn, Elias A. Castilla, Jorge Moscat, Christian M. Metallo, Maria T. Diaz-Meco
    更新日期:2017-10-05
  • Metabolic Disease Therapies
    Cell Metab. (IF 18.164) Pub Date : 2017-10-03
    更新日期:2017-10-03
  • Antigen-Specific Peptide Immunotherapy for Type 1 Diabetes: Proof of Safety, Hope for Efficacy
    Cell Metab. (IF 18.164) Pub Date : 2017-10-03
    Ken Coppieters, Matthias von Herrath
    更新日期:2017-10-03
  • The Burgeoning World of Immunometabolites: Th17 Cells Take Center Stage
    Cell Metab. (IF 18.164) Pub Date : 2017-10-03
    Glenn R. Bantug, Christoph Hess
    更新日期:2017-10-03
  • Fasting the Microbiota to Improve Metabolism?
    Cell Metab. (IF 18.164) Pub Date : 2017-10-03
    Joel T. Haas, Bart Staels

    While intermittent or periodic fasting provides a variety of favorable health benefits, the molecular mediators of these effects are poorly understood. In this issue ofCell Metabolism, Li and colleagues (2017) highlight the role of gut microbiota in mediating benefits of intermittent fasting through activation of adipose tissue beiging.

    更新日期:2017-10-03
  • Slowing Down Aging
    Cell Metab. (IF 18.164) Pub Date : 2017-10-03
    Katharina Meyer, Bruce A. Yankner
    更新日期:2017-10-03
  • Dietary Carbohydrates Impair Healthspan and Promote Mortality
    Cell Metab. (IF 18.164) Pub Date : 2017-10-03
    Meenakshi Ravichandran, Gerald Grandl, Michael Ristow
    更新日期:2017-10-03
  • TREM2: Keeping Microglia Fit during Good Times and Bad
    Cell Metab. (IF 18.164) Pub Date : 2017-10-03
    Soyon Hong, Beth Stevens

    Microglia are the macrophages of the brain and play an important role in Alzheimer’s disease (AD). InCell, Ulland et al. (2017) recently reported that mutations in TREM2, a protein implicated in AD, disrupt microglial energy state and function, thus sabotaging the microglia’s ability to defend the brain against amyloid plaques.

    更新日期:2017-10-03
  • MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation
    Cell Metab. (IF 18.164) Pub Date : 2017-10-03
    Kyung-min Lee, Jennifer M. Giltnane, Justin M. Balko, Luis J. Schwarz, Angel L. Guerrero-Zotano, Katherine E. Hutchinson, Mellissa J. Nixon, Mónica V. Estrada, Violeta Sánchez, Melinda E. Sanders, Taekyu Lee, Henry Gómez, Ana Lluch, J. Alejandro Pérez-Fidalgo, Melissa Magdalene Wolf, Gabriela Andrejeva, Jeffrey C. Rathmell, Stephen W. Fesik, Carlos L. Arteaga
    更新日期:2017-10-03
  • Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition
    Cell Metab. (IF 18.164) Pub Date : 2017-10-03
    Ruud S. Kootte, Evgeni Levin, Jarkko Salojärvi, Loek P. Smits, Annick V. Hartstra, Shanti D. Udayappan, Gerben Hermes, Kristien E. Bouter, Annefleur M. Koopen, Jens J. Holst, Filip K. Knop, Ellen E. Blaak, Jing Zhao, Hauke Smidt, Amy C. Harms, Thomas Hankemeijer, Jacques J.G.H.M. Bergman, Hans A. Romijn, Frank G. Schaap, Steven W.M. Olde Damink, Mariette T. Ackermans, Geesje M. Dallinga-Thie, Erwin Zoetendal, Willem M. de Vos, Mireille J. Serlie, Erik S.G. Stroes, Albert K. Groen, Max Nieuwdorp
    更新日期:2017-10-03
  • Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity
    Cell Metab. (IF 18.164) Pub Date : 2017-10-03
    Lawrence Kazak, Edward T. Chouchani, Gina Z. Lu, Mark P. Jedrychowski, Curtis J. Bare, Amir I. Mina, Manju Kumari, Song Zhang, Ivan Vuckovic, Dina Laznik-Bogoslavski, Petras Dzeja, Alexander S. Banks, Evan D. Rosen, Bruce M. Spiegelman

    (Cell Metabolism 26, 1–12; October 3, 2017)

    更新日期:2017-10-03
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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