Differential effects of sugar and fat on adipose tissue inflammation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE212875 | GEO | 2023/07/19
REPOSITORIES: GEO
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Project description:During obesity, adipose tissue macrophages (ATM) colonize the white adipose tissue (WAT), where they adapt inflammatory and metabolically activated phenotypes. Here, we demonstrate that COMMD10 is a key regulator of macrophage oxidative capacity in response to chronic caloric excess. Mice with COMMD10-deficiency targeted to macrophages were fed with high-fat-diet (HFD) for 12 weeks. They gained less weight despite similar food intake, and showed improved systemic metabolic indices, sustained adipose tissue insulin sensitivity, increased lipolysis and reduced adipocyte hypertrophy and liver steatosis. COMMD10-deficient ATM directly improved insulin sensitivity and increase lipolysis in co-cultured adipocytes. COMMD10-deficient ATM exhibited increased oxidative respiration and mitochondrial membrane potential after short term (five weeks) and chronic (12 weeks) HFD. Their oxidative respiration was fueled by both glucose and lipids. They better adapted to mitochondrial activation by upregulating NRF2-dependent antioxidant transcriptional module. their increase in mitochondrial activity was furthered supported by COMMD10 modulation of cellular copper-iron balance and interaction with various oxidative phosphorylation related proteins. Our study illuminates COMMD10 as a pivotal regulator of mitochondrial energy production in ATM during constant energy surplus.
2024-11-30 | GSE247350 | GEO
Project description:Background: Systemic glucose homeostasis is affected by adipose cell function. Still, the cellular events preceding the onset of insulin resistance in adipocytes are not yet resolved. To capture the immediate cellular changes during diet-induced expansion of cell volume and number, we characterized the initial changes in mature adipocytes during a short high fat diet (HFD) intervention. Methods: C57BL6/J male mice were fed chow diet, and switched to HFD for 2, 4, 6 or 14 days. Systemic glucose clearance was assessed by glucose tolerance test. Adipose tissue was dissected for RNA seq analysis and cell size distribution analyzed using coulter counter technique. Insulin response in isolated adipocytes was measured by glucose uptake and Western blotting of insulin signaling intermediates. Confocal microscopy was used to assess autophagic flux in cells pre-incubated with rapamycin and chloroquine. Results: Switching to HFD was accompanied by an immediate adipose cell size expansion followed by recruitment of new adipocytes. Despite an increase in both basal and insulin-stimulated glucose uptake in adipocytes, we observed a progressive decrease in insulin-stimulated activation of Protein Kinase B (PKB) Ser473, PKB Thr308 and Akt substrate of 160 (AS160) Tyr642, and onset of systemic insulin-resistance already after two days. Moreover, RNA-seq analysis of adipose tissue revealed marked changes in gene expression at day four, of which the most significant included genes directly involved in autophagy (Trp53Inp2 and Beclin1). Enhanced autophagy was observed in isolated adipocytes from HFD-fed mice, detected as an increased density of LC3-positive puncta by confocal microscopy, and increase of LC3II. Conclusions: HFD rapidly caused impaired insulin signal transduction in adipocytes, while both basal and insulin-stimulated glucose uptake increased, which support the concept of spare signaling. Interestingly, our data suggests autophagy as one of the early cellular events that could contribute to insulin resistance.
2018-10-25 | GSE106174 | GEO
Project description:Insulin action in adipocytes affects whole-body insulin sensitivity. Studies of adipose-specific Glut4 knockout mice have established that adipose Glut4 contributes to the control of systemic glucose homeostasis. Presumably, this reflects a role for Glut4-mediated glucose transport in the regulation of secreted adipokines. In cultured 3T3-L1 adipocytes, Rab10 GTPase is required for insulin-stimulated translocation of Glut4 (Sano et al., 2007). The physiological importance of adipose Rab10 and the significance of its role in the control of Glut4 vesicle trafficking in vivo are unknown. Here we report that adipocytes from adipose-specific Rab10 knockout mice have a ~50% reduction in glucose uptake and Glut4 translocation to the cell surface in response to insulin, demonstrating a role for Rab10 in Glut4 trafficking. Moreover, hyperinsulinemic-euglycemic clamp shows decreased whole-body glucose uptake as well as impaired suppression of hepatic glucose production in adipose Rab10 knockout mice. Thus, fully functional Glut4 vesicle trafficking in adipocytes is critical for maintaining insulin sensitivity. Comparative transcriptome analysis of perigonadal adipose tissue demonstrates significant transcriptional similarities between adipose Rab10 knockout mice and adipose Glut4 knockout mice, consistent with the notion that the phenotypic similarities between the two models are mediated by reduced insulin-stimulated glucose transport into adipocytes. Transcriptome sequencing of perigonadal white adipose tissue
2016-06-30 | E-GEOD-70123 | biostudies-arrayexpress
Project description:Adipose tissue is one of the main regulative sites for energy metabolism. Excess lipid storage and expansion of white adipose tissue (WAT) is the primary contributor to obesity, a strong predisposing factor for development of insulin resistance. Sentrin-specific protease (SENP) 2 has been shown to play a role in metabolism in murine fat and skeletal muscle cells, and we have previously demonstrated its role in energy metabolism of human skeletal muscle cells. In the present work, we have investigated the impact of SENP2 on fatty acid and glucose metabolism in primary human fat cells by using cultured primary human adipocytes to knock down the SENP2 gene. Glucose uptake and oxidation, as well as accumulation and distribution of oleic acid into complex lipids were decreased while oleic acid oxidation was increased in SENP2-knockdown cells compared to control cells. Furthermore, de novo lipogenesis was reduced by SENP2-knockdown in the adipocytes and expression of several metabolically important regulators and markers of browning of WAT were upregulated both on gene and protein level. In conclusion, SENP2 is an important regulator of energy metabolism in primary human adipocytes, and the results indicates a potential role in browning of the cells as well.
2023-02-10 | PXD033508 | Pride
Project description:Brown adipose tissue (BAT) is a promising weapon to combat obesity and metabolic disease. BAT is thermogenic and consumes substantial amounts of glucose and fatty acids as fuel for thermogenesis and energy expenditure. To study BAT function in large human longitudinal cohorts, safe and precise detection methodologies are needed. Although regarded a gold standard, the foray of PET-CT into BAT research and clinical applications is limited by its high ionizing radiation doses. Here, we show that brown adipocytes release exosomes in blood plasma which can be utilized to assess BAT activity. In this study, we investigated circulating protein biomarkers that can accurately and reliably reflect BAT activation triggered by cold exposure, capsinoids ingestion and thyroid hormone excess in humans.
2022-06-09 | PXD023909 | Pride
Project description:Adipose tissue is central to regulation of systemic energy homeostasis. Adaptive thermogenesis in brown and beige adipocytes, which relies on mitochondrial oxidative phosphorylation, dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to insulin resistance, type 2 diabetes and obesity. Here we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves systemic glucose homeostasis via up-regulation of oxidative phosphorylation and reciprocal down-regulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance, increased energy expenditure and limited weight gain on high fat diet. NFIA coordinately up-regulate genes involved in oxidative phosphorylation as well as a battery of brown-fat-specific genes through enhancer activation that involves facilitated genomic binding of PPARγ. In contrast, NFIA in adipocytes, but not in macrophages, down-regulate pro-inflammatory cytokine genes to ameliorate adipose tissue inflammation in vivo. NFIA binds to enhancer/promoter region of Ccl2 gene that encodes pro-inflammatory cytokine MCP-1, to down-regulate its transcription. NFIA expression and CCL2 expression was negatively correlated in human adipose tissue. These results indicate that NFIA in adipocytes reciprocally regulate mitochondrial and inflammatory gene program to improve systemic glucose homeostasis.
2023-07-25 | GSE200192 | GEO
Project description:Adipose tissue is central to regulation of systemic energy homeostasis. Adaptive thermogenesis in brown and beige adipocytes, which relies on mitochondrial oxidative phosphorylation, dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to insulin resistance, type 2 diabetes and obesity. Here we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves systemic glucose homeostasis via up-regulation of oxidative phosphorylation and reciprocal down-regulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance, increased energy expenditure and limited weight gain on high fat diet. NFIA coordinately up-regulate genes involved in oxidative phosphorylation as well as a battery of brown-fat-specific genes through enhancer activation that involves facilitated genomic binding of PPARγ. In contrast, NFIA in adipocytes, but not in macrophages, down-regulate pro-inflammatory cytokine genes to ameliorate adipose tissue inflammation in vivo. NFIA binds to enhancer/promoter region of Ccl2 gene that encodes pro-inflammatory cytokine MCP-1, to down-regulate its transcription. NFIA expression and CCL2 expression was negatively correlated in human adipose tissue. These results indicate that NFIA in adipocytes reciprocally regulate mitochondrial and inflammatory gene program to improve systemic glucose homeostasis.
2023-07-25 | GSE228492 | GEO
Project description:Adipose tissue is central to regulation of systemic energy homeostasis. Adaptive thermogenesis in brown and beige adipocytes, which relies on mitochondrial oxidative phosphorylation, dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to insulin resistance, type 2 diabetes and obesity. Here we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves systemic glucose homeostasis via up-regulation of oxidative phosphorylation and reciprocal down-regulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance, increased energy expenditure and limited weight gain on high fat diet. NFIA coordinately up-regulate genes involved in oxidative phosphorylation as well as a battery of brown-fat-specific genes through enhancer activation that involves facilitated genomic binding of PPARγ. In contrast, NFIA in adipocytes, but not in macrophages, down-regulate pro-inflammatory cytokine genes to ameliorate adipose tissue inflammation in vivo. NFIA binds to enhancer/promoter region of Ccl2 gene that encodes pro-inflammatory cytokine MCP-1, to down-regulate its transcription. NFIA expression and CCL2 expression was negatively correlated in human adipose tissue. These results indicate that NFIA in adipocytes reciprocally regulate mitochondrial and inflammatory gene program to improve systemic glucose homeostasis.
2023-07-25 | GSE228490 | GEO
Project description:Adipose tissue is central to regulation of systemic energy homeostasis. Adaptive thermogenesis in brown and beige adipocytes, which relies on mitochondrial oxidative phosphorylation, dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to insulin resistance, type 2 diabetes and obesity. Here we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves systemic glucose homeostasis via up-regulation of oxidative phosphorylation and reciprocal down-regulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance, increased energy expenditure and limited weight gain on high fat diet. NFIA coordinately up-regulate genes involved in oxidative phosphorylation as well as a battery of brown-fat-specific genes through enhancer activation that involves facilitated genomic binding of PPARγ. In contrast, NFIA in adipocytes, but not in macrophages, down-regulate pro-inflammatory cytokine genes to ameliorate adipose tissue inflammation in vivo. NFIA binds to enhancer/promoter region of Ccl2 gene that encodes pro-inflammatory cytokine MCP-1, to down-regulate its transcription. NFIA expression and CCL2 expression was negatively correlated in human adipose tissue. These results indicate that NFIA in adipocytes reciprocally regulate mitochondrial and inflammatory gene program to improve systemic glucose homeostasis.
2023-07-25 | GSE200193 | GEO
Project description:The MondoA transcription factor forms a heterocomplex with its obligate partner Mlx to regulate ~75% of glucose-dependent transcription. By mediating glucose-induced activation of thioredoxin-interacting protein (TXNIP), MondoA directly represses glucose uptake. Given the predominant role of MondoA in controlling glucose-dependent transcription and glucose uptake, we asked whether glutamine regulates MondoA activity. Expression profiles from glucose and glutamine starved BxPC-3 cells (-G-Q) were compared with those from cells grown in glucose only (+G-Q), glutamine only (-G+Q) or glucose plus glutamine (+G+Q). As expected, TXNIP expression was highly induced by glucose. However, the addition of glutamine repressed the glucose-dependent induction of TXNIP. We show that glutamine inhibits MondoA-dependent transcriptional activation of TXNIP by triggering the recruitment of a histone deacetylase-dependent corepressor to the amino terminus of MondoA. Consistent with the repression of TXNIP, glucose uptake is elevated in cells grown in the presence of glucose and glutamine. Finally, alpha-ketoglutarate, a tricarboxylic acid cycle intermediate, also blocks MondoA-dependent activation of TXNIP and stimulates glucose uptake. Together, these results suggest that glutamine-dependent mitochondrial anapleurosis stimulates glucose uptake by restricting TXNIP expression via MondoA:Mlx complexes. Four growth conditons; four biological replicates
2010-08-18 | E-GEOD-17632 | biostudies-arrayexpress