Characterising the transcriptional profile of murine 3T3-L1 adipocytes with altered expression of IRF3.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE81193 | GEO | 2016/05/31
SECONDARY ACCESSION(S): PRJNA320871
REPOSITORIES: GEO
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Project description:The chronic inflammatory state that accompanies obesity is a major contributor to insulin resistance and other metabolic dysfunction features. Despite recent advances in our understanding of the cellular and secreted factors that promote the inflammatory milieu of obesity, we have much less insight into the transcriptional pathways that drive these processes. While most attention has focused on the canonical inflammatory transcription factor NF-KB, other potentially important factors exist, including members of the interferon regultory factor (IRF) family. Here we show that IRF3 expression is upregulated in the adipocytes of obese mice and humans. TLR3/TLR4 activation induces insulin resistance in adipocytes, which can be prevented by IRF3 knockdown. Furthermore, Irf3KO mice display improved insulin sensitivity, associated with reduced intra-adipose and systemic inflammation in the high-fat fed state, enhanced browning of subcutaneous fat, and increased adipose expression of Glut4. Taken together, our data indicates that IRF3 is a major transcriptional regulator of adipose inflammation to maintain systemic glucose and energy homeostasis. Transcriptional profiling of murine 3T3-L1 adipocytes with altered expression of IRF3. Overexpression or knockdown of IRF3 was achieved by lentivirus transduction for 6 days. 3T3-L1 adipocytes with IRF3 knockdown were further treated in the absence or presence of LPS for 6 days. Samples consist of triplicate replica with appropriate control.
2016-05-31 | E-GEOD-81193 | biostudies-arrayexpress
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: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.
2016-06-30 | GSE70123 | GEO
Project description:Obesity-induced inflammation metabolic dysfunction, but the mechanisms remain elusive. Here we showed that the innate immune factor IRF3 is a direct transcriptional regulator of glucose homeostasis through induction of endogenous FAHFA hydrolase Aig1 in adipocytes. Adipocyte-specific knockout IRF3 protects mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity.
2024-02-09 | GSE213048 | GEO
Project description:Cytokines of the IL-1 family are important modulators of obesity-induced inflammation and the development of systemic insulin resistance. Here, we report that IL-37, a newly-described antiinflammatory member of the IL-1 family, affects obesity-induced inflammation and insulin resistance. IL-37 transgenic mice (IL-37tg) did not develop an obese phenotype in response to a high-fat diet (HFD). Unlike WT mice, IL-37tg mice exhibited reduced numbers of adipose tissue macrophages and preserved glucose tolerance and insulin sensitivity after 16 weeks of HFD. A short-term HFD intervention revealed that the IL-37-mediated improvement in glucose tolerance is independent of bodyweight. IL-37tg mice manifested a beneficial metabolic profile with higher circulating levels of the anti-inflammatory adipokine adiponectin. In vitro treatment of differentiating adipocytes with recombinant IL-37 reduced adipogenesis. The beneficial effects of recombinant IL-37 involved activation of AMPK signaling. In humans, steady-state IL-37 adipose tissue mRNA levels were positively correlated with insulin sensitivity, lower adipose tissue levels of leptin and a lower inflammatory status of the adipose tissue. These findings reveal IL-37 as an important anti-inflammatory modulator during obesity-induced inflammation and insulin resistance in both mice and humans and suggest that IL-37 is a potential target for the treatment of obesity-induced insulin resistance and type 2 diabetes. Gene arrays were performed on epidydimal white adipose tissue samples from wild type and human IL37-overexpressing transgenic mice fed a high fat diet for 16 weeks.
2015-05-18 | E-GEOD-58952 | biostudies-arrayexpress
Project description:Background. Obesity and body fat distribution are important risk factors for the development of type 2 diabetes and metabolic syndrome. Evidence has accumulated that this risk is related to intrinsic differences in behavior of adipocytes in different fat depots. LIM Domain Only 3 (LMO3) plays a crucial role in adipogenesis modulating the key adipogenic master switch PPARγ in human, but not mouse, visceral adipose progenitors; however, despite high expression in mature adipocytes, its function in these cells is currently unknown. Aims/Hypothesis. The aim of this study was to determine the potential involvement of LMO3-dependent pathways in the modulation of key functions of mature adipocytes during obesity. Methods. Based on a recently engineered hybrid rAAV serotype Rec2 shown to efficiently transduce both brown adipose tissue (BAT) and white adipose tissue (WAT), we delivered YFP or Lmo3 to epididymal WAT (eWAT) of C57Bl6/J mice on a high fat diet (HFD). The effects of eWAT transduction on metabolic parameters were evaluated 10 weeks later. To further define the role of LMO3 in insulin-stimulated glucose uptake, insulin signaling, adipocyte bioenergetics as well as endocrine function, experiments were conducted in 3T3-L1 adipocytes and newly differentiated human primary mature adipocytes, engineered for transient gain- or loss of LMO3 expression, respectively.Results. AAV transduction of eWAT results in strong and stable Lmo3 expression specifically in the adipocyte fraction over a course of 10 weeks with HFD feeding. Lmo3 expression in eWAT significantly improved glucose clearance and insulin sensitivity in diet-induced obesity, paralleled by increased serum adiponectin. In vitro, Lmo3 expression in 3T3-L1 adipocytes increased insulin-stimulated GLUT4 translocation and glucose uptake as well as mitochondrial oxidative capacity in addition to fatty acid oxidation. On a molecular level, LMO3 augmented PPARg activity, oxidative mitochondrial gene expression, which depended on and the expression of the PPARg co-activator Ncoa1, which was required for LMO3 effects on mitochondria and glucose uptake. In human mature adipocytes, LMO3 overexpression promoted, while silencing of LMO3 suppressed mitochondrial oxidative capacity. Conclusions. LMO3 expression in visceral adipose tissue regulates multiple genes that preserve adipose tissue functionality during obesity, such as glucose tolerance, insulin sensitivity and adiponectin secretion. Together with increased PPARγ activity, these gene expression changes promote insulin-induced GLUT4 translocation, glucose uptake in addition to increased mitochondrial oxidative capacity, limiting HFD-induced adipose dysfunction. These data add LMO3 as a novel regulator improving visceral adipose tissue function during obesity.
2021-08-24 | GSE155781 | 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: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