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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Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome

Journal of Clinical Investigation, Journal Year: 2019, Volume and Issue: 129(10), P. 3990 - 4000

Published: Sept. 30, 2019

Over the past decade, great progress has been made in understanding complexity of adipose tissue biology and its role metabolism. This includes new insights into multiple layers heterogeneity, not only differences between white brown adipocytes, but also at depot level even heterogeneity adipocytes within a single depot. These inter- intra-depot are developmentally programmed contribute to wide range effects observed disorders with fat excess (overweight/obesity) or loss (lipodystrophy). Recent studies highlight underappreciated dynamic nature tissue, including potential undergo rapid turnover dedifferentiation as source stem cells. Finally, we explore rapidly expanding field an endocrine organ, how communicates other tissues regulate systemic metabolism both centrally peripherally through secretion adipocyte-derived peptide hormones, inflammatory mediators, signaling lipids, miRNAs packaged exosomes. Together these attributes complexities create robust, multidimensional network that is central metabolic homeostasis.

Language: Английский

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Metabolic Inflammation and Insulin Resistance in Obesity

Circulation Research, Journal Year: 2020, Volume and Issue: 126(11), P. 1549 - 1564

Published: May 21, 2020

Obesity is becoming an epidemic in the United States and worldwide increases risk for many diseases, particularly insulin resistance, type 2 diabetes mellitus, cardiovascular disease. The mechanisms linking obesity with these diseases remain incompletely understood. Over past to 3 decades, it has been recognized that obesity, inflammation, increased accumulation inflammatory polarization of immune cells, takes place various tissues, including adipose tissue, skeletal muscle, liver, gut, pancreatic islet, brain may contribute obesity-linked metabolic dysfunctions, leading resistance mellitus. Therapies targeting inflammation have shed light on certain mellitus atherosclerotic disease, but be tested further confirmed clinical trials. This review focuses tissue its potential role associated obesity.

Language: Английский

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Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade

Hepatology, Journal Year: 2020, Volume and Issue: 73(2), P. 833 - 842

Published: Aug. 12, 2020

Nonalcoholic fatty liver disease (NAFLD) is an epidemic disease, affecting approximately one quarter of the entire population in world.(1) This encompasses a broad spectrum clinical phenotypes ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrotic NASH, advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Although inflammation NAFLD appears less prognostically relevant when compared fibrosis,(2) latter may be cumulative result former.(3) Noninvasive assessment fibrosis (e.g., by transient elastography) has reduced need for invasive procedures such as biopsy,(4) although late-stage trials still require histologic endpoints. The plays crucial role glucose lipid metabolism. frequently present obesity reflects risk factor many metabolic diseases type 2 diabetes (T2D).(5) In turn, T2D associated with up 90% patients. been linked various extrahepatic disorders cardiovascular complications(6) chronic kidney disease.(7) Furthermore, not only major HCC but also increased rate malignancies gastrointestinal gynecological malignancies.(4) cancer seems even higher than itself.(8) As such, prototypic systemic disorder targeting organs throughout body. pathophysiology underlying this complex incompletely understood. A decade ago, we proposed multiple parallel hits hypothesis which lipotoxicity adipose tissue (AT) alterations gut microbial functions contribute evolution NAFLD.(9) Progress over last was substantial that AT inflammation(10) microbiome (and related metabolites) evolved players pathogenesis NAFLD.(11, 12) dietary components other proinflammatory potential have identified. Finally, genetic pathways play manifestation; several hits, patatin-like phospholipase domain containing 3, transmembrane 6 superfamily member 2, glucokinase regulator, membrane-bound O-acyltransferase 7, hydroxysteroid 17-beta dehydrogenase 13, are involved especially metabolism.(13) review, will discuss pathophysiological factors focusing on intricate triangular interplay between tract, AT, liver. Normal composed adipocytes, fibroblasts, endothelial cells, resident macrophages cells immune system collectively regulate host metabolism energy storage.(14) White depots comprise visceral (VAT) subcutaneous (SAT), which, together liver, participate acid health, communicates control homeostasis.(15) obesity, characterized cytokine chemokine expression infiltration example, leukocytes, serve fuel local inflammation. inflammatory state contributes inflammation, deteriorate insulin resistance, exemplifying aspects AT–liver axis.(9, 10) hallmarks influx macrophages, cluster differentiation 4–positive (CD4+) CD8+ T dendritic natural killer (NK) cytokines/chemokines.(16) Primary cues remain poorly explored arguably involve diet-induced stress subsequently induces response cell infiltration. initial fueled self-maintained tissue-infiltrating cells. For recruitment (ATMs) dependent chemokines C-C motif ligand (CCL2), expressed obese animals patients.(17) Adaptive immunity cells) recruited antigen-presenting precedes ATM accumulation.(18) Expression (besides CCL2) CCL5 (also known regulated upon activation, normal expressed, secreted) or CCL13 patients.(19) Importantly, most these cytokines tumor necrosis alpha (TNFα), interleukin 1-beta (IL-1β), IL-6. TNFα first described adipokine obesity-related resistance murine models, its human obesity.(20) Similarly, preclinical evidence indicated key IL-1β IL-1α-deficient, IL-1β-deficient, 1 IL-1 receptor–deficient mice protected against high-fat diet–induced resistance(21); expression.(22) IL-37, anti-inflammatory family member, highly subjects able improve experimental models.(23, 24) IL-6 produced mostly ATMs adipocytes.(25) importance SAT source circulating convincingly demonstrated, 15%-35% being derived tissue.(26) Both VAT produce large amounts disorders, both sources biologically affect sensitivity.(27) We investigated morbidly patients undergoing bariatric surgery. TNFα, IL-1β, IL-6, strongly after successful weight loss.(23, 28) adiponectin leptin (prototypic immunomodulatory adipokines) critically disorders.(29) Collectively, studies highlight cellular, cytokine, adipokine. networks (see Fig. 1). Clinical provide cellular molecular correlate degree disease. Du Plessis colleagues studied transcriptomic profiles VAT, functional characteristics ATMs, severity 113 surgery.(30) They found genes comparing NASH. NASH exhibited number CD11c+CD206+ (C-C motif) receptor–positive accompanied release chemokines. Most importantly, directly correlated inflammation.(30) study investigating 3,197 participants observed independently obesity.(31) no proof concept NAFLD, they clearly link light (mechanistic) report axis disorders. Insulin hallmark NAFLD,(32) occurs tissues muscle, AT.(33) While it commonly conceived emerges consequent recent demonstrated through monocyte chemoattractant protein 1–regulated leukocyte recruitment.(34) These findings interesting accelerates lipolysis mitogen-activated kinase (MAPK) signaling, results activation ß3-adrenergic receptor.(35) Lipolysis enhanced free export promoting potentially NAFLD. line this, correlates (especially fibrosis); improvement pioglitazone, peroxisome proliferator–activated receptor-gamma agonist, resulted decrease hepatocyte ballooning patients.(36) Indeed, NAFLD.(37) study, authors established macrophage measuring soluble CD183, proposing acids might involved. support crosstalk aforementioned notable, descriptive can indirect mammals. Bijnen transplanted lean, obese, ATM-depleted lean Ldr−/− mice.(38) transplantation injury pronounced AT. Liver paralleled numbers neutrophils, effect mainly attributed synthesis neutrophil chemotaxis proteins (C-X-C ligands 14 16 ATM.(38) previously hypothesized tissue-specific knockout (KO) models AT-specific KO mice) would reveal numerous reported took advantage adipocyte-specific mouse models; few discussed here. deletion receptor and/or insulin-like growth severe lipodystrophy progressive resembling dysplastic nodules at week 52.(39) Lipid peroxidation critical mechanism model.(39) deficiency hormone-sensitive lipase causes increase lipodystrophy, impaired synthesis, resistance.(40) contrast, lipoprotein angiopoietin-like 4 (which controls metabolism) attenuates steatosis, atherosclerosis.(41) shown I interferon worsens perturbation, gain, intolerance.(42) However, did impact our model. indicate specific hubs deserve dissected more detail. Various impinge gut–liver axis. shaped metabolites hormones system.(43) section made deciphering intestinal microbiota identification NASH-associated signature,(44) preceded smaller NAFLD.(45) abundance Proteobacteria, Enterobacteriaceae, Escherichia coli differed microbiomes(45); association Bacteroidetes simple healthy controls.(46) Boursier histology-proven 57 patients.(47) Bacteroides depending while Prevotella decreased. convincing example signature comes Loomba colleagues.(44) 86 histologically defined identified 37 bacterial species, allowed them distinguish mild versus fibrosis. Advanced Proteobacteria Firmicutes Faecalibacterium prausnitzii. Such prevalent case cirrhosis.(48) An important bacteria-derived endotoxin disease-contributing had claimed already 20 years ago.(49) confirmed presence livers. Patients concentrations similar accumulation hepatocytes, toll-like macrophages.(50) Further intrahepatic another reporting portal tract.(51) Experimental endotoxin-producing strains Enterobacter cloacae B29, PY102, Klebsiella pneumoniae A7 promoted germ-free diet.(52) Moreover, ethanol-producing isolated caused oral gavaging.(53) Due space constraints, do barrier NAFLD.(54) Vice versa, modulate susceptibility excellently reviewed recently(55) conclusion, overwhelming underpins very exciting rapidly evolving topic (i.e., AT) blood) expands beyond dysbiosis Bacterial 16S ribosomal DNA indeed detected blood, diabetes,(56) blood NAFLD.(57) tissue, material taxa two cohorts NAFLD.(51) Sookoian colleagues(51) severely (similar microbiome). different including solid cancers,(58) T2D, obesity.(59) reminiscent omental, SAT, subjects.(60) Schierwagen central, hepatic, venous peripheral cirrhosis receiving transjugular portosystemic shunt(61); some bacteria could cultivated sites. and, cases, live circulation diseased liver/AT. implications health describe compelling window opportunity research were considered sterile. Metagenomic sequencing metabolite screens (metabolomics) allow insight into repertoire communities. metabolomics recently.(12) Hoyles plasma urine metabolome, fecal metagenome bacteria), transcriptome transcriptional profile) women.(62) phenylacetate) steatosis. Fecal transfer women high-grade feeding phenylacetate mice.(62) search vein dysfunction, Koh discovered imidazole propionate, microbially histidine-derived metabolite.(63) metabolite, propionate affected signaling p38 MAPK phosphorylation p62, finally mechanistic target rapamycin.(63) Levels N,N,N-trimethyl-5-aminovaleric acid, bacteria, serum NAFLD; deteriorated steatosis.(64) Other 3-(4-hydroxphenyl)lactate discriminated without unknown.(65) combination 10 showed powerful discriminatory effects detecting greater diagnostic accuracy Fibrosis-4 index.(66) increasingly recognized intestine, Future fascinating insights bears therapeutic) use. Besides pathways, interactions. Colonic sensitivity under diet.(67) By generating macrophage-specific epithelium–specific mice, decreased colonic permeability, improved tolerance, highlighting gut–AT axis.(67) Interestingly, products commensal L-lactate acetate enterocyte altered storage oxidation.(68) distal effects, influencing lipid-driven atherosclerosis Many exert development NAFLD.(69) Dietary metabolism(70) act microbiome, referred "dysbiosis."(71) so far damage Western diet high fat consumption intake alcohol, salt, refrained grains, fructose, red processed meat developing progressing NAFLD.(69, 72) volunteers endotoxemia low-grade inflammation.(73) Trans-fatty unsaturated vegetables enriched snack foods, fried margarines. Intake trans-fat negatively all-cause mortality coronary heart mortality.(74) well studied. Trans-fat single function tests index.(75) Preclinical data propose trans-fats promote cholesterogenesis,(76) trans-fat-induced if trans-fatty deleted pool, exact mechanisms elusive.(77) Fructose fibrosis.(78) triggers de novo lipogenesis process involves microbiota-derived acetate.(79) subjects, however, excess isocaloric fructose 8 weeks detrimental liver.(80) raises doubts whether damages Wheat amylase trypsin inhibitors, common wheat component, activates macrophages(81) aggravates inflammation.(82) converts nutrients choline carnitine trimethylamine, metabolized flavin monooxygenases trimethylamine N-oxide (TMAO),(83) discontinuation TMAO levels within weeks.(84) Numerous diseases.(85) relationship trial 60 biopsy-proven lower betaine betaine/choline ratio.(86) Administration diet, involving bile farnesoid X antagonism.(87) Therefore, food thereby initiate processes outside tract. oppose above-described pool metabolites. indole, tryptophan derivate microbiota, improves mice; low NAFLD.(88) interventional using either low-sugar diet,(89) carbohydrate-restricted diet,(90) Mediterranean diet(91) beneficial defined. intervention promising strategy treat future.(69) decade, tract emerged drivers Despite fact pathogenesis, randomized controlled specifically lacking. Altered involving, NAFLD.(92) Interactions bidirectional, experiments transgenic exemplified plethora define loss behind metabolism.(33, 54, 93) corroborated 2010 hypothesis,(9) forming based gained animal trials. better understanding translation novel therapeutics endemic gratefully acknowledge Austrian Federal Ministry Science, Research, Economy National Foundation Technology, Development. All contributions discussion content wrote, edited article.

Language: Английский

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Obese visceral fat tissue inflammation: from protective to detrimental?

BMC Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: Dec. 27, 2022

Abstract Obesity usually is accompanied by inflammation of fat tissue, with a prominent role visceral fat. Chronic in obese tissue lower grade than acute immune activation for clearing the from an infectious agent. It loss adipocyte metabolic homeostasis that causes resident cells supporting functions and regaining homeostasis. Initially, excess influx lipids glucose context overnutrition met growth proliferation. Eventual lipid overload hypertrophic adipocytes leads to endoplasmic reticulum stress secretion variety signals causing increased sympathetic tone, lipolysis adipocytes, uptake macrophages, matrix remodeling, angiogenesis, cell activation. Pro-inflammatory signaling system release amounts pro-inflammatory other mediators resulting enhanced tissue-protective responses. With chronic overnutrition, these protective actions are insufficient, death as well senescence several types seen. This structural damage expression or immunostimulatory components monocytes many types, contribution stromal cells. Matrix remodeling angiogenesis further intensified possibly detrimental fibrosis. The accumulation senescent also may be via eventual spread state affected neighboring microRNA-containing vesicles. Obese can viewed initially response order cope ambient nutrients restore but contribute at later stage.

Language: Английский

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Female reproductive life span is extended by targeted removal of fibrotic collagen from the mouse ovary

Science Advances, Journal Year: 2022, Volume and Issue: 8(24)

Published: June 17, 2022

The female ovary contains a finite number of oocytes, and their release at ovulation becomes sporadic disordered with aging obesity, leading to loss fertility. Understanding the molecular defects underpinning this pathology is essential as age childbearing obesity rates increase globally. We identify that fibrosis within ovarian stromal compartment an underlying mechanism responsible for impaired oocyte release, which initiated by mitochondrial dysfunction diminished bioenergetics, oxidative damage, inflammation, collagen deposition. Furthermore, antifibrosis drugs (pirfenidone BGP-15) eliminate fibrotic restore in reproductively old obese mice, association dampened M2 macrophage polarization up-regulated MMP13 protease. This first evidence reversible indicates targeting metabolism may be viable therapeutic strategy women metabolic disorders or advancing maintain function extend

Language: Английский

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Extracellular Matrix (ECM) and Fibrosis in Adipose Tissue: Overview and Perspectives

Comprehensive physiology, Journal Year: 2023, Volume and Issue: unknown, P. 4387 - 4407

Published: Jan. 30, 2023

Fibrosis in adipose tissue is a major driver of obesity-related metabolic dysregulation. It characterized by an overaccumulation extracellular matrix (ECM) during unhealthy expansion response to over nutrition. In obese adipose-depots, hypoxia stimulates multiple pro-fibrotic signaling pathways different cell populations, thereby inducing the overproduction ECM components, including collagens, noncollagenous proteins, and additional enzymatic components synthesis. As consequence, local fibrosis develops. The result fibrosis-induced mechanical stress not only triggers necrosis inflammation locally but also leads system-wide lipotoxicity insulin resistance. A better understanding mechanisms underlying obesity-induced will help design therapeutic approaches reduce or reverse pathological changes associated with tissue. Here, we aim summarize advances field, which include newly identified fibrotic factors, populations that contribute tissue, as well novel development fibrosis. We further discuss potential strategies target for treatment obesity-linked diseases cancer. © 2023 American Physiological Society. Compr Physiol 13:4387-4407, 2023.

Language: Английский

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Enhancing adipose tissue plasticity: progenitor cell roles in metabolic health

Nature Reviews Endocrinology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 6, 2025

Language: Английский

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Decellularized extracellular matrix scaffolds identify full-length collagen VI as a driver of breast cancer cell invasion in obesity and metastasis

Science Advances, Journal Year: 2020, Volume and Issue: 6(43)

Published: Oct. 21, 2020

The extracellular matrix (ECM), a major component of the tumor microenvironment, promotes local invasion to drive metastasis. Here, we describe method study whole-tissue ECM effects from disease states associated with metastasis on cell phenotypes and identify individual proteins signaling pathways that are driving these effects. We show decellularized tumor-bearing obese mammary glands drives TNBC invasion. Proteomics gland led us full-length collagen VI as novel driver whose abundance in stroma increases body mass index human patients. Last, mechanism by which contributes via NG2-EGFR cross-talk MAPK signaling. Overall, studies demonstrate value scaffolds obtained tissues functions ECM.

Language: Английский

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Adipose Tissue Fibrosis: Mechanisms, Models, and Importance

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(17), P. 6030 - 6030

Published: Aug. 21, 2020

Increases in adipocyte volume and tissue mass due to obesity can result inflammation, further dysregulation adipose function, eventually fibrosis. Like other fibrotic diseases, fibrosis is the accumulation increased production of extracellular matrix (ECM) proteins. Adipose has been linked decreased insulin sensitivity, poor bariatric surgery outcomes, difficulty weight loss. With rising rates obesity, it important create accurate models for gain mechanistic insights develop targeted treatments. This article discusses recent research modeling using vivo vitro (2D 3D) methods with considerations biomaterial selections. Additionally, this outlines importance treating diseases used detect characterize

Language: Английский

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