Genetic, metabolic, and molecular insights into the diverse outcomes of diet-induced obesity in mice
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ABSTRACT:
PROVIDER: PRJNA757394 | ENA |
REPOSITORIES: ENA
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Project description:Overweight and obesity are increasingly common public health issues worldwide, leading to a wide range of diseases from metabolic syndrome to steatohepatitis and cardiovascular diseases. While the increase in the prevalence of obesity is partly attributable to changes in lifestyle (i.e. increased sedentarity and changes in eating behaviour), the metabolic and clinical impacts of these obesogenic conditions varies between sexes and genetic backgrounds. The conception of personalised treatments of obesity and its complications require a thorough understanding of the diversity of responses to conditions such as high-fat diet intake. By analysing nine genetically diverse mouse strains, we show that much like humans, mice respond to high-fat diet in a genetic- and sex-dependent manner. Results: Physiological and molecular responses to high-fat diet are associated with expression of genes involved in immunity and mitochondrial function. Finally, we find that mitochondrial function and supercomplex assembly may explain part of the diversity of physiological responses. By exploring the complex interactions between genetics and metabolic phenotypes via gene expression and molecular traits, we shed light on the importance of genetic background and sex in determining metabolic outcomes. In addition to providing the community with an extensive resource for optimizing future experiments, our work serves as an exemplary design for more generalizable translational studies.
2021-09-07 | GSE182668 | GEO
Project description:Diet-Induced Obesity Leads to Infarct Expansion, increased neuroinflammation, and Worsened Outcomes after Stroke
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Project description:We used RNA-seq to show that high-fat-diet-fed mice have a larger neuroinflammatory response following stroke. Elucidating these mechanisms may lead to the development of treatments that will benefit people with obesity who suffer from a stroke.
2018-05-01 | GSE104882 | GEO
Project description:Obesity is a growing global concern in adults and youth along with a parallel rise in associated complications, including cognitive impairment. Obesity induces brain inflammation and activates microglia, which contribute to cognitive impairment by aberrantly phagocytosing synaptic spines. Local and systemic signals, such as inflammatory cytokines and metabolites likely participate in obesity-induced microglial activation. However, the precise mechanisms mediating microglial activation during obesity remain incompletely understood. Herein, we leveraged our mouse model of high-fat diet (HFD)-induced obesity, which mirrors human obesity, and develops hippocampal-dependent cognitive impairment. We assessed hippocampal microglial activation by morphological and single-cell transcriptomic analysis to evaluate this heterogeneous, functionally diverse, and dynamic class of cells over time after 1 and 3 months of HFD. HFD altered cell-to-cell communication, particularly immune modulation and cellular adhesion signaling, and induced a differential gene expression signature of protein processing in the endoplasmic reticulum in a time-dependent manner.
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Project description:High-fat diet and obesity are high risk factors for colorectal cancer. The underlying mechanism is still unclear. Environmental factors alter the epigenome to affect gene expression thus the phenotype. In response to external stimuli, the cis-regulatory regions, especially enhancer loci, are key elements for regulating selective gene expression. We thus explored the effects of high-fat diet and the accompanying obesity on gene expression and the enhancer landscape in colon epithelium. High-fat diet exposed binding sites of transcription factors downstream of signaling pathways important in the initiation and progression of colon cancer. Meantime, colon specific enhancers were lost rendering the cells potential for dedifferentiation. The alteration at enhancer regions drives a specific transcription program promoting colon cancer progression. The comprehensive interrogation of enhancer changes by high-fat diet in colon epithelium provides a number of insights into the underlying biology of high-fat diet and obesity in increasing colon cancer risk, and provides potential therapeutic targets to treat obese colon cancer patients. ChIP sequencing of active enhancer mark h3k27ac in colon epithelium from wild type mice and NAG-1 transgenic mice treated with either low-fat diet or high-fat diet. The gene expression component of the study is included in GSE46843.
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Project description:The pediatric obesity influences all the organs and is closely linked to an increased risk of diverse diseases such as diabetes, cardiovascular, stroke, social problems and depression. Therefore, there is needed to diverse study for effective methods for the prevention and treatment of pediatric obesity. Diverse evidences suggest that gut microbiome and its metabolites affect metabolic disease such as obesity, diabetes, and heart disease. Previous studies in human and fecal transplantation experiments in animal models identified connections between the metabolic diseases and gut microbiota [4]. Moreover, metabolites can be fulfilled as diagnostic, prognostic, and therapeutic targets for diseases. Thus, approaches using metagenomics and metabolomics have the potential to provide new insights into metabolomic pathways of the diseases and help personalized and efficient treatments. In this study, we aimed to investigate metabolomic pathways of pediatric obesity analyzing both metabolome and microbiome profiles. In addition, we proceeded obese intervention with obese children to examine underlying metabolomic pathways related to effect of the intervention.
2022-07-04 | ST002261 | MetabolomicsWorkbench
Project description:Cardiorespiratory Fitness in Children with Overweight-Obesity: Insights into the Molecular Mechanisms
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Project description:Insulin resistance not compensated by secretion reduces energy storage, but little is known about its effect upon energy expenditure (EE). Insulin receptor substrates Irs1 and Irs2 mediate signaling in all tissues, resulting in the inhibition of FoxO transcription factors. We found that hepatic disruption of Irs1 and Irs2 (LDKO mice) attenuated high-fat diet (HFD)-induced obesity and increased whole-body EE in a FoxO1-dependent manner. Hepatic disruption of Fst (follistatin), a FoxO1-regulated hepatokine, normalized EE in LDKO mice and restored adipose mass during HFD consumption. Moreover, hepatic Fst disruption alone increased fat mass accumulation, whereas hepatic overexpression of Fst attenuated high HFD-induced obesity. Excess circulating Fst in overexpressing mice neutralized Mstn (myostatin), activating mTORC1-promoted pathways of nutrient uptake and EE in skeletal muscle. Similar to Fst overexpression, direct activation of muscle mTORC1 also reduced adipose mass. We conclude that Fst-promoted EE in muscle attenuates obesity during hepatic insulin resistance.
2024-02-29 | GSE260531 | GEO
Project description:Obesity and insulin resistance are associated with oxidative stress, which may be implicated in their progression. The kinase JNK1 emerged as a promising drug target for the treatment of obesity and type-2 diabetes. However, JNK1 is a key mediator of the oxidative stress response, promoting either cell dead or survival depending on magnitude and context of its activation. Furthermore, JNK inactivation shortens lifespan in drosophila and c. elegans. To learn on the safety and efficacy of long-term JNK inhibition in vertebrates, we investigated mice lacking JNK1 (JNK1-/-) exposed over a long period to an obesogenic high-fat diet (HFD). JNK1-/- mice chronically fed an HFD developed more skin oxidative damage because of reduced catalase expression, but also showed sustained protection from obesity, adipose tissue inflammation, steatosis, and insulin resistance, paralleled by decreased oxidative damage in fat and liver. We conclude that JNK1 is a relatively safe drug target for obesity-related diseases. RNA was collected from liver, skin and epididymal fat tissues from JNK1 KO mice and WT mice fed in high fat diet. Each condition was run in quadruplicate
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