Hai-Yan Zhou, Xu Feng, Li-Wen Wang, Rui Zhou, Heng Sun, Xin Chen, Ren-Bin Lu, Yan Huang, Qi Guo, Xiang-Hang Luo
Weight regain after weight loss is a major challenge in the treatment of obesity. Immune cells adapt to fluctuating nutritional stress, but their roles in regulating weight regain remain unclear. Here, we identify a stem cell-like CD7+ monocyte subpopulation accumulating in the bone marrow (BM) of mice and humans that experienced dieting-induced weight loss. Adoptive transfer of CD7+ monocytes suppresses weight regain, whereas inducible depletion of CD7+ monocytes accelerates it. These cells, accumulating metabolic memories via epigenetic adaptations, preferentially migrate to the subcutaneous white adipose tissue (WAT), where they secrete fibrinogen-like protein 2 (FGL2) to activate the protein kinase A (PKA) signaling pathway and facilitate beige fat thermogenesis...
September 7, 2023: Cell Metabolism
Alex Colville, Jie-Yu Liu, Cristina Rodriguez-Mateo, Samantha Thomas, Heather D Ishak, Ronghao Zhou, Julian D D Klein, David W Morgens, Armon Goshayeshi, Jayesh S Salvi, David Yao, Kaitlyn Spees, Scott J Dixon, Chun Liu, June-Wha Rhee, Celine Lai, Joseph C Wu, Michael C Bassik, Thomas A Rando
Selectively ablating damaged cells is an evolving therapeutic approach for age-related disease. Current methods for genome-wide screens to identify genes whose deletion might promote the death of damaged or senescent cells are generally underpowered because of the short timescales of cell death as well as the difficulty of scaling non-dividing cells. Here, we establish "Death-seq," a positive-selection CRISPR screen optimized to identify enhancers and mechanisms of cell death. Our screens identified synergistic enhancers of cell death induced by the known senolytic ABT-263...
September 5, 2023: Cell Metabolism
Lewin Small, Leonidas S Lundell, Jo Iversen, Amy M Ehrlich, Morten Dall, Astrid L Basse, Emilie Dalbram, Ann N Hansen, Jonas T Treebak, Romain Barrès, Juleen R Zierath
Except for latitudes close to the equator, seasonal variation in light hours can change dramatically between summer and winter. Yet investigations into the interplay between energy metabolism and circadian rhythms typically use a 12 h light:12 h dark photoperiod corresponding to the light duration at the equator. We hypothesized that altering the seasonal photoperiod affects both the rhythmicity of peripheral tissue clocks and energy homeostasis. Mice were housed at photoperiods representing either light hours in summer, winter, or the equinox...
September 1, 2023: Cell Metabolism
Dusanka Milenkovic, Jelena Misic, Johannes F Hevler, Thibaut Molinié, Injae Chung, Ilian Atanassov, Xinping Li, Roberta Filograna, Andrea Mesaros, Arnaud Mourier, Albert J R Heck, Judy Hirst, Nils-Göran Larsson
The mammalian respiratory chain complexes I, III2 , and IV (CI, CIII2 , and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI-CIII2 -CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and the regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate the in vivo role of the respirasome, we generated homozygous knockin mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes...
August 22, 2023: Cell Metabolism
Daniel S Whittaker, Laila Akhmetova, Daniel Carlin, Haylie Romero, David K Welsh, Christopher S Colwell, Paula Desplats
Circadian disruptions impact nearly all people with Alzheimer's disease (AD), emphasizing both their potential role in pathology and the critical need to investigate the therapeutic potential of circadian-modulating interventions. Here, we show that time-restricted feeding (TRF) without caloric restriction improved key disease components including behavioral timing, disease pathology, hippocampal transcription, and memory in two transgenic (TG) mouse models of AD. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and memory, and normalizing daily transcription patterns of multiple genes, including those associated with AD and neuroinflammation...
August 19, 2023: Cell Metabolism
Subodh Verma, Barry A Borlaug, Javed Butler, Melanie J Davies, Dalane W Kitzman, Mark C Petrie, Sanjiv J Shah, Nitish K Dhingra, Mikhail N Kosiborod
In the STEP-HFpEF trial, 2.4 mg semaglutide produced marked improvements in heart failure-related symptoms, physical limitations, and exercise function, and reduced inflammation and body weight in individuals with obesity HFpEF phenotype. These data usher in a new paradigm of targeting obesity as a therapeutic strategy in HFpEF.
August 17, 2023: Cell Metabolism
Feng Cai, Divya Bezwada, Ling Cai, Rohit Mahar, Zheng Wu, Mario C Chang, Panayotis Pachnis, Chendong Yang, Sherwin Kelekar, Wen Gu, Bailey Brooks, Bookyung Ko, Hieu S Vu, Thomas P Mathews, Lauren G Zacharias, Misty Martin-Sandoval, Duyen Do, K Celeste Oaxaca, Eunsook S Jin, Vitaly Margulis, Craig R Malloy, Matthew E Merritt, Ralph J DeBerardinis
Stable isotopes are powerful tools to assess metabolism. 13 C labeling is detected using nuclear magnetic resonance (NMR) spectroscopy or mass spectrometry (MS). MS has excellent sensitivity but generally cannot discriminate among different 13 C positions (isotopomers), whereas NMR is less sensitive but reports some isotopomers. Here, we develop an MS method that reports all 16 aspartate and 32 glutamate isotopomers while requiring less than 1% of the sample used for NMR. This method discriminates between pathways that result in the same number of 13 C labels in aspartate and glutamate, providing enhanced specificity over conventional MS...
August 15, 2023: Cell Metabolism
Mark D Benson, Aaron S Eisman, Usman A Tahir, Daniel H Katz, Shuliang Deng, Debby Ngo, Jeremy M Robbins, Alissa Hofmann, Xu Shi, Shuning Zheng, Michelle Keyes, Zhi Yu, Yan Gao, Laurie Farrell, Dongxiao Shen, Zsu-Zsu Chen, Daniel E Cruz, Mario Sims, Adolfo Correa, Russell P Tracy, Peter Durda, Kent D Taylor, Yongmei Liu, W Craig Johnson, Xiuqing Guo, Jie Yao, Yii-Der Ida Chen, Ani W Manichaikul, Deepti Jain, Qiong Yang, Claude Bouchard, Mark A Sarzynski, Stephen S Rich, Jerome I Rotter, Thomas J Wang, James G Wilson, Clary B Clish, Indra Neil Sarkar, Pradeep Natarajan, Robert E Gerszten
Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings...
August 11, 2023: Cell Metabolism
Junliang Kuang, Jieyi Wang, Yitao Li, Mengci Li, Mingliang Zhao, Kun Ge, Dan Zheng, Kenneth C P Cheung, Boya Liao, Shouli Wang, Tianlu Chen, Yinan Zhang, Congrong Wang, Guang Ji, Peng Chen, Hongwei Zhou, Cen Xie, Aihua Zhao, Weiping Jia, Xiaojiao Zheng, Wei Jia
Non-alcoholic fatty liver disease (NAFLD) is regarded as a pandemic that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as distinct mechanistic pathways implicated in the development of NAFLD. Here, we report that a group of gut microbiota-modified bile acids (BAs), hyodeoxycholic acid (HDCA) species, are negatively correlated with the presence and severity of NAFLD. HDCA treatment has been shown to alleviate NAFLD in multiple mouse models by inhibiting intestinal farnesoid X receptor (FXR) and upregulating hepatic CYP7B1...
August 9, 2023: Cell Metabolism
Jonathan E Campbell, Timo D Müller, Brian Finan, Richard D DiMarchi, Matthias H Tschöp, David A D'Alessio
The incretin system is an essential metabolic axis that regulates postprandial metabolism. The two incretin peptides that enable this effect are the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide 1 (GLP-1), which have cognate receptors (GIPR and GLP-1R) on islet β cells as well as in other tissues. Pharmacologic engagement of the GLP-1R is a proven strategy for treating hyperglycemia in diabetes and reducing body weight. Tirzepatide is the first monomeric peptide with dual activity at both incretin receptors now available for clinical use, and in clinical trials it has shown unprecedented effects to reduce blood glucose and body weight...
August 8, 2023: Cell Metabolism
John D Douglass, Kelly M Ness, Martin Valdearcos, Alice Wyse-Jackson, Mauricio D Dorfman, Jeremy M Frey, Rachael D Fasnacht, Olivia D Santiago, Anzela Niraula, Jineta Banerjee, Megan Robblee, Suneil K Koliwad, Joshua P Thaler
Hypothalamic gliosis associated with high-fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain. However, the body-weight-independent contribution of microglia to glucose regulation has not been determined. Here, we show that reducing microglial nuclear factor κB (NF-κB) signaling via cell-specific IKKβ deletion exacerbates HFD-induced glucose intolerance despite reducing body weight and adiposity. Conversely, two genetic approaches to increase microglial pro-inflammatory signaling (deletion of an NF-κB pathway inhibitor and chemogenetic activation through a modified Gq-coupled muscarinic receptor) improved glucose tolerance independently of diet in both lean and obese rodents...
August 7, 2023: Cell Metabolism
Tingjin Chen, Zhi-Gang Xu, Jie Luo, Rajesh Kumar Manne, Zhengyu Wang, Che-Chia Hsu, Bo-Syong Pan, Zhen Cai, Pei-Jane Tsai, Yau-Sheng Tsai, Zhong-Zhu Chen, Hong-Yu Li, Hui-Kuan Lin
Glucose metabolism is known to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Here, we report that glucose is a cofactor binding to methyltransferase NSUN2 at amino acid 1-28 to promote NSUN2 oligomerization and activation. NSUN2 activation maintains global m5 C RNA methylation, including TREX2, and stabilizes TREX2 to restrict cytosolic dsDNA accumulation and cGAS/STING activation for promoting tumorigenesis and anti-PD-L1 immunotherapy resistance...
August 3, 2023: Cell Metabolism
Alba Capelo-Diz, Sofía Lachiondo-Ortega, David Fernández-Ramos, Jorge Cañas-Martín, Naroa Goikoetxea-Usandizaga, Marina Serrano-Maciá, Maria J González-Rellan, Laura Mosca, Joan Blazquez-Vicens, Alberto Tinahones-Ruano, Marcos F Fondevila, Mason Buyan, Teresa C Delgado, Virginia Gutierrez de Juan, Paula Ayuso-García, Alejandro Sánchez-Rueda, Sergio Velasco-Avilés, Héctor Fernández-Susavila, Cristina Riobello-Suárez, Bartlomiej Dziechciarz, Cristina Montiel-Duarte, Fernando Lopitz-Otsoa, Maider Bizkarguenaga, Jon Bilbao-García, Ganeko Bernardo-Seisdedos, Ana Senra, Mario Soriano-Navarro, Oscar Millet, Ángel Díaz-Lagares, Ana B Crujeiras, Aida Bao-Caamano, Diana Cabrera, Sebastiaan van Liempd, Miguel Tamayo-Carro, Luigi Borzacchiello, Beatriz Gomez-Santos, Xabier Buqué, Diego Sáenz de Urturi, Francisco González-Romero, Jorge Simon, Rubén Rodríguez-Agudo, Asier Ruiz, Carlos Matute, Daniel Beiroa, Juan M Falcon-Perez, Patricia Aspichueta, Juan Rodríguez-Cuesta, Marina Porcelli, María A Pajares, Cristina Ameneiro, Miguel Fidalgo, Ana M Aransay, Tomas Lama-Díaz, Miguel G Blanco, Miguel López, Ricardo Villa-Bellosta, Timo D Müller, Rubén Nogueiras, Ashwin Woodhoo, María Luz Martínez-Chantar, Marta Varela-Rey
There has been an intense focus to uncover the molecular mechanisms by which fasting triggers the adaptive cellular responses in the major organs of the body. Here, we show that in mice, hepatic S-adenosylmethionine (SAMe)-the principal methyl donor-acts as a metabolic sensor of nutrition to fine-tune the catabolic-fasting response by modulating phosphatidylethanolamine N-methyltransferase (PEMT) activity, endoplasmic reticulum-mitochondria contacts, β-oxidation, and ATP production in the liver, together with FGF21-mediated lipolysis and thermogenesis in adipose tissues...
July 31, 2023: Cell Metabolism
María J Gonzalez-Rellan, Uxía Fernández, Tamara Parracho, Eva Novoa, Marcos F Fondevila, Natalia da Silva Lima, Lucía Ramos, Amaia Rodríguez, Marina Serrano-Maciá, Gonzalo Perez-Mejias, Pilar Chantada-Vazquez, Cristina Riobello, Christelle Veyrat-Durebex, Sulay Tovar, Roberto Coppari, Ashwin Woodhoo, Markus Schwaninger, Vincent Prevot, Teresa C Delgado, Miguel Lopez, Antonio Diaz-Quintana, Carlos Dieguez, Diana Guallar, Gema Frühbeck, Irene Diaz-Moreno, Susana B Bravo, Maria L Martinez-Chantar, Ruben Nogueiras
Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues-K278, K342, and K387...
July 28, 2023: Cell Metabolism
Liraz Shmuel-Galia, Fiachra Humphries, Tim Vierbuchen, Zhaozhao Jiang, Nolan Santos, John Johnson, Boris Shklyar, Leonel Joannas, Nicholas Mustone, Shany Sherman, Doyle Ward, JeanMarie Houghton, Christina E Baer, Aisling O'Hara, Jorge Henao-Mejia, Kasper Hoebe, Katherine A Fitzgerald
This study reveals a previously uncharacterized mechanism to restrict intestinal inflammation via a regulatory RNA transcribed from a noncoding genomic locus. We identified a novel transcript of the lncRNA HOXA11os specifically expressed in the distal colon that is reduced to undetectable levels in colitis. HOXA11os is localized to mitochondria under basal conditions and interacts with a core subunit of complex 1 of the electron transport chain (ETC) to maintain its activity. Deficiency of HOXA11os in colonic myeloid cells results in complex I deficiency, dysfunctional oxidative phosphorylation (OXPHOS), and the production of mitochondrial reactive oxygen species (mtROS)...
July 20, 2023: Cell Metabolism
Mark A Atkinson, Raghavendra G Mirmira
Type 1 diabetes (T1D) is widely considered to result from the autoimmune destruction of insulin-producing β cells. This concept has been a central tenet for decades of attempts seeking to decipher the disorder's pathogenesis and prevent/reverse the disease. Recently, this and many other disease-related notions have come under increasing question, particularly given knowledge gained from analyses of human T1D pancreas. Perhaps most crucial are findings suggesting that a collective of cellular constituents-immune, endocrine, and exocrine in origin-mechanistically coalesce to facilitate T1D...
July 17, 2023: Cell Metabolism
Jee Hyung Sohn, Beste Mutlu, Pedro Latorre-Muro, Jiaxin Liang, Christopher F Bennett, Kfir Sharabi, Noa Kantorovich, Mark Jedrychowski, Steven P Gygi, Alexander S Banks, Pere Puigserver
Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis...
July 14, 2023: Cell Metabolism
Kim A Sjøberg, Casper M Sigvardsen, Abdiel Alvarado-Diaz, Nicoline Resen Andersen, Mark Larance, Randy J Seeley, Peter Schjerling, Jakob G Knudsen, Georgios Katzilieris-Petras, Christoffer Clemmensen, Sebastian Beck Jørgensen, Katrien De Bock, Erik A Richter
Growth differentiation factor 15 (GDF15) induces weight loss and increases insulin action in obese rodents. Whether and how GDF15 improves insulin action without weight loss is unknown. Obese rats were treated with GDF15 and displayed increased insulin tolerance 5 h later. Lean and obese female and male mice were treated with GDF15 on days 1, 3, and 5 without weight loss and displayed increased insulin sensitivity during a euglycemic hyperinsulinemic clamp on day 6 due to enhanced suppression of endogenous glucose production and increased glucose uptake in WAT and BAT...
July 12, 2023: Cell Metabolism
Xin Yang, Zhe Wang, Fereshteh Zandkarimi, Yanqing Liu, Shoufu Duan, Zhiming Li, Ning Kon, Zhiguo Zhang, Xuejun Jiang, Brent R Stockwell, Wei Gu
Here, we identified vitamin K epoxide reductase complex subunit 1 like 1 (VKORC1L1) as a potent ferroptosis repressor. VKORC1L1 protects cells from ferroptosis by generating the reduced form of vitamin K, a potent radical-trapping antioxidant, to counteract phospholipid peroxides independent of the canonical GSH/GPX4 mechanism. Notably, we found that VKORC1L1 is also a direct transcriptional target of p53. Activation of p53 induces downregulation of VKORC1L1 expression, thus sensitizing cells to ferroptosis for tumor suppression...
July 12, 2023: Cell Metabolism
Junpeng Yang, Xueli Yang, Guojun Wu, Fenglian Huang, Xiaoyang Shi, Wei Wei, Yingchao Zhang, Haihui Zhang, Lina Cheng, Lu Yu, Jing Shang, Yinghua Lv, Xiaobing Wang, Rui Zhai, Pan Li, Bota Cui, Yuanyuan Fang, Xinru Deng, Shasha Tang, Limin Wang, Qian Yuan, Liping Zhao, Faming Zhang, Chenhong Zhang, Huijuan Yuan
The pathogenic mechanisms underlying distal symmetric polyneuropathy (DSPN), a common neuropathy in patients with diabetes mellitus (DM), are not fully understood. Here, we discover that the gut microbiota from patients with DSPN can induce a phenotype exhibiting more severe peripheral neuropathy in db/db mice. In a randomized, double-blind, and placebo-controlled trial (ChiCTR1800017257), compared to 10 patients who received placebo, DSPN was significantly alleviated in the 22 patients who received fecal microbiota transplants from healthy donors, independent of glycemic control...
July 10, 2023: Cell Metabolism
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