Autoinflammatory diseases are a heterogenous group of disorders defined by fever and systemic inflammation suggesting involvement of genes regulating innate immune responses. Patients with homozygous ...loss‐of‐function variants in the OTU‐deubiquitinase OTULIN suffer from neonatal‐onset OTULIN‐related autoinflammatory syndrome (ORAS) characterized by fever, panniculitis, diarrhea, and arthritis. Here, we describe an atypical form of ORAS with distinct clinical manifestation of the disease caused by two new compound heterozygous variants (c.258G>A (p.M86I)/c.500G>C (p.W167S)) in the OTULIN gene in a 7‐year‐old affected by a life‐threatening autoinflammatory episode with sterile abscess formation. On the molecular level, we find binding of OTULIN to linear ubiquitin to be compromised by both variants; however, protein stability and catalytic activity is most affected by OTULIN variant p.W167S. These molecular changes together lead to increased levels of linear ubiquitin linkages in patient‐derived cells triggering the disease. Our data indicate that the spectrum of ORAS patients is more diverse than previously thought and, thus, supposedly asymptomatic individuals might also be affected. Based on our results, we propose to subdivide the ORAS into classical and atypical entities.
Synopsis
The OTULIN‐Related Autoinflammatory Syndrome (ORAS) is known to be caused by homozygous variants in the OTULIN gene. This study discovers that two new compound‐heterozygous variants in OTULIN are associated with an atypical, but potentially fatal, late‐onset form of ORAS.
Atypical ORAS is characterized by multiorgan abscess formation and bears the risk of being clinically inapparent.
OTULIN variants p.M86I and p.W167S disrupt OTULIN function leading to increased levels of linear ubiquitin linkages in patient‐derived fibroblasts and B cells.
Molecularly, atypical ORAS resembles classical ORAS with enhanced TNF production in monocytes, but diminished TNF‐induced gene activation and sensitization to TNF‐mediated cell death (in the presence of cycloheximide) in fibroblasts.
Anti‐TNF therapy with Adalimumab resulted in normalization of the patient's inflammatory plasma protein profile suggesting that patients with atypical ORAS might benefit from TNF‐blocking agents as seen in patients with classical ORAS.
The OTULIN‐Related Autoinflammatory Syndrome (ORAS) is known to be caused by homozygous variants in the OTULIN gene. This study discovers that two new compound‐heterozygous variants in OTULIN are associated with an atypical, but potentially fatal, late‐onset form of ORAS.
RBP4: a controversial adipokine Kotnik, Primoz; Fischer-Posovszky, Pamela; Wabitsch, Martin
European journal of endocrinology,
11/2011, Letnik:
165, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Adipose tissue is an endocrine organ secreting biologically active factors called adipokines that act on both local and distant tissues. Adipokines have an important role in the development of ...obesity-related comorbidities not only in adults but also in children and adolescents. Retinol binding protein 4 (RBP4) is a recently identified adipokine suggested to link obesity with its comorbidities, especially insulin resistance, type 2 diabetes (T2D), and certain components of the metabolic syndrome. However, data, especially resulting from the clinical studies, are conflicting. In this review, we summarize up-to-date knowledge on RBP4's role in obesity, development of insulin resistance, and T2D. Special attention is given to studies on children and adolescents. We also discuss the role of possible confounding factors that should be taken into account when critically evaluating published studies or planning new studies on this exciting adipokine.
Abstract
Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity‐associated disorders, thermogenic adipocytes are linked to ...cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this plasticity could help improving metabolism. Here, we show that the lncRNA Apoptosis associated transcript in bladder cancer (AATBC) is a human‐specific regulator of adipocyte plasticity. Comparing transcriptional profiles of human adipose tissues and cultured adipocytes we discovered that AATBC was enriched in thermogenic conditions. Using primary and immortalized human adipocytes we found that AATBC enhanced the thermogenic phenotype, which was linked to increased respiration and a more fragmented mitochondrial network. Expression of AATBC in adipose tissue of mice led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, BMI, and other measures of metabolic health. In conclusion, AATBC is a novel obesity‐linked regulator of adipocyte plasticity and mitochondrial function in humans.
Synopsis
image
Screening of human adipose tissue and cultured human adipocytes has identified the lncRNA AATBC, which is a obesity‐linked regulator of adipocyte plasticity and mitochondrial function in adipocytes.
The human‐specific lncRNA AATBC is highly expressed in thermogenic adipocytes.
AATBC enhances adipocyte browning and mitochondrial respiration.
In obesity, AATBC in adipose tissue was inversely correlated with metabolic health.
Second mitochondria‐derived activator of caspase (SMAC) mimetics (SMs) targeting inhibitor of apoptosis proteins (IAPs) activate cell death pathways, and are currently being evaluated in clinical ...trials. Their successful therapeutic implementation requires upfront identification of patients who could benefit from a SM‐based treatment but biomarkers for SM sensitivity have not yet been described. Here, we analyzed the intrinsic activity of two monovalent (AT406 and LCL161) and two bivalent (Birinapant and BV6) SMs on unselected patient‐derived pediatric precursor B‐cell acute lymphoblastic leukemia (BCP‐ALL) identifying a subset of patient samples to be particularly sensitive to SM‐induced cell death. This subset was defined by a characteristic gene expression signature with 127 differentially regulated genes, amongst them TNFRSF1A encoding TNFR1, and a critical role of TNFR1 in SM‐induced cell death in sensitive BCP‐ALL was confirmed on the functional level. Interestingly, samples with intermediate or low sensitivity to SMs were sensitized to SM‐induced cell death by inhibition of caspases using zVAD.fmk or Emricasan, a pan‐caspase inhibitor in clinical trials. When we compared our expression data to published data sets, we identified an overlap of four genes to be commonly differentially regulated in SM‐sensitive BCP‐ALL, that is, TSPAN7, DIPK1C, MTX2 and, again, TNFRSF1A. Functional testing revealed that this set of genes identified samples with high sensitivity to SM treatment. In summary, our data suggest using this gene signature as biomarker predicting response to SM treatment and point to the development of new combinatorial treatments consisting of SMs and pan‐caspase inhibitors for a successful clinical implementation of SMs in treatment of BCP‐ALL.
What's new?
SMAC mimetics can activate cell death pathways and are currently undergoing clinical trials for treatment of advanced solid tumors and multiple myeloma. Successful therapeutic implementation would require upfront identification of patients most likely to benefit, but biomarkers for SMAC mimetics sensitivity have not yet been described. Here, the authors identified a highly sensitive subset of B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) primografts that showed a characteristic gene expression pattern consisting in high TSPAN7, DIPK1C, and TNFRSF1A and low MTX2. The gene signature could potentially be used in the clinic as a biomarker predicting response to SMAC mimetics treatment.
Objective
This study aimed at establishing bacterial flagellin‐recognizing toll‐like receptor 5 (TLR5) as a novel link between gut microbiota composition, adipose tissue inflammation, and obesity.
...Methods
An adipose tissue microarray database was used to compare women having the highest (n = 4, H‐TLR) and lowest (n = 4, L‐TLR) expression levels of TLR5‐signaling pathway genes. Gut microbiota composition was profiled using flow cytometry and FISH. Standard laboratory techniques were used to determine anthropometric and clinical variables. In vivo results were verified using cultured human adipocytes.
Results
The H‐TLR group had higher flagellated Clostridium cluster XIV abundance and Firmicutes‐to‐Bacteroides ratio. H‐TLR subjects had obese phenotype characterized by greater waist circumference, fat %, and blood pressure (P < 0.05 for all). They also had higher leptin and lower adiponectin levels (P < 0.05 for both). Six hundred and sixty‐eight metabolism‐ and inflammation‐related adipose tissue genes were differentially expressed between the groups. In vitro studies confirmed that flagellin activated TLR5 inflammatory pathways, decreased insulin signaling, and increased glycerol secretion.
Conclusions
The in vivo findings suggest that flagellated Clostridium cluster XIV bacteria contribute to the development of obesity through distorted adipose tissue metabolism and inflammation. The in vitro studies in adipocytes show that the underlying mechanisms of the human findings may be due to flagellin‐activated TLR5 signaling.
Adipocytes undergo intense energetic stress in obesity resulting in loss of mitochondrial mass and function. We have found that adipocytes respond to mitochondrial stress by rapidly and robustly ...releasing small extracellular vesicles (sEVs). These sEVs contain respiration-competent, but oxidatively damaged mitochondrial particles, which enter circulation and are taken up by cardiomyocytes, where they trigger a burst of ROS. The result is compensatory antioxidant signaling in the heart that protects cardiomyocytes from acute oxidative stress, consistent with a preconditioning paradigm. As such, a single injection of sEVs from energetically stressed adipocytes limits cardiac ischemia/reperfusion injury in mice. This study provides the first description of functional mitochondrial transfer between tissues and the first vertebrate example of “inter-organ mitohormesis.” Thus, these seemingly toxic adipocyte sEVs may provide a physiological avenue of potent cardio-protection against the inevitable lipotoxic or ischemic stresses elicited by obesity.
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•Mitochondrial stress stimulates adipocyte sEV release•Adipocyte stress-induced sEVs are enriched with oxidatively damaged mitochondria•Mitochondria in sEVs from stressed adipocytes induce a burst of ROS in cardiac tissue•The adipocyte-derived pro-oxidant signal protects the heart through hormesis
Crewe et al. report that adipocytes release sEVs containing damaged mitochondria in response to energetic stress, such as seen in chronic obesity. The sEV-associated mitochondria induce transient mitochondrial oxidative stress in cardiac tissue, resulting in an antioxidant response. Adipocyte sEVs thereby precondition the heart to protect against ischemia/reperfusion injury.
Brown and beige adipocytes dissipate energy by uncoupling protein 1 (UCP1)‐dependent and UCP1‐independent thermogenesis, which may be utilized to develop treatments against obesity. We have found ...that mRNA and protein expression of the alanine/serine/cysteine transporter‐1 (ASC‐1) was induced during adipocyte differentiation of human brown‐prone deep neck and beige‐competent subcutaneous neck progenitors, and SGBS preadipocytes. cAMP stimulation of differentiated adipocytes led to elevated uptake of serine, cysteine, and glycine, in parallel with increased oxygen consumption, augmented UCP1‐dependent proton leak, increased creatine‐driven substrate cycle‐coupled respiration, and upregulation of thermogenesis marker genes and several respiratory complex subunits; these outcomes were impeded in the presence of the specific ASC‐1 inhibitor, BMS‐466442. Our data suggest that ASC‐1‐dependent consumption of serine, cysteine, and glycine is required for efficient thermogenic stimulation of human adipocytes.
MicroRNAs (miRNAs) play an important role in the regulation of gene expression. The binding to target messenger RNAs (mRNAs) results in mRNA cleavage or inhibition of the translational machinery ...leading to decreased protein levels. Various signalling pathways, including apoptosis are modulated by miRNAs. Here, we investigated the role of miR-744-5p in apoptosis signalling in ovarian cancer cell lines. MiR-744-5p expression was reduced in the cancer cell lines independent of the host gene MAP2K4. Overexpression of miR-744-5p activated the intrinsic apoptotic pathway in SKOV3, OVCAR3 and Cisplatin resistant (A2780-cis) and non-resistant A2780 cells leading to cell death. Notably, miR-744-5p overexpression together with Carboplatin treatment led to at least additive pro-apoptotic effects. Investigation of the apoptotic signalling pathways mediated by miR-744-5p revealed that its elevated expression directly downregulated mRNA and protein expression of nuclear factor I X (NFIX) and heterogeneous nuclear ribonucleoprotein C (HNRNPC). HNRNPC caused diminished miR-21 expression and AKT phosphorylation, while NFIX decreased Bcl2 levels, leading to the detected pro-apoptotic effects. Finally, Kaplan-Meier-Plots showed a prolonged median disease-free survival in ovarian serous cystadenocarcinoma patients with high miR-744 expression.
The phytochemical resveratrol has recently gained attention for its protection against metabolic disease and for extension of life span, which have been linked to its metabolic effects and SIRT1 ...activation in fat cells. However, little is known about the effect of resveratrol on fat cell apoptosis. Here, we identify a novel, SIRT1-independent mechanism by which resveratrol regulates fat cell numbers. We demonstrate for the first time that resveratrol enhances TNF-related apoptosis-inducing ligand (TRAIL)- or CD95-induced apoptosis of human preadipocytes in a highly synergistic manner (EC₅₀ at 72 h: resveratrol, >300 μM; TRAIL, >100 ng/ml; combination: 30 μM resveratrol and 10 ng/ml TRAIL, combination index 0.4). Similar results in primary human preadipocytes prepared from subcutaneous white adipose tissue and mature human adipocytes underline the relevance to human physiology. Mechanistic studies reveal that resveratrol inhibits PI3K-driven phosphorylation of Akt, leading to increased Bax activation, loss of mitochondrial membrane potential, cytochrome c release, and caspase-dependent apoptosis. The synergistic interaction of resveratrol and TRAIL depends on the intrinsic apoptosis pathway and caspases, since Bcl-2 overexpression and the caspase inhibitor zVAD.fmk inhibit apoptosis, whereas knockdown of SIRT1 by RNA interference has no effect. The discovery of this novel activity of resveratrol significantly advances the knowledge of fat tissue regulation by resveratrol and has important implications for its use in metabolic and age-related diseases.--Mader, I., Wabitsch, M., Debatin, K.-M., Fischer-Posovszky, P., Fulda, S. Identification of a novel proapoptotic function of resveratrol in fat cells: SIRT1-independent sensitization to TRAIL-induced apoptosis.
Mitochondrial dysfunction in white adipose tissue plays a key role in the pathogenesis of type 2 diabetes. Emerging evidence specifically suggests that altered oxidative phosphorylation in adipocytes ...may have a relevant effect on systemic glucose homeostasis, requiring understanding of adipocyte bioenergetics. We analyzed energetic flux of an intact human adipocyte cell model by plate‐based respirometry and extracellular acidification. During differentiation, we discovered that glycolytic ATP production was increasingly replaced by mitochondrial oxidative metabolism (from 20 to 60%). This observation was corroborated by simultaneous up‐regulation of canonical mitochondrial gene programs, such as peroxisome proliferator‐activated receptor γ coactivator α (PGC1α; 150‐fold) and cytochrome c‐1 (CytC; 3‐fold). Mimicking diabetic phenotypes by exposure to various glucose levels (0, 5, and 25 mM) resulted in immediate adjustments of glycolytic and mitochondrial activity that aimed to maintain intracellular ATP. We conclude that ATP deficits by mitochondrial failure are compensated by glycolytic ATP production, resulting in inefficient conversion of glucose to cellular ATP. Metabolic inefficiency may enhance glucose uptake, therefore improving systemic glucose homeostasis. Notably, mature adipocytes developed a high spare respiratory capacity (increased by 6‐fold) permitting rapid adaptation to metabolic changes. Spare respiratory capacity may also allow additional metabolic scope for energy dissipation, potentially offering new therapeutic targets for the treatment of metabolic disease.—Keuper, M., Jastroch, M., Yi, C.‐X., Fischer‐Posovszky, P., Wabitsch, M., Tschöp, M. H., Hofmann, S. M. Spare mitochondrial respiratory capacity permits human adipocytes to maintain ATP homeostasis under hypoglycemic conditions. FASEB J. 28, 761–770 (2014). www.fasebj.org
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