White adipocyte dysfunction and obesity-associated pathologies in humans

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(4), P. 270 - 289

Published: Dec. 12, 2023

Language: Английский

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Inflammasomes in chronic liver disease: Hepatic injury, fibrosis progression and systemic inflammation

Journal of Hepatology, Journal Year: 2024, Volume and Issue: 81(5), P. 895 - 910

Published: June 20, 2024

Chronic liver disease leads to hepatocellular injury that triggers a pro-inflammatory state in several parenchymal and non-parenchymal hepatic cell types, ultimately resulting fibrosis, cirrhosis, portal hypertension failure. Thus, an improved understanding of inflammasomes - as key molecular drivers may result the development novel diagnostic or prognostic biomarkers effective therapeutics. In disease, innate immune cells respond insults by activating cell-intrinsic via toll-like receptors NF-κB, releasing cytokines (such IL-1β, IL-18, TNF-α IL-6). Subsequently, adaptive system are recruited fuel inflammation undergo gasdermin D-mediated programmed death, termed pyroptosis. With progression, there is shift towards type 2 inflammatory response, which promotes tissue repair but also fibrogenesis. Inflammasome activation occur at extrahepatic sites, such white adipose MASH (metabolic dysfunction-associated steatohepatitis). end-stage flares (e.g., severe alcohol-related hepatitis) spark on dysfunctional system, contribute inflammasome-mediated potentially organ dysfunction/failure, seen ACLF (acute-on-chronic failure). This review provides overview current concepts regarding inflammasome with focus related therapeutic approaches being developed for patients disease.

Language: Английский

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Thermogenesis in Adipose Tissue Activated by Thyroid Hormone

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(8), P. 3020 - 3020

Published: April 24, 2020

Thermogenesis is the production of heat that occurs in all warm-blooded animals. During cold exposure, there obligatory thermogenesis derived from body metabolism as well adaptive through shivering and non-shivering mechanisms. The latter mainly brown adipose tissue (BAT) muscle; however, white (WAT) also can undergo browning via adrenergic stimulation to acquire thermogenic potential. Thyroid hormone (TH) exerts profound effects on thermoregulation, decreased temperature increased occur during hypothyroidism hyperthyroidism, respectively. We have termed TH-mediated under thermoneutral conditions “activated” thermogenesis. TH acts and/or tissues induce uncoupled respiration induction uncoupling protein (Ucp1) generate heat. centrally activate BAT sympathetic nervous system. However, recent studies show peripherally directly stimulate Ucp1 expression an autophagy-dependent mechanism. Additionally, THs exert Ucp1-independent thermogenesis, most likely activation exothermic metabolic pathways. This review summarizes tissues.

Language: Английский

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Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue

Cell Death and Disease, Journal Year: 2020, Volume and Issue: 11(1)

Published: Jan. 23, 2020

Decreased expression of mitochondrial frataxin (FXN) causes Friedreich's ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is mitochondria-enriched and anti-diabetic that turns excess energy into heat to maintain metabolic homeostasis. Here we report the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced expenditure insulin sensitivity, elevated plasma leptin, recapitulating T2D-like signatures. deficiency leads disrupted ultrastructure oxygen consumption well lipid accumulation in BAT. Transcriptomic data highlights cold intolerance association iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis genes controlling metabolism, catabolism adipogenesis were observed BAT KIKO mice FXN-deficient T37i brown primary adipocytes. Significant susceptibility ferroptosis was adipocyte precursors showed increased peroxidation decreased glutathione peroxidase 4. Collectively our point dysfunction FRDA suggest promising therapeutic target overcome T2D FRDA.

Language: Английский

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Single-Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis

Cell Reports, Journal Year: 2020, Volume and Issue: 32(5), P. 107998 - 107998

Published: Aug. 1, 2020

Adipocytes deficient in fatty acid synthase (iAdFASNKO) emit signals that mimic cold exposure to enhance the appearance of thermogenic beige adipocytes mouse inguinal white adipose tissues (iWATs). Both and iAdFASNKO upregulate sympathetic nerve fiber (SNF) modulator Neuregulin 4 (Nrg4), activate SNFs, require adipocyte cyclic AMP/protein kinase A (cAMP/PKA) signaling for appearance, as it is blocked by Gsα deficiency. Surprisingly, however, contrast cold-exposed mice, neither iWAT denervation nor Nrg4 loss attenuated browning mice. Single-cell transcriptomic analysis stromal cells revealed increased macrophages displaying gene expression signatures alternately activated type their depletion abrogated beiging. Altogether, these findings reveal divergent cellular pathways are sufficient cause browning. Importantly, alternatively mice associated with enhanced thermogenesis independent neuron involvement this process requires cold.

Language: Английский

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Beyond Erectile Dysfunction: cGMP-Specific Phosphodiesterase 5 Inhibitors for Other Clinical Disorders

The Annual Review of Pharmacology and Toxicology, Journal Year: 2022, Volume and Issue: 63(1), P. 585 - 615

Published: Oct. 7, 2022

Cyclic guanosine monophosphate (cGMP), an important intracellular second messenger, mediates cellular functional responses in all vital organs. Phosphodiesterase 5 (PDE5) is one of the 11 members cyclic nucleotide phosphodiesterase (PDE) family that specifically targets cGMP generated by nitric oxide-driven activation soluble guanylyl cyclase. PDE5 inhibitors, including sildenafil and tadalafil, are widely used for treatment erectile dysfunction, pulmonary arterial hypertension, certain urological disorders. Preclinical studies have shown promising effects inhibitors myocardial infarction, cardiac hypertrophy, heart failure, cancer anticancer-drug-associated cardiotoxicity, diabetes, Duchenne muscular dystrophy, Alzheimer's disease, other aging-related conditions. Many clinical trials with focused on potential cardiovascular, anticancer, neurological benefits. In this review, we provide overview current state knowledge their therapeutic indications various disorders beyond dysfunction.

Language: Английский

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Signaling Pathways Regulating Thermogenesis

Frontiers in Endocrinology, Journal Year: 2021, Volume and Issue: 12

Published: March 26, 2021

Obesity, an excess accumulation of white adipose tissue (WAT), has become a global epidemic and is associated with complex diseases, such as type 2 diabetes cardiovascular diseases. Presently, there are no safe effective therapeutic agents to treat obesity. In contrast adipocytes that store energy triglycerides in unilocular lipid droplet, brown brown-like or beige utilize fatty acids (FAs) glucose at high rate mainly by uncoupling protein 1 (UCP1) action uncouple mitochondrial proton gradient from ATP synthesis, dissipating heat. Recent studies on the presence adult humans have revealed their potential targets combating Classically, main signaling pathway known activate thermogenesis β 3 -adrenergic signaling, which activated norepinephrine response cold, leading activation thermogenic program browning. addition numerous other hormones secreted factors been reported affect thermogenesis. this review, we discuss several major pathways, -adrenergic, insulin/IGF1, thyroid hormone TGFβ family, regulate browning WAT.

Language: Английский

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Of mice and men: Pinpointing species differences in adipose tissue biology

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: Sept. 15, 2022

The prevalence of obesity and metabolic diseases continues to rise, which has led an increased interest in studying adipose tissue elucidate underlying disease mechanisms. use genetic mouse models been critical for understanding the role specific genes function tissue’s impact on other organs. However, displays key differences human fat, led, some cases, emergence confounding concepts field. Such include depot-specific characteristics visceral subcutaneous divergences thermogenic fat phenotype between species. Adipose may therefore not always be directly compared species, is important consider when setting up new studies or interpreting results. This mini review outlines our current knowledge about cell biological adipocytes depots, highlighting examples where inadequate species-specific can lead results, presenting plausible anatomic explanations that underlie differences. article thus provides insights guidance researchers working primarily with only tissue, contribute ideas evolving field biology.

Language: Английский

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Regulatory microRNAs in Brown, Brite and White Adipose Tissue

Cells, Journal Year: 2020, Volume and Issue: 9(11), P. 2489 - 2489

Published: Nov. 16, 2020

MicroRNAs (miRNAs) constitute a class of short noncoding RNAs which regulate gene expression by targeting messenger RNA, inducing translational repression and RNA degradation. This regulation miRNAs in adipose tissue (AT) can impact on the metabolism energy homeostasis, particularly considering different types adipocytes exist mammals, i.e., white (white AT; WAT), brown (brown BAT), inducible WAT (beige or brite brown-in-white adipocytes). Indeed, an increasing number has been identified to key signaling pathways adipogenesis BAT, AT, acting transcription factors that promote inhibit adipocyte differentiation. For example, MiR-328, MiR-378, MiR-30b/c, MiR-455, MiR-32, MiR-193b-365 activate adipogenesis, whereas MiR-34a, MiR-133, MiR-155, MiR-27b are inhibitors. Given mainly stores as lipids, whilst BAT dissipates heat, clarifying effects AT recently attracted significant research interest, aiming also develop novel miRNA-based therapies against obesity, diabetes, other obesity-related diseases. Therefore, this review presents up-to-date comprehensive overview role regulatory WAT.

Language: Английский

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The NLRP3 inflammasome regulates adipose tissue metabolism

Biochemical Journal, Journal Year: 2020, Volume and Issue: 477(6), P. 1089 - 1107

Published: March 23, 2020

Adipose tissue regulates metabolic homeostasis by participating in endocrine and immune responses addition to storing releasing lipids from adipocytes. Obesity skews adipose adipokine degrades the coordination of adipocyte lipogenesis lipolysis. These defects metabolism can promote ectopic lipid deposition inflammation insulin-sensitive tissues such as skeletal muscle liver. Sustained caloric excess expand white a point maladaptation exacerbating both local systemic inflammation. Multiple sources, instigators propagators occur during obesity. Cross-talk between professional cells (i.e. macrophages) adipocytes) stress metaflammation). Metabolic endogenous danger signals engage pathogen recognition receptors (PRRs) innate system thereby activating pro-inflammatory pathways tissue. The Nod-like receptor protein 3 (NLRP3) inflammasome act sensor wide range pathogen- damage-associated molecular patterns (PAMPs DAMPs). Activation NLRP3 facilitates caspase-1 dependent production cytokines IL-1β IL-18. pyroptotic cell death, but is also involved adipogenesis. This review discusses role immunometabolism relevant disease. Understanding potential sources activation consequences effectors may reveal therapeutic opportunities break or fine-tune connection

Language: Английский

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