Obesity-related T cell dysfunction impairs immunosurveilance and increases cancer risk
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE245657 | GEO | 2024/03/11
REPOSITORIES: GEO
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Project description:Obesity-related T cell dysfunction impairs immunosurveilance and increases cancer risk
| PRJNA1029522 | ENA
Project description:Obesity is a well-established risk factor for human cancer, yet the underlying mechanisms remain elusive. Immune dysfunction is commonly associated with obesity but whether compromised immune surveillance contributes to cancer susceptibility in individuals with obesity is unclear. Here we use a mouse model of diet-induced obesity to investigate tumor-infiltrating CD8 + T cell responses in lean, obese, and previously obese hosts that lost weight through either dietary restriction or treatment with semaglutide. While both strategies reduce body mass, only dietary intervention restores T cell function and improves responses to immunotherapy. In mice exposed to a chemical carcinogen, obesity-related immune dysfunction leads to higher incidence of sarcoma development. However, impaired immunoediting in the obese environment enhances tumor immunogenicity, making the malignancies highly sensitive to immunotherapy. These findings offer insight into the complex interplay between obesity, immunity and cancer, and provide explanation for the obesity paradox observed in clinical immunotherapy settings.
| S-EPMC10987624 | biostudies-literature
Project description:Insulin resistance is the hallmark of obese and type 2 diabetes patients. Defective insulin sensitivity in the liver results in increased glucsoe production, which is the major cause of hyperglycemia in diabetic patients. Increased lipopolysaccharide (LPS) leakage from the gut of diet-induced obesity causes insulin resisitance; moreover, activation of deacetylase Sirtuin1 restore insulin sensitivity in obesity. However, the mechanism resulting in insulin resistance by LPS remains poorly understood. Here, we show that Ep300 (P300) harboring an intrinsic acetyltransferase activity was rapidly induced in the liver of animals fed a high-fat diet, and the induction of Ep300 is through LPS-stimulated activation of ER stress. Induced Ep300 impairs insulin signaling by acetylating mediators in insulin signaling. Inhibition of P300 acetyltransferase activity improves insulin signaling. Thus, Ep300 acetyltransferase activity is a therapeutic target.
2017-05-08 | GSE86108 | GEO
Project description:Obesity is an independent risk factor for colorectal cancer (CRC) although the underlying mechanisms have not been elucidated. Dietary nutrients play a key role in both the prevention and promotion of CRC. While iron is an essential nutrient, excess iron is associated with carcinogenesis. Unlike the systemic compartment, the intestinal lumen lacks an efficient system to regulate iron. In conditions when dietary iron malabsorption and intestinal inflammation co-exist, greater luminal iron is associated with increased intestinal inflammation and a shift in the gut microbiota to more pro-inflammatory strains. However, treatments designed to reduce luminal, including diet restriction and chelation, are associated with lower intestinal inflammation and the colonization of protective gut microbes. Obesity is associated with inflammation-induced, hepcidin-mediated, iron metabolism dysfunction characterized by iron deficiency and dietary iron malabsorption. Obesity is also linked to intestinal inflammation. Currently, there is a fundamental gap in understanding how altered iron metabolism impacts CRC risk in obesity.
The investigator’s objective is to conduct a crossover controlled feeding trial of: 1) a "Typical American" diet with "high" heme/non-heme iron", 2) a "Typical American" diet with "low" iron, and 3) a Mediterranean diet with "high" non heme iron and examine effects on colonic and systemic inflammation and the gut microbiome.
| 2274754 | ecrin-mdr-crc
Project description:Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-Dexamethasone co-agonist in which GLP-1 selectively delivers Dexamethasone to GLP-1 receptor-expressing cells. GLP-1-Dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptors bypasses deleterious effects of Dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents an efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity.
2017-09-04 | GSE102415 | GEO
Project description:This study defines the impact of in vivo thrombospondin-1 (THBS1) ablation on diaphram stromal cell profile, histology and contractile funciton in a mosue model of diet-induced obesity
2023-08-16 | GSE241005 | GEO
Project description:G-protein-coupled receptors (GPCRs) represent targets for improved low-side-effect therapies to tackle the evolving Western obesity epidemic. The orphan (o) GPCR GPR101 emerged as an attractive candidate in this regard. Expressed on cells in brain areas regulating energy homeostasis, including the hunger-suppressing proopiomelanocortin (POMC) + neurons, it is minimally expressed outside the brain. To understand the function of this receptor in vivo, we herein generated and comprehensively characterized a Gpr101 knockout mouse line, either under standard feeding conditions or with chronic high-fat diet (HFD) access (16 weeks). GPR101 loss accelerated the risk for diet-induced obesity (DIO), hyperinsulinemia and disrupted glucose homeostasis. Hypothalamic transcriptomic analysis revealed also decreased Pomc activation with HFD suggesting impaired hunger suppression. Moreover, on a standard diet, there was a molecular signature of downregulated tristetrapolin (TTP) pathway gene activation suggesting impaired inflammation resolution and one of aberrant microglial phagocytosis and lipid metabolism on HFD. Morphometry revealed altered hypothalamic arcuate nucleus microglial morphology consistent with the transcriptomic profile. We discuss how the GPR101 specialized pro-resolving mediator (SPM) receptor capacity likely underlies the aberrant microglial function and contributes to DIO risk. Thus, this evidence shows that GPR101 is a potential therapeutic target for DIO through, among other factors, effects on hypothalamic inflammation resolution.
2023-04-18 | GSE220533 | GEO
Project description:Obesity is a global health concern affecting over 650 million adults with a major contributor being an increased consumption of a high-fat diet. Maternal obesity often results in an increased risk of offspring developing obesity. In this study, we examined the effect of diet on visceral adipose in a pre-clinical model of generational diet-induced obesity that included maternal cohorts of C57BL/6 mice fed either a control diet (10% fat) or a high-fat diet (45% fat) and the resulting female offspring fed either diet. Using bottom-up proteomics on omental adipose tissue, differential protein expression was determined with the greatest difference resulting from the generational obese cohort. Differentially expressed proteins were involved in pathways related to cancer, inflammatory disease and immune response. Taken together, the results of this study provide molecular-level insight that will enable the development of more targeted, modifiable interventions that could be implemented pre-, during and post-pregnancy.
2024-10-17 | PXD042092 | Pride
Project description:This study defines the impact of in vivo thrombospondin-1 (THBS1) ablation on diaphram stromal cell profile, histology and contractile funciton in a mosue model of diet-induced obesity
2023-08-18 | GSE241168 | GEO
Project description:In the UK, around 1 in 16 men and 1 in 20 women will develop bowel cancer at some point in their lives. Most bowel cancers happen when a type of growth in the bowel called an adenoma eventually becomes cancerous. Cutting out adenomas reduces the risk of developing bowel cancer.
Certain people are more likely to have adenomas than others, for example people who are overweight. People who are overweight are also more likely to develop liver disease by laying too much fat down in the liver. Studies in Asia have shown that people with fatty liver disease are more likely to have adenomas and these are more commonly found in the part of the bowel (right colon) furthest from the bottom end.
Information on the link between obesity, fatty liver disease and adenomas is very limited, particularly in the Western population.
The investigators will assess the link between body weight, fatty liver and adenomas in the UK population. 1430 patients will be invited; some through the bowel cancer screening programme and some with symptoms such as low blood count, bleeding or changed bowel habit. These patients will already have been referred for a camera test looking into the bowel, called a colonoscopy. Information including height, weight and some health questions will be taken. Blood samples will be taken. The investigators will compare the number of patients with adenomas who have liver disease or who are overweight with those who don’t. This information will be used to develop a scoring system to predict risk of adenomas. This will help the investigators to decide if undertaking colonoscopies in these patients will identify those at increased risk of bowel cancer.
| 2283518 | ecrin-mdr-crc