Similar Datasets
Project description:Mammals adaptively regulate energy metabolism in response to environmental changes such as starvation and cold circumstances. Thioredoxin-interacting protein (Txnip), known as a redox regulator, serves as a nutrient sensor regulating energy homeostasis. Txnip is essential for mice to adapt to starvation, but its role in adapting to cold circumstances remains unclear. Here, we identified Txnip as a pivotal factor for maintaining non-shivering thermogenesis in mice. Txnip protein levels in brown adipose tissue (BAT) were upregulated by the acute cold exposure. Txnip-deficient (Txnip-/-) mice acclimated to thermoneutrality (30°C) exhibited significant BAT enlargement and triglyceride accumulation with downregulation of BAT signature and metabolic gene expression. Upon acute cold exposure (5°C), Txnip-/- mice showed a rapid decline in BAT surface temperatures with the failure of increasing metabolic respiration, developing lethal hypothermia. The BAT dysfunction and cold susceptibility in Txnip-/- mice were corrected by acclimation to 16°C, protecting the mice from life-threatening hypothermia. Transcriptomic and metabolomic analysis using dissected BAT revealed that despite preserving glycolysis, the BAT of Txnip-/- mice failed to activate the catabolism of branched-chain amino acids and fatty acids in response to acute cold stress. These findings illustrate that Txnip is required for maintaining basal BAT function and ensuring cold-induced thermogenesis.
2025-01-01 | GSE251656 | GEO
Project description:Mammals adaptively regulate energy metabolism in response to environmental changes such as starvation and cold circumstances. Thioredoxin-interacting protein (Txnip), known as a redox regulator, serves as a nutrient sensor regulating energy homeostasis. Txnip is essential for mice to adapt to starvation, but its role in adapting to cold circumstances remains unclear. Here, we identified Txnip as a pivotal factor for maintaining non-shivering thermogenesis in mice. Txnip protein levels in brown adipose tissue (BAT) were upregulated by the acute cold exposure. Txnip-deficient (Txnip-/-) mice acclimated to thermoneutrality (30°C) exhibited significant BAT enlargement and triglyceride accumulation with downregulation of BAT signature and metabolic gene expression. Upon acute cold exposure (5°C), Txnip-/- mice showed a rapid decline in BAT surface temperatures with the failure of increasing metabolic respiration, developing lethal hypothermia. The BAT dysfunction and cold susceptibility in Txnip-/- mice were corrected by acclimation to 16°C, protecting the mice from life-threatening hypothermia. Transcriptomic and metabolomic analysis using dissected BAT revealed that despite preserving glycolysis, the BAT of Txnip-/- mice failed to activate the catabolism of branched-chain amino acids and fatty acids in response to acute cold stress. These findings illustrate that Txnip is required for maintaining basal BAT function and ensuring cold-induced thermogenesis.
2025-01-01 | GSE251653 | GEO
Project description:Txnip deficiency causes a susceptibility to acute cold stress with brown fat dysfunction in mice
| PRJNA1055010 | ENA
Project description:Txnip deficiency causes a susceptibility to acute cold stress with brown fat dysfunction in mice [RNA-seq]
| PRJNA1055025 | ENA
Project description:Txnip deficiency causes a susceptibility to acute cold stress with brown fat dysfunction in mice [ChIP-seq]
| PRJNA1055026 | ENA
Project description:The disruption of the retinal pigment epithelium (RPE), for example, through oxidative damage, is a common factor underlying age-related macular degeneration (AMD). Aberrant autophagy also contributes to AMD pathology, as autophagy maintains RPE homeostasis to ensure blood-retinal barrier (BRB) integrity and protect photoreceptors. Thioredoxin-interacting protein (TXNIP) promotes cellular oxidative stress by inhibiting thioredoxin reducing capacity and is in turn inversely regulated by reactive oxygen species levels; however, its role in oxidative stress-induced RPE cell dysfunction and the mechanistic link between TXNIP and autophagy are largely unknown. Here, we observed that TXNIP expression was rapidly downregulated in RPE cells under oxidative stress and that RPE cell proliferation was decreased. TXNIP knockdown demonstrated that the suppression of proliferation resulted from TXNIP depletion-induced autophagic flux, causing increased p53 activation via nuclear localization, which in turn enhanced AMPK phosphorylation and activation. Moreover, TXNIP downregulation further negatively impacted BRB integrity by disrupting RPE cell tight junctions and enhancing cell motility by phosphorylating, and thereby activating, Src kinase. Finally, we also revealed that TXNIP knockdown upregulated HIF-1?, leading to the enhanced secretion of VEGF from RPE cells and the stimulation of angiogenesis in cocultured human retinal microvascular endothelial cells. This suggests that the exposure of RPE cells to sustained oxidative stress may promote choroidal neovascularization, another AMD pathology. Together, these findings reveal three distinct mechanisms by which TXNIP downregulation disrupts RPE cell function and thereby exacerbates AMD pathogenesis. Accordingly, reinforcing or restoring BRB integrity by targeting TXNIP may serve as an effective therapeutic strategy for preventing or attenuating photoreceptor damage in AMD.
| S-EPMC6802648 | biostudies-literature
Project description:Brown adipose tissue (BAT) mitochondria exhibit high oxidative capacity and abundant expression of both electron transport chain components and uncoupling protein 1 (UCP1). UCP1 dissipates the mitochondrial proton motive force (Δp) generated by the respiratory chain and increases thermogenesis. Here we find that in mice genetically lacking UCP1, cold-induced activation of metabolism triggers innate immune signaling and markers of cell death in BAT. Moreover, global proteomic analysis reveals that this cascade induced by UCP1 deletion is associated with a dramatic reduction in electron transport chain abundance. UCP1-deficient BAT mitochondria exhibit reduced mitochondrial calcium buffering capacity and are highly sensitive to mitochondrial permeability transition induced by reactive oxygen species (ROS) and calcium overload. This dysfunction depends on ROS production by reverse electron transport through mitochondrial complex I, and can be rescued by inhibition of electron transfer through complex I or pharmacologic depletion of ROS levels. Our findings indicate that the interscapular BAT of Ucp1 knockout mice exhibits mitochondrial disruptions that extend well beyond the deletion of UCP1 itself. This finding should be carefully considered when using this mouse model to examine the role of UCP1 in physiology.
| S-EPMC5544316 | biostudies-literature
Project description:Although macroautophagy/autophagy deficiency causes degenerative diseases, the deletion of essential autophagy genes in adipocytes paradoxically reduces body weight. Brown adipose tissue (BAT) plays an important role in body weight regulation and metabolic control. However, the key cellular mechanisms that maintain BAT function remain poorly understood. in this study, we showed that global or brown adipocyte-specific deletion of pink1, a Parkinson disease-related gene involved in selective mitochondrial autophagy (mitophagy), induced BAT dysfunction, and obesity-prone type in mice. Defective mitochondrial function is among the upstream signals that activate the NLRP3 inflammasome. NLRP3 was induced in brown adipocyte precursors (BAPs) from pink1 knockout (KO) mice. Unexpectedly, NLRP3 induction did not induce canonical inflammasome activity. Instead, NLRP3 induction led to the differentiation of pink1 KO BAPs into white-like adipocytes by increasing the expression of white adipocyte-specific genes and repressing the expression of brown adipocyte-specific genes. nlrp3 deletion in pink1 knockout mice reversed BAT dysfunction. Conversely, adipose tissue-specific atg7 KO mice showed significantly lower expression of Nlrp3 in their BAT. Overall, our data suggest that the role of mitophagy is different from general autophagy in regulating adipose tissue and whole-body energy metabolism. Our results uncovered a new mitochondria-NLRP3 pathway that induces BAT dysfunction. The ability of the nlrp3 knockouts to rescue BAT dysfunction suggests the transcriptional function of NLRP3 as an unexpected, but a quite specific therapeutic target for obesity-related metabolic diseases.Abbreviations: ACTB: actin, beta; BAPs: brown adipocyte precursors; BAT: brown adipose tissue; BMDMs: bone marrow-derived macrophages; CASP1: caspase 1; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; ChIP: chromatin immunoprecipitation; EE: energy expenditure; HFD: high-fat diet; IL1B: interleukin 1 beta; ITT: insulin tolerance test; KO: knockout; LPS: lipopolysaccharide; NLRP3: NLR family, pyrin domain containing 3; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RD: regular diet; ROS: reactive oxygen species; RT: room temperature; UCP1: uncoupling protein 1 (mitochondrial, proton carrier); WT: wild-type.
| S-EPMC8143238 | biostudies-literature
Project description:While TXNIP (thioredoxin interacting protein) in the plasma membrane and vesicular location is known to negatively regulate cellular glucose uptake by facilitating glucose transporter endocytosis, the function of TXNIP in the nucleus is far less understood. Herein, we sought to determine the function of nuclear TXNIP in vivo, using a new HA-tagged TXNIP knock-in mouse model. We observed that TXNIP can be found in the nucleus of a variety of cells from different tissues including hepatocytes (liver), enterocytes (small intestine), exocrine cells (pancreas), and brown adipocytes (BAT). Further investigations into the role of nuclear TXNIP in BAT revealed that cold stress rapidly and transiently activated HSF1 (heat shock factor 1). HSF1 interaction with TXNIP during its activation is required for optimal HSF1 directed cold shock response in BAT.
| S-EPMC10164894 | biostudies-literature
Project description:Caveolins (CAVs) are essential components of caveolae, plasma membrane invaginations with reduced fluidity, reflecting cholesterol accumulation. CAV proteins bind cholesterol, and CAV's ability to move between cellular compartments helps control intracellular cholesterol fluxes. In humans, CAV1 mutations result in lipodystrophy, cell transformation, and cancer. CAV1 gene-disrupted mice exhibit cardiovascular diseases, diabetes, cancer, atherosclerosis, and pulmonary fibrosis. The mechanism or mechanisms underlying these disparate effects are unknown, but our past work suggested that CAV1 deficiency might alter metabolism: CAV1(-/-) mice exhibit impaired liver regeneration unless supplemented with glucose, suggesting systemic inefficiencies requiring additional metabolic intermediates. Establishing a functional link between CAV1 and metabolism would provide a unifying theme to explain these myriad pathologies. Here we demonstrate that impaired proliferation and low survival with glucose restriction is a shortcoming of CAV1-deficient cells caused by impaired mitochondrial function. Without CAV1, free cholesterol accumulates in mitochondrial membranes, increasing membrane condensation and reducing efficiency of the respiratory chain and intrinsic antioxidant defense. Upon activation of oxidative phosphorylation, this promotes accumulation of reactive oxygen species, resulting in cell death. We confirm that this mitochondrial dysfunction predisposes CAV1-deficient animals to mitochondrial-related diseases such as steatohepatitis and neurodegeneration.
| S-EPMC3409647 | biostudies-literature