Netrin-1 disrupt high-fat-diet-induced adipogenesis via the PPARγ and Wnt/β-catenin signaling pathways
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE254894 | GEO | 2025/11/17
REPOSITORIES: GEO
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Project description:Rates of overweight and obesity continue to rise in the population worldwide. Obesity reduces life expectancy because it is an important predisposing factor for cancer, cardiovascular diseases and diabetes mellitus. Adipose tissue (AT), the main organ for fat storage with endocrine capacity, plays fundamental roles in systemic metabolism and in obesity-related diseases. Adiposity and lipodystrophy are associated with metabolic disorders, indicating that normal AT function is required for metabolic health. Dido1 is a marker gene for stemness and gene-targeting experiments compromised several functions from cell division to embryonic stem cell differentiation, in vivo and in vitro. Using animals carrying a DIDO mutant without the N-terminal, we report that these mice display a lean phenotype with reduced adipose tissue and hypolipidemia even when fed with an obesogenic diet. The phenotype related to impaired adipogenesis, partially corrected by transcription factors C/EBPα or PPARγ expression and to hypothermia subsequent to dermal fat thinning. Deep sequencing of the epididymal white fat (Epi WAT) transcriptome shows the role of Dido1 in the control of cellular lipases. The molecular analysis involves Dido1 in orchestrating adipogenesis and altogether offers a model different from described lipodystrophies in mice and pioneers a new path to understand obesity and identify mechanism for obesity intervention.
2024-01-09 | GSE195908 | GEO
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2013-12-31 | GSE25423 | 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:Obesity is a global health problem, which is characterized by the excessive fat accumulation or adiposity in the body and associated with other chronic metabolic disorders. Excess energy induces adipogenesis and lipid accumulation inside the existing adipocytes during obesity, which involves transcriptional changes and regulation. Recently, long non-coding RNAs (lncRNAs) have been implicated in regulation of adipogenesis and adipose tissue function. Mouse lncRNA U90926 was previously identified as a repressor of in vitro adipogenesis in 3T3-L1 preadipocytes. Based on this, we hypothesized that U90926 may repress weight gain and adiposity in vivo. To test the hypothesis, we leveraged U90926-deficient (U9-KO) mice, which we recently generated, with a generalized high-throughput phenotyping pipeline and focused follow-up phenotyping experiments. Compared with WT, U9-KO mice showed no major differences across a wide range of behavioral, neurological, and other physiological parameters. In mice fed a standard diet, we have found no differences in obesity-related phenotypes such as weight gain, fat mass accumulation, and plasma concentration of glucose, insulin, triglycerides, and free fatty acids in U9-KO mice in comparison with WT. U90926 deficiency did not have a major effect on perigonadal white adipose tissue morphology and gene expression profile. Furthermore, in mice fed a high fat diet, we found increased expression of U90926, yet no effect of U90926 deficiency on weight gain, fat mass, adipogenesis marker expression, and immune cell infiltration into the adipose tissue. Taken together, these data suggest that the lncRNA U90926 lacks an essential role in obesity-related phenotypes as well as adipocyte biology in vivo.
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Project description:Obesity, defined as excessive or abnormal body fat accumulation, which could significantly increase the risk of cardiovascular disease, type 2 diabetes mellitus (T2DM) diseases and seriously affect people's quality of life. More than 2 billion people are overweight, and the incidence of obesity is increasing rapidly worldwide, it has become a widely concerned public health issue in the world. Diverse evidence show that active metabolites are involved in the pathophysiological processes of obesity. However, whether the downstream catabolite of tryptophan, 3-indole acrylic acid (IA), is involved in obesity remains unclear. Here, we found that the content of IA in peripheral blood serum of overweight people was significantly lower than that of normal people. In addition, supplementation with IA in zebrafish larvae induced by a high fat diet (HFD) dramatically reduced HFD induced lipid accumulation. IA had no effect on proliferation and apoptosis of preadipocytes, but significantly inhibited adipogenesis of preadipocytes by down-regulate CEBPα and PPARγ. RNA-Seq and functional analysis revealed that IA regulated the adipogenesis of preadipocytes through stimulate the phosphorylation of STAT1. Taken together, IA has been identified as a potent metabolite for the prevention or treatment of obesity.
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Project description:Obesity is an independent risk factor for diabetes and cardiovascular disease. Before effective anti-obesity therapies can be developed, understanding of what governs the production of healthy versus unhealthy fat tissue is required, as not all types confer equal risk. Adipogenesis requires the precise transduction of signals and coordination of transcription factor cascades. Molecular adaptor proteins of the 14-3-3 family are known to coordinate signaling events from multiple cues, but whether specific isoforms have unique, non-redundant roles in adipogenesis remains unclear. RNAi screening revealed 14-3-3ζ as the critical isoform for in vitro adipocyte differentiation. This study aims to understand the role of 14-3-3ζ in adipogenesis program and the differentiation in health adipose tissue.
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Project description:Obesity is often associated with a low-grade systemic inflammation state that contributes to the development of insulin resistance and atherosclerotic complications. This is usually coupled with increased macrophage infiltration in the adipose tissue and a defect in adipocyte differentiation that results in accumulation of hypertrophic fat cells characterized by a deregulated pattern of adipokine expression. Here we show that knockdown of histone demethylase lsd1 in 3T3-L1 preadipocytes results in defective adipogenesis and derepression of an inflammatory program in these cells. The dataset consists of four sample groups: [1] 3T3-L1 preadipocytes (passage 19) transfected with a control scrambled siRNA at 24h after transfection (siC.24h), [2] 3T3-L1 preadipocytes (p.19) transfected with a siRNA directed against LSD1 at 24h after transfection (siLsd1.24h), [3] 3T3-L1 preadipocytes (p.21) transfected with a control scrambled siRNA at 48h after transfection (siC.48h), and [4] 3T3-L1 preadipocytes (p.21) transfected with a siRNA directed against LSD1 at 48h after transfection (siLsd1.48h). The 24h sample groups (siC.24h and siLsd1.24h) consist of two biological replicate samples; the 48h sample groups (siC.48h and siLsd1.48h) consist of three biological replicate samples. Each sample was hybridized to a separate array, for a total of ten arrays.
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Project description:Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-beta/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3 deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3-/- white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3-/- adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-alpha1 expression. We observe significant correlation between TGF-beta1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-beta1 signaling protects mice from obesity, diabetes and hepatic steatosis. Together, these results demonstrate that TGF-beta signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-beta1 activity might be an effective treatment strategy for obesity and diabetes. Smad3-/- and WT mice were fed with regular diet (RD) and high fat diet (HFD), and diet induced obese (DIO) mice were treated with IgG and anti-TGF-b1 antibody
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Project description:The prevalence of overweight and obesity continues to rise in the population worldwide. Because it is an important predisposing factor for cancer, cardiovascular diseases, diabetes mellitus, and COVID-19, obesity reduces life expectancy. Adipose tissue (AT), the main fat storage organ with endocrine capacity, plays fundamental roles in systemic metabolism and obesity-related diseases. Dysfunctional AT can induce excess or reduced body fat (lipodystrophy). Dido1 is a marker gene for stemness; gene-targeting experiments compromised several functions ranging from cell division to embryonic stem cell differentiation, both in vivo and in vitro. We report that mutant mice lacking the DIDO N terminus show a lean phenotype. This consists of reduced AT and hypolipidemia, even when mice are fed a high-nutrient diet. DIDO mutation caused hypothermia due to lipoatrophy of white adipose tissue (WAT) and dermal fat thinning. Deep sequencing of the epididymal white fat (Epi WAT) transcriptome supported Dido1 control of the cellular lipid metabolic process. We found that, by controlling the expression of transcription factors such as C/EBPα or PPARγ, Dido1 is necessary for adipocyte differentiation, and that restoring their expression reestablished adipogenesis capacity in Dido1 mutants. Our model differs from other lipodystrophic mice and could constitute a new system for the development of therapeutic intervention in obesity.
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Project description:The prevalence of overweight and obesity continues to rise in the population worldwide. Because it is an important predisposing factor for cancer, cardiovascular diseases, diabetes mellitus, and COVID-19, obesity reduces life expectancy. Adipose tissue (AT), the main fat storage organ with endocrine capacity, plays fundamental roles in systemic metabolism and obesity-related diseases. Dysfunctional AT can induce excess or reduced body fat (lipodystrophy). Dido1 is a marker gene for stemness; gene-targeting experiments compromised several functions ranging from cell division to embryonic stem cell differentiation, both in vivo and in vitro. We report that mutant mice lacking the DIDO N terminus show a lean phenotype. This consists of reduced AT and hypolipidemia, even when mice are fed a high nutrient diet. DIDO mutation caused hypothermia due to lipoatrophy of white adipose tissue (WAT) and dermal fat thinning. Deep sequencing of the epididymal white fat (Epi WAT) transcriptome supported Dido1 control of the lipid metabolic process. We found that, by controlling expression of transcription factors such as C/EBPα or PPARγ, Dido1 is necessary for adipocyte differentiation, and that restoring their expression reestablished adipogenesis capacity in Dido1 mutants. Our model differs from other lipodystrophic mice and could constitute a new system for the development of therapeutic intervention in obesity.
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