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Cell Metabolism

Ulrike Kaufmann, Sascha Kahlfuss, Jun Yang, Elitza Ivanova, Sergei B Koralov, Stefan Feske
Pathogenic Th17 cells play important roles in many autoimmune and inflammatory diseases. Their function depends on T cell receptor (TCR) signaling and cytokines that activate signal transducer and activator of transcription 3 (STAT3). TCR engagement activates stromal interaction molecule 1 (STIM1) and calcium (Ca2+ ) influx through Ca2+ -release-activated Ca2+ (CRAC) channels. Here, we show that abolishing STIM1 and Ca2+ influx in T cells expressing a hyperactive form of STAT3 (STAT3C) attenuates pathogenic Th17 cell function and inflammation associated with STAT3C expression...
February 12, 2019: Cell Metabolism
Simon Schwörer, Santosha A Vardhana, Craig B Thompson
The metabolic reprogramming associated with malignant transformation has led to a growing appreciation of the nutrients required to support anabolic cell growth. Less well studied is how cancer cells satisfy those demands in vivo, where they are dispersed within a complex microenvironment. Tumor-associated stromal components can support tumor growth by providing nutrients that supplement those provided by the local vasculature. These non-malignant stromal cells are phenotypically similar to those that accumulate during wound healing...
February 11, 2019: Cell Metabolism
Yaarit Adamovich, Benjamin Ladeuix, Jonathan Sobel, Gal Manella, Adi Neufeld-Cohen, Mohammad H Assadi, Marina Golik, Yael Kuperman, Ariel Tarasiuk, Maarten P Koeners, Gad Asher
Daily rhythms in animal physiology are driven by endogenous circadian clocks in part through rest-activity and feeding-fasting cycles. Here, we examined principles that govern daily respiration. We monitored oxygen consumption and carbon dioxide release, as well as tissue oxygenation in freely moving animals to specifically dissect the role of circadian clocks and feeding time on daily respiration. We found that daily rhythms in oxygen and carbon dioxide are clock controlled and that time-restricted feeding restores their rhythmicity in clock-deficient mice...
February 11, 2019: Cell Metabolism
Shamina M Rangwala, Katharine D'Aquino, Yue-Mei Zhang, Lindsay Bader, Wilson Edwards, Songmao Zheng, Annette Eckardt, Ann Lacombe, Rebecca Pick, Veronica Moreno, Lijuan Kang, Wenying Jian, Eric Arnoult, Martin Case, Celia Jenkinson, Ellen Chi, Ronald V Swanson, Paul Kievit, Kevin Grove, Mark Macielag, Mark D Erion, Ranabir SinhaRoy, James N Leonard
The gut hormone PYY3-36 reduces food intake in humans and exhibits at least additive efficacy in combination with GLP-1. However, the utility of PYY analogs as anti-obesity agents has been severely limited by emesis and rapid proteolysis, a profile similarly observed with native PYY3-36 in obese rhesus macaques. Here, we found that antibody conjugation of a cyclized PYY3-36 analog achieved high NPY2R selectivity, unprecedented in vivo stability, and gradual infusion-like exposure. These properties permitted profound reduction of food intake when administered to macaques for 23 days without a single emetic event in any animal...
February 11, 2019: Cell Metabolism
Yilin Yu, Hunter Newman, Leyao Shen, Deepika Sharma, Guoli Hu, Anthony J Mirando, Hongyuan Zhang, Everett Knudsen, Guo-Fang Zhang, Matthew J Hilton, Courtney M Karner
Skeletal stem cells (SSCs) are postulated to provide a continuous supply of osteoblasts throughout life. However, under certain conditions, the SSC population can become incorrectly specified or is not maintained, resulting in reduced osteoblast formation, decreased bone mass, and in severe cases, osteoporosis. Glutamine metabolism has emerged as a critical regulator of many cellular processes in diverse pathologies. The enzyme glutaminase (GLS) deaminates glutamine to form glutamate-the rate-limiting first step in glutamine metabolism...
February 9, 2019: Cell Metabolism
Arianne E Rodriguez, Gregory S Ducker, Leah K Billingham, Carlos A Martinez, Nello Mainolfi, Vipin Suri, Adam Friedman, Mark G Manfredi, Samuel E Weinberg, Joshua D Rabinowitz, Navdeep S Chandel
Serine is a substrate for nucleotide, NADPH, and glutathione (GSH) synthesis. Previous studies in cancer cells and lymphocytes have shown that serine-dependent one-carbon units are necessary for nucleotide production to support proliferation. Presently, it is unknown whether serine metabolism impacts the function of non-proliferative cells, such as inflammatory macrophages. We find that in macrophages, serine is required for optimal lipopolysaccharide (LPS) induction of IL-1β mRNA expression, but not inflammasome activation...
February 7, 2019: Cell Metabolism
Kevin H Lin, Abigail Xie, Justine C Rutter, Yeong-Ran Ahn, Julia M Lloyd-Cowden, Amanda G Nichols, Ryan S Soderquist, Timothy R Koves, Deborah M Muoio, Nancie J MacIver, Jatinder K Lamba, Timothy S Pardee, Chad M McCall, David A Rizzieri, Kris C Wood
Crosstalk between metabolic and survival pathways is critical for cellular homeostasis, but the connectivity between these processes remains poorly defined. We used loss-of-function CRISPR/Cas9 knockout screening to identify metabolic genes capable of influencing cellular commitment to apoptosis, using sensitization to the BCL-2 inhibitor ABT-199 in BCL-2-dependent acute myeloid leukemia (AML) cell lines as a proxy for apoptotic disposition. This analysis revealed metabolic pathways that specifically cooperate with BCL-2 to sustain survival...
February 5, 2019: Cell Metabolism
Liming Du, Liangyu Lin, Qing Li, Keli Liu, Yin Huang, Xuefeng Wang, Kai Cao, Xiaodong Chen, Wei Cao, Fengying Li, Changshun Shao, Ying Wang, Yufang Shi
Recent investigations revealed that macrophages could be trained with an altered responsiveness, raising the possibility of combating autoimmune diseases by imparting anti-inflammatory capabilities to these cells. While investigating the effect of mesenchymal stem cells on experimental autoimmune encephalomyelitis (EAE), we found a critical role of insulin-like growth factor 2 (IGF-2) in training macrophages to become anti-inflammatory during their maturation. IGF-2 exerts its effects by preprogramming maturing macrophages to commit oxidative phosphorylation (OXPHOS)...
February 4, 2019: Cell Metabolism
Michinari Nakamura, Tong Liu, Seema Husain, Peiyong Zhai, Junco S Warren, Chiao-Po Hsu, Takahisa Matsuda, Christopher J Phiel, James E Cox, Bin Tian, Hong Li, Junichi Sadoshima
Obesity induces lipotoxic cardiomyopathy, a condition in which lipid accumulation in cardiomyocytes causes cardiac dysfunction. Here, we show that glycogen synthase kinase-3α (GSK-3α) mediates lipid accumulation in the heart. Fatty acids (FAs) upregulate GSK-3α, which phosphorylates PPARα at Ser280 in the ligand-binding domain (LBD). This modification ligand independently enhances transcription of a subset of PPARα targets, selectively stimulating FA uptake and storage, but not oxidation, thereby promoting lipid accumulation...
February 2, 2019: Cell Metabolism
Adeola O Adebayo Michael, Sungjin Ko, Junyan Tao, Akshata Moghe, Hong Yang, Meng Xu, Jacquelyn O Russell, Tirthadipa Pradhan-Sundd, Silvia Liu, Sucha Singh, Minakshi Poddar, Jayvir S Monga, Pin Liu, Michael Oertel, Sarangarajan Ranganathan, Aatur Singhi, Sandra Rebouissou, Jessica Zucman-Rossi, Silvia Ribback, Diego Calvisi, Natalia Qvartskhava, Boris Görg, Dieter Häussinger, Xin Chen, Satdarshan P Monga
Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-β-catenin signaling. Activating β-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets. Here, we identify a positive relationship between β-catenin activation, its transcriptional target glutamine synthetase (GS), and p-mTOR-S2448, an indicator of mTORC1 activation...
January 28, 2019: Cell Metabolism
Yue J Wang, Daniel Traum, Jonathan Schug, Long Gao, Chengyang Liu, Mark A Atkinson, Alvin C Powers, Michael D Feldman, Ali Naji, Kyong-Mi Chang, Klaus H Kaestner
The interaction between the immune system and endocrine cells in the pancreas is crucial for the initiation and progression of type 1 diabetes (T1D). Imaging mass cytometry (IMC) enables multiplexed assessment of the abundance and localization of more than 30 proteins on the same tissue section at 1-μm resolution. Herein, we have developed a panel of 33 antibodies that allows for the quantification of key cell types including pancreatic exocrine cells, islet cells, immune cells, and stromal components. We employed this panel to analyze 12 pancreata obtained from donors with clinically diagnosed T1D and 6 pancreata from non-diabetic controls...
January 28, 2019: Cell Metabolism
Mikihito Hayashi, Tomoki Nakashima, Noriko Yoshimura, Kazuo Okamoto, Sakae Tanaka, Hiroshi Takayanagi
Osteocyte survival is key to bone homeostasis and is perturbed in menopause and aging. However, it remains unknown how osteocyte-mediated maintenance of the skeleton is regulated by the osteoprotective factor semaphorin 3A (Sema3A), a secreted protein that is known to reduce bone resorption and enhance bone formation. Here, we show that estrogen induces osteocyte expression of Sema3A, which acts on its receptor on osteocytes to promote their survival and maintain bone homeostasis. Postnatal global and conditional deletion of Sema3a in osteoblastic cells resulted in a severe osteoporotic phenotype marked by fewer osteocytes...
January 17, 2019: Cell Metabolism
Ming Lu, Wen-Wei Zhu, Xuan Wang, Jing-Jie Tang, Kai-Li Zhang, Guang-Yang Yu, Wei-Qing Shao, Zhi-Fei Lin, Sheng-Hao Wang, Lu Lu, Jian Zhou, Lian-Xin Wang, Hu-Liang Jia, Qiong-Zhu Dong, Jin-Hong Chen, Jian-Quan Lu, Lun-Xiu Qin
Metabolic reprogramming plays an important role in supporting tumor growth. However, little is known about the metabolic alterations that promote cancer metastasis. In this study, we identify acyl-CoA thioesterase 12 (ACOT12) as a key player in hepatocellular carcinoma (HCC) metastasis. The expression of ACOT12 is significantly down-regulated in HCC tissues and is closely associated with HCC metastasis and poor survival of HCC patients. Gain- and loss-of-function studies demonstrate that ACOT12 suppresses HCC metastasis both in vitro and in vivo...
January 16, 2019: Cell Metabolism
Wondong Kim, Amy Deik, Clicerio Gonzalez, Maria Elena Gonzalez, Feifei Fu, Michele Ferrari, Claire L Churchhouse, Jose C Florez, Suzanne B R Jacobs, Clary B Clish, Eugene P Rhee
The reactions catalyzed by the delta-5 and delta-6 desaturases (D5D/D6D), key enzymes responsible for highly unsaturated fatty acid (HUFA) synthesis, regenerate NAD+ from NADH. Here, we show that D5D/D6D provide a mechanism for glycolytic NAD+ recycling that permits ongoing glycolysis and cell viability when the cytosolic NAD+ /NADH ratio is reduced, analogous to lactate fermentation. Although lesser in magnitude than lactate production, this desaturase-mediated NAD+ recycling is acutely adaptive when aerobic respiration is impaired in vivo...
January 14, 2019: Cell Metabolism
Nicolas Damond, Stefanie Engler, Vito R T Zanotelli, Denis Schapiro, Clive H Wasserfall, Irina Kusmartseva, Harry S Nick, Fabrizio Thorel, Pedro L Herrera, Mark A Atkinson, Bernd Bodenmiller
Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing β cells. A comprehensive picture of the changes during T1D development is lacking due to limited sample availability, inability to sample longitudinally, and the paucity of technologies enabling comprehensive tissue profiling. Here, we analyzed 1,581 islets from 12 human donors, including eight with T1D, using imaging mass cytometry (IMC). IMC enabled simultaneous measurement of 35 biomarkers with single-cell and spatial resolution...
January 11, 2019: Cell Metabolism
Xiangyang Xie, Haili Yang, Juan Ji An, Jessica Houtz, Ji-Wei Tan, Haifei Xu, Guey-Ying Liao, Zhi-Xiang Xu, Baoji Xu
Anxiety disorders are associated with body weight changes in humans. However, the mechanisms underlying anxiety-induced weight changes remain poorly understood. Using Emx1Cre/+ mice, we deleted the gene for brain-derived neurotrophic factor (BDNF) in the cortex, hippocampus, and some amygdalar subregions. The resulting mutant mice displayed impaired GABAergic transmission and elevated anxiety. They were leaner when fed either a chow diet or a high-fat diet, owing to higher sympathetic activity, basal metabolic rate, brown adipocyte thermogenesis, and beige adipocyte formation, compared to control mice...
January 11, 2019: Cell Metabolism
Tatiana V Esipova, Matthew J P Barrett, Eva Erlebach, Artëm E Masunov, Bruno Weber, Sergei A Vinogradov
Quantitative imaging of oxygen distributions in tissue can provide invaluable information about metabolism in normal and diseased states. Two-photon phosphorescence lifetime microscopy (2PLM) has been developed to perform measurements of oxygen in vivo with micron-scale resolution in 3D; however, the method's potential has not yet been fully realized due to the limitations of current phosphorescent probe technology. Here, we report a new sensor, Oxyphor 2P, that enables oxygen microscopy twice as deep (up to 600 μm below the tissue surface) and with ∼60 times higher speed than previously possible...
January 9, 2019: Cell Metabolism
Russell E Ericksen, Siew Lan Lim, Eoin McDonnell, Wai Ho Shuen, Maya Vadiveloo, Phillip J White, Zhaobing Ding, Royston Kwok, Philip Lee, George K Radda, Han Chong Toh, Matthew D Hirschey, Weiping Han
Tumors display profound changes in cellular metabolism, yet how these changes aid the development and growth of tumors is not fully understood. Here we use a multi-omic approach to examine liver carcinogenesis and regeneration, and find that progressive loss of branched-chain amino acid (BCAA) catabolism promotes tumor development and growth. In human hepatocellular carcinomas and animal models of liver cancer, suppression of BCAA catabolic enzyme expression led to BCAA accumulation in tumors, though this was not observed in regenerating liver tissues...
January 8, 2019: Cell Metabolism
Frode Norheim, Yehudit Hasin-Brumshtein, Laurent Vergnes, Karthickeyan Chella Krishnan, Calvin Pan, Marcus M Seldin, Simon T Hui, Margarete Mehrabian, Zhiqiang Zhou, Sonul Gupta, Brian W Parks, Axel Walch, Karen Reue, Susanna M Hofmann, Arthur P Arnold, Aldons J Lusis
We studied sex differences in over 50 cardio-metabolic traits in a panel of 100 diverse inbred strains of mice. The results clearly showed that the effects of sex on both clinical phenotypes and gene expression depend on the genetic background. In support of this, genetic loci associated with the traits frequently showed sex specificity. For example, Lyplal1, a gene implicated in human obesity, was shown to underlie a sex-specific locus for diet-induced obesity. Global gene expression analyses of tissues across the panel implicated adipose tissue "beiging" and mitochondrial functions in the sex differences...
January 8, 2019: Cell Metabolism
Satish Patel, Anna Alvarez-Guaita, Audrey Melvin, Debra Rimmington, Alessia Dattilo, Emily L Miedzybrodzka, Irene Cimino, Anne-Catherine Maurin, Geoffrey P Roberts, Claire L Meek, Samuel Virtue, Lauren M Sparks, Stephanie A Parsons, Leanne M Redman, George A Bray, Alice P Liou, Rachel M Woods, Sion A Parry, Per B Jeppesen, Anders J Kolnes, Heather P Harding, David Ron, Antonio Vidal-Puig, Frank Reimann, Fiona M Gribble, Carl J Hulston, I Sadaf Farooqi, Pierre Fafournoux, Steven R Smith, Jorgen Jensen, Danna Breen, Zhidan Wu, Bei B Zhang, Anthony P Coll, David B Savage, Stephen O'Rahilly
GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin...
January 2, 2019: Cell Metabolism
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