New Advances in Adaptive Thermogenesis: UCP1 and Beyond

Cell Metabolism, Journal Year: 2018, Volume and Issue: 29(1), P. 27 - 37

Published: Nov. 29, 2018

Language: Английский

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Adipose-tissue plasticity in health and disease

Cell, Journal Year: 2022, Volume and Issue: 185(3), P. 419 - 446

Published: Feb. 1, 2022

Language: Английский

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The cellular and functional complexity of thermogenic fat

Nature Reviews Molecular Cell Biology, Journal Year: 2021, Volume and Issue: 22(6), P. 393 - 409

Published: March 23, 2021

Language: Английский

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Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues

Nutrients, Journal Year: 2018, Volume and Issue: 10(10), P. 1383 - 1383

Published: Sept. 29, 2018

De novo lipogenesis (DNL) is a complex and highly regulated process in which carbohydrates from circulation are converted into fatty acids that then used for synthesizing either triglycerides or other lipid molecules. Dysregulation of DNL contributes to human diseases such as obesity, type 2 diabetes, cardiovascular diseases. Thus, the lipogenic pathway may provide new therapeutic opportunity combating various pathological conditions associated with dysregulated metabolism. Hepatic has been well documented, but adipocytes its contribution energy homeostasis insulin sensitivity less studied. Recent reports have gained significant insights signaling pathways regulate transcription factors role adipose tissues. In this review, we will update current knowledge white brown tissues focus on transcriptional, post-translational, central regulation DNL. We also summarize recent findings adipocyte source some molecules critically

Language: Английский

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Metabolic adaptation and maladaptation in adipose tissue

Nature Metabolism, Journal Year: 2019, Volume and Issue: 1(2), P. 189 - 200

Published: Jan. 9, 2019

Language: Английский

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Brown Adipose Tissue Energy Metabolism in Humans

Frontiers in Endocrinology, Journal Year: 2018, Volume and Issue: 9

Published: Aug. 7, 2018

The demonstration of metabolically active brown adipose tissue (BAT) in humans primarily using positron emission tomography coupled to computed (PET/CT) with the glucose tracer 18-fluorodeoxyglucose (18FDG) has renewed interest scientific and medical community possible role BAT as a target for prevention treatment obesity type 2 diabetes (T2D). Here, we offer comprehensive review energy metabolism humans. Considerable advances methods measure metabolism, including nonesterified fatty acids (NEFA), chylomicron-triglycerides (TG), oxygen, Krebs cycle rate, intracellular TG have led very good quantification substrate per volume vivo. These studies also shown that are likely primary source upon activation by cold. Current estimates BAT's contribution expenditure range at lower end what would be potentially clinically relevant if chronically sustained. Yet, 18FDG PET/CT remains gold-standard defining method quantify total activity, used calculate expenditure. Unfortunately, better reflects insulin sensitivity blood flow. It is now clear most taken up does not fuel mitochondrial oxidative uptake can therefore disconnected from thermogenesis. Furthermore, thermogenesis efficiently recruited repeated cold exposure, doubling tripling its capacity, reciprocal reduction muscle Recent data suggest may much larger than typically observed 50 150 ml PET/CT. Therefore, current thermogenesis, largely relying on PET/CT, underestimate true Quantification begs development more integrated whole body vivo methods.

Language: Английский

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Lipid droplet‐dependent fatty acid metabolism controls the immune suppressive phenotype of tumor‐associated macrophages

EMBO Molecular Medicine, Journal Year: 2019, Volume and Issue: 11(11)

Published: Oct. 10, 2019

Article10 October 2019Open Access Source Data Lipid droplet-dependent fatty acid metabolism controls the immune suppressive phenotype of tumor-associated macrophages Hao Wu The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China Medical Department for Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member Freie Universität Humboldt-Universität zu Berlin Institute Health, Germany Biology, Chemistry, Pharmacy, Search more papers by this author Yijie Han University Chinese Academy Sciences, Beijing, Key Laboratory Protein Peptide Pharmaceuticals, Biophysics, Yasmina Rodriguez Sillke Nutritional Science, Potsdam, Nuthetal, Hongzhang Deng Polymer Science Engineering, Systems, Bioengineering (Ministry Education), School Chemical Engineering Technology, Tianjin Tianjin, Sophiya Siddiqui Christoph Treese Health (BIH), Franziska Schmidt Marie Friedrich Jacqueline Keye Jiajia Wan Yue Qin orcid.org/0000-0001-9793-7964 National Center Nanoscience Anja A Kühl iPATH.Berlin – Core Unit Charité, Zhihai Corresponding Author [email protected] Britta Siegmund Rainer Glauben orcid.org/0000-0003-2889-2525 Information Wu1,2,3, Han4,5, Sillke2,6, Deng7, Siddiqui2,3, Treese2,8, Schmidt2,3, Friedrich2,3, Keye2,3, Wan1, Qin9, Kühl10, *,1, Siegmund2,‡ *,2,‡ 1The 2Medical 3Department 4University 5Key 6Institute 7Department 8Berlin 9National 10iPATH.Berlin ‡These authors contributed equally to work ‡[Correction added on 13 November 2019, after first online publication: affiliations have been corrected.] *Corresponding author. Tel: +86 371 6691 3632; E-mail: +49 30 4505 14343; EMBO Mol Med (2019)11:e10698https://doi.org/10.15252/emmm.201910698 PDFDownload PDF article text main figures. Peer ReviewDownload a summary editorial decision process including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Tumor-associated (TAMs) promote tumor growth metastasis suppressing surveillance. Herein, we provide evidence that immunosuppressive TAMs is controlled long-chain metabolism, specifically unsaturated acids, here exemplified oleate. Consequently, en-route enriched lipid droplets were identified as essential organelles, which represent effective targets chemical inhibitors block in vitro polarization vivo. In line, analysis human tumors revealed myeloid cells infiltrating colon cancer but not gastric tissue indeed accumulate droplets. Mechanistically, our data indicate oleate-induced depends mammalian target rapamycin pathway. Thus, findings reveal an alternative therapeutic strategy targeting pro-tumoral metabolic level. Synopsis are regulatory cell type stroma well microenvironment. This study describes how acids polarize metabolism. acid-enriched environment itself was sufficient induce TAMs, up-regulation classical markers like CD206, IL-6, VEGFα, MMP9 or Arg1. acid-induced TAM droplet dependent. mTORC2 activation played critical role generation phenotype. Cell-specific inhibition DGAT1 2 prevented into murine culture systems vivo model. Introduction Reprogramming pathways guarantees viability proliferative capacity nutrient-poor (Pavlova Thompson, 2016). These alterations include aerobic glycolysis (termed Warburg effect; Warburg, 1956), increased glutamine uptake (Eagle, 1955), amplified de novo synthesis (Currie et al, 2013). Additionally, cell-derived metabolites shown contribute harsh microenvironment (Anderson 2017). previous studies already indicated decades ago stromal prefer export resulting niche (Spector, 1967). abundant population multi-cellular fact, infiltration differentiation correlate positively with all stages progression (Noy Pollard, 2014). Characterized M2-like macrophages, exert multiple properties. only hamper anti-tumor via regulating T NK apoptosis, also facilitate angiogenesis (Lin 2007; Gajewski 2013; Yeo Accordingly, macrophage-targeting therapies led positive results models. Clodronate-liposome-mediated abrogation example, resulted limited xenograft model (Zeisberger 2006). Furthermore, macrophage recruitment, instance, CCR2 silencing, followed significant development both solid hematologic models (Leuschner 2011; Lesokhin 2012). However, strategies still early (Cook Hagemann, Previous distinct pathway between pro- anti-inflammatory macrophages. Activated pro-inflammatory rely meet rapid energy consumption, while alternatively activated use oxidation (Biswas Mantovani, 2012; Galván-Peña O'Neill, Considering propose extracellular monocytes Here, found especially bone marrow-derived robust capacity. (LDs) play catabolism free (FFA) mitochondrial respiration. Mammalian (mTOR) eliminates LD-derived respiration therefore suppression, indicating mTOR signaling process. intra-tumoral injection LD-associated specific disruption LD formation liposome-mediated delivery system attenuated Finally, patients confirmed correlation accumulation LDs clinical stage tumor. Our novel mechanism escape from Results Oleate-induced regulates Previously, Gr1−CD11b+ subset within oleate-polarized potent T-cell presence granulocyte–macrophage colony-stimulating factor (GM-CSF; show promotes (Appendix Fig S1). To characterize population, acid-treated sorted analyzed microarray (Fig 1), included further Gene Ontology (GO) Table Interestingly, expression level differentially expressed genes stearate-treated close bovine serum albumin (BSA) control group, differed significantly oleate-treated unique effect oleate stearate 1A). As expected, core associated desaturation, Fasn Fads2, Fads3 Scd1 were, down-regulated 1B) when external source. Remarkably, formation-related genes, Dgat1 Agpat9, up-regulated. GM-CSF could functionally dendritic (DC) vitro, DC signature first: out 24 overlapping transcripts them group compared BSA 1B; Miller Essential transcription factors Flt3 Btla regulate maturation DCs down-regulated. Hence, concluded potently suppresses GM-CSF-induced transcriptional Former Herber al (2010) containing failed present antigen. Indeed, 14 MHCII complex-associated Ciita, master regulator expression, either treatment GO term Go: 42613; 2504), flow cytometry 1C). contrast DCs, five mature expressed, three up-regulated (Gautier From these data, that, following treatment, exhibits immature Flow staining F4/80 CD11b addition, innate response-associated Oas1a, Oas2, Oas3, Ifi202b, Irf7, Tlr9, down-regulated, deficiency response (Fuertes cluster TAM-associated surface marker Mrc1, M2 phenotyping Arg1, Retnla, Chil3, functional Vegfa Mmp9 1B). An conventional CD206+ arginase activity detected cytometry, mRNA Recently inhibitory cells, CD38 CD73 (Beavis Karakasheva 2015), elevated determined during differentiation, alone phenotypical Figure 1. Oleate polarizes A. Bone marrow polarized 40 ng/ml treated 0.2 mM compounds 7 days. lysed microarray. hierarchical clustering based different (Con) group. B, C. Signature involved maturation, phenotype, complex, listed (B) validated (C) catalytic assay. mean ± SD two four independent experiments. Unpaired Student's two-tailed t-tests performed compare proteins groups. *P < 0.05; **P ≤ 0.01. Download figure PowerPoint Prostaglandin E2 (PGE2) acts malignancy niches (Torroella-Kouri 2009). ptgs1 (COX1), producer PGE2 eukaryotes. wondering whether COX1 contributes cells. Myeloid celecoxib, inhibitor COX1, effectively impaired function through diminishing nitric oxide (NO) production S2A B). CD38, did alter, downstream cascade S2C). Fatty required membrane consumption purified increase respiratory under quiescent stressed conditions 2A), basal oxygen spare capacity, maximal respiration, adenosine triphosphate (ATP) production, proton leak. contrast, glycolysis, defined acidification rate (ECAR), alter 2B). determine contribution etomoxir applied carnitine palmitoyltransferase 1 (CPT1), enzyme outer transfers acyl coenzyme carnitine, transport matrix (Yao 2018). it has published high concentrations (100 μM) directly impair decreasing concentration CoA cytosol inhibiting complex I (Divakaruni 2018; Yao (40 reduction both, 2C D). Simultaneously, exerted comprehensive effects, 2E F), proliferation NO 2G–I), confirming vital driving David E. Sanin proved recently functions negative modulating malate–aspartate shuttle, thus explaining, why affect (Sanin Stearoyl-CoA desaturase-1 (SCD1) plays crucial endogenous acids. SCD1 CAY10566 served estimate TAMs. hampered compensatory S3). summary, acid-derived maintains vitro. 2. A, B. detection. (OCR) monitored addition oligomycin (OA; μM), carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP, electron rotenone antimycin (R/AA; 0.5 at time points. OCR, leak, ATP OCR value quantified. C, D. Forty micromolar starting day 0 polarization, assay using same amount 7. XFe96 Analyzer. E, F. Exemplary plots proportion fluorescence intensity (MFI) cytometry. G–I. co-culture CD4+ ratios M (myeloid cells): (T cells) = 1:30 (G, H). (I) Nitric supernatant quantified Griess reaction. information: experiments one-way variance (ANOVA) two-way ANOVA Tukey's post hoc test (D, F, H, I). 0.01; ***P 0.001. available figure. [emmm201910698-sup-0002-SDataFig2.xlsx] droplet-derived demonstrated intimate enrichment MSC-2 line primary (Wu proposed act stable source maintain Diacylglycerol O-acyltransferase (DGAT) responsible import FFAs LDs, lipases adipose triglyceride lipase (ATGL), hormone-sensitive (HSL), monoacylglycerol (MAGL) depletion upon activation. Therefore, ATGL HSL translocate cleave stored triglycerides degradation LDs. MAGL converts monoacylglycerols FFA glycerol (Smirnova 2006; Wang 2009; Nomura 2010; 3A). We uncovered activities DGAT, ATGL, 3B), CD206 their 3C–F). fact contributing 3. utilization Five combination DGAT (DGAT1 A922500 DGAT2 PF-06424439), μM atglistatin (Atg), 5 MJN110 × 105 described ECAR (extracellular rate), state evaluated CD206. employing variant ratios. BODIPY staining. percentage divided index calculated. co

Language: Английский

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Brown adipose tissue whitening leads to brown adipocyte death and adipose tissue inflammation

Journal of Lipid Research, Journal Year: 2018, Volume and Issue: 59(5), P. 784 - 794

Published: Jan. 1, 2018

In mammals, white adipose tissue (WAT) stores and releases lipids, whereas brown (BAT) oxidizes lipids to fuel thermogenesis. obese individuals, WAT undergoes profound changes; it expands, becomes dysfunctional, develops a low-grade inflammatory state. Importantly, BAT content activity decline in subjects, mainly as result of the conversion adipocytes white-like unilocular cells. Here, we show that "whitening" is induced by multiple factors, including high ambient temperature, leptin receptor deficiency, β-adrenergic signaling impairment, lipase each which capable inducing macrophage infiltration, adipocyte death, crown-like structure (CLS) formation. Brown-to-white increased CLS formation were most marked from triglyceride (Atgl)-deficient mice, where, according transmission electron microscopy, whitened contained enlarged endoplasmic reticulum, cholesterol crystals, some degenerating mitochondria, surrounded an number collagen fibrils. Gene expression analysis showed whitening Atgl-deficient mice was associated strong response NLRP3 inflammasome activation. Altogether, present findings suggest converted are highly prone which, promoting inflammation BAT, may contribute typical state seen obesity.

Language: Английский

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Lipolysis in Brown Adipocytes Is Not Essential for Cold-Induced Thermogenesis in Mice

Cell Metabolism, Journal Year: 2017, Volume and Issue: 26(5), P. 764 - 777.e5

Published: Oct. 11, 2017

Language: Английский

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Mechanisms of insulin resistance related to white, beige, and brown adipocytes

Molecular Metabolism, Journal Year: 2020, Volume and Issue: 34, P. 27 - 42

Published: Jan. 7, 2020

The diminished glucose lowering effect of insulin in obesity, called "insulin resistance," is associated with intolerance, type 2 diabetes, and other serious maladies. Many publications on this topic have suggested numerous hypotheses the molecular cellular disruptions that contribute to syndrome. However, significant uncertainty remains mechanisms its initiation long-term maintenance. To simplify resistance analysis, review focuses unifying concept adipose tissue a central regulator systemic homeostasis by controlling liver skeletal muscle metabolism. Key aspects function related reviewed are: 1) modes which specific tissues control hepatic output disposal, 2) recently acquired understanding underlying these regulation, 3) steps pathways adversely affected obesity cause resistance. Adipocyte heterogeneity required mediate multiple tolerance. White adipocytes specialize sequestering triglycerides away from liver, muscle, limit toxicity. In contrast, brown/beige are very active directly taking up response β adrenergic signaling enhancing energy expenditure. Nonetheless, white, beige, brown all share common feature secreting factors possibly exosomes act distant homeostasis. Obesity exerts deleterious effects each adipocyte functions

Language: Английский

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