Wild type and Neuregulin 4 (Nrg4) knockout mouse livers
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE53877 | GEO | 2014/11/17
SECONDARY ACCESSION(S): PRJNA233620
REPOSITORIES: GEO
Similar Datasets
Project description:Nrg4 is a brown fat-enriched adipokine that binds to the liver and preserves metabolic homeostasis during chronic energy excess. Adipose tissue Nrg4 expression is reduced in mouse and human obesity. Nrg4 deficient mice develp more severe insulin resistance and hepatic fat accumulation upon high-fat diet feeding. We used microarrays to elucidate the metabolic pathways that are regulated by Nrg4 in the liver. Wild type and Neuregulin 4 (Nrg4) knockout mice were fed high-fat diet (Research Diets D12492) for eight weeks. Tissues were harvested under ad lib condition for RNA isolation and microarray hybridization using Affymetrix Mouse MG-430 PM Strip arrays. Three independent pools of WT and KO mouse liver RNA were included in the study. Manuscript title: A brown fat-enriched secreted factor preserves metabolic homeostasis through attenuating hepatic lipogenesis, (journal information TBD)
2014-11-17 | E-GEOD-53877 | biostudies-arrayexpress
Project description:Nrg4 is a brown fat-enriched adipokine that binds to the liver and suppress the process of steatosis-to-NASH progression. Adipose tissue Nrg4 expression was reduced in mice under NASH diet feeding. Nrg4 homozygous knockout mice are prone to diet-induced steatohepatitis We used microarrays to elucidate the pathogenic pathways that are regulated by Nrg4 deficiency in the livers of mice under NASH diet feeding.
2018-02-14 | GSE99753 | GEO
Project description:Interorgan crosstalk via secreted hormones and metabolites is a fundamental aspect of mammalian metabolic physiology. Beyond the highly specialized endocrine cells, peripheral tissues are emerging as an important source of metabolic hormones that influence energy and nutrient metabolism and contribute to disease pathogenesis. Neuregulin 4 (Nrg4) is a fat-derived hormone that protects mice from nonalcoholic steatohepatitis (NASH) and NASH-associated liver cancer by shaping hepatic lipid metabolism and the liver immune microenvironment. Despite its enriched expression in brown fat, whether NRG4 plays a role in thermogenic response and mediates the metabolic benefits of cold exposure remain unexplored. Here we show that Nrg4 expression in inguinal white adipose tissue (iWAT) is highly responsive to chronic cold exposure. Nrg4 deficiency impairs beige fat induction and renders mice more susceptible to diet-induced metabolic disorders under mild cold conditions. Using mice with adipocyte and hepatocyte-specific Nrg4 deletion, we reveal that adipose tissue-derived NRG4, but not hepatic NRG4, is essential for beige fat induction following cold acclimation. Furthermore, treatment with recombinant NRG4-Fc fusion protein promotes beige fat induction in iWAT and improves metabolic health in diet-induced obese mice. These findings highlight a critical role of NRG4 in mediating beige fat induction and preserving metabolic health under mild cold conditions.
2024-01-01 | GSE246993 | GEO
Project description:The mammalian liver comprises heterogeneous cell types within its tissue microenvironment that respond to physiological cues and undergo pathophysiological reprogramming in disease states, such as nonalcoholic steatohepatitis (NASH). Patients with NASH are at increased risk for the development of hepatocellular carcinoma (HCC). However, the molecular and cellular nature of liver microenvironment remodeling that links NASH to liver carcinogenesis remains obscure. Here we show that diet-induced NASH is characterized by induction of tumor-associated macrophage (TAM)-like macrophages and exhaustion of cytotoxic T cells in mouse liver. The adipose-derived endocrine factor Neuregulin 4 (NRG4) serves as a hormonal checkpoint that restrains this pathological reprogramming during NASH. NRG4 deficiency exacerbates the induction of tumor-prone liver immune microenvironment and NASH-associated HCC, whereas transgenic NRG4 overexpression elicits protective effects in mice. In a therapeutic setting, recombinant NRG4 protein exhibits remarkable efficacy in inhibiting HCC in mice with NASH, thereby paving the way for future therapeutic development.
2022-08-15 | GSE185042 | GEO
Project description:Growth factors are essential for maintenance of intestinal health at homeostasis and during inflammation. We have previously shown that exogenous treatment with the growth factor neuregulin-4 (NRG4) promotes colonocyte survival during cytokine challenge and is protective in acute models of intestinal inflammation. However, the role of endogenously expressed NRG4 in colitis is not well understood. Using NRG4-/- mice, we tested the effect of endogenous NRG4 on colitis. NRG4-/- and wild type cage-mate mice were subjected to an IL-10R neutralization model of chronic colitis. NRG4-/- mice displayed reduced inflammatory cytokine expression in the colon and a reduction in tissue CD8+ T cells at 5 weeks post induction of colitis. In unchallenged NRG4-/- mice, baseline numbers of colonic CD8+ T cell numbers were unchanged. However, there was a significant decrease in splenic CD8+ T cells. RNA sequencing from colonic homogenates showed a loss of St3gal4, a sialyltransferase involved in immune cell trafficking, in the NRG4-null animals. This loss was verified in both tissue and epithelium. The regulation of St3gal4 by NRG4 was confirmed with ex vivo epithelial colon organoid cultures from NRG4-/- mice and by induction of St3gal4 in vivo following NRG4 treatment. Together our data suggest that NRG4 regulates colonic epithelial ST3GAL4 and thus the recruitment of CD8+ T cells, but also has systemic effects on T cell maturation. These effects may combine to stimulate immune mediated inflammation during IL-10R neutralization colitis.
2023-05-23 | GSE206965 | GEO
Project description:The white adipose organ is composed of both subcutaneous and several intra-abdominal depots. Excess abdominal adiposity is a major risk factor for metabolic disease in rodents and humans, while expansion of subcutaneous fat does not carry the same risks. Brown adipose produces heat as a defense against hypothermia and obesity, and the appearance of brown-like adipocytes within white adipose tissue depots is associated with improved metabolic phenotypes. Thus, understanding the differences in cell biology and function of these different adipose cell types and depots may be critical to the development of new therapies for metabolic disease. Here, we found that BEN, a determination factor of brown fat function. BEN transgenic mice displayed increased energy expenditure, limited weight gain, and improved glucose tolerance in response to a high-fat diet. These results demonstrate that BEN is a cell-autonomous determinant of a brown fat function and thermogenesis.
2018-01-10 | E-MTAB-4163 | biostudies-arrayexpress
Project description:Adipocytes are key players in maintaining energy homeostasis and are classified into two different categories: white and brown adipocyte. While white adipocytes store energy as triacylglycerols in lipid droplets, brown adipocytes combust excess chemical energy and release in the form of heat through uncoupled respiration. This characteristic phenomenon of brown fat attracts researchers and pharmacological industries to view brown fat as one of the potential therapeutic targets for obesity and associated metabolic disease. In the current study, we investigated the effect of a small molecule, sesaminol (SML) on brown fat activity and found that SML induces thermogenic program in primary white adipocytes as well as chow diet fed mice. In particular, SML treatment to mice elevated mitochondrial complex proteins and the rate oxygen consumption in brown and white fat. Administration of SML to high fat diet (HFD) challenged mice decreased weight gain, adiposity and cholesterol levels along with an increase of brown fat gene program in brown and white fat. Mechanistically, SML repressed the myogenic gene program in C2C12 myoblasts and increased all mitochondrial marker genes as appeared in brown adipose cells. Together, our results demonstrate that SML stimulates brown adipose function and protects mice against diet induced weight gain.
2020-03-27 | GSE147599 | GEO
Project description:Strategies to increase energy expenditure are an attractive approach to reduce excess fat storage and body weight to improve metabolic health. In mammals, uncoupling protein-1 (UCP1) in brown and beige adipocytes uncouples fatty acid oxidation from ATP generation in mitochondria and promotes energy dissipation as heat. We set out to identify small molecules that enhance UCP1 levels and activity using a high-throughput screen of nearly 12,000 compounds in mouse brown adipocytes. We identified Z16078526 that increases Ucp1 and mitochondrial-related gene expression in mouse brown adipocytes.
2019-12-01 | GSE138264 | GEO
Project description:Background and Aims: Recent studies have implicated platelets, particularly α-granules, in the development of steatohepatitis (NASH). However, the specific mechanisms involved have yet to be determined. Notably, thrombospondin 1 (TSP1) is a major component of the platelet α-granules released during platelet activation. The role of platelet-derived TSP1 in NASH remains unknown and was investigated in this study. Approach and Results: Platelet-specific TSP1 knockout mice (TSP1Δpf4) and their wild type littermates (TSP1F/F) were used. NASH was induced by feeding the mice a diet enriched in fat, sucrose, fructose, and cholesterol (AMLN diet). A human liver NASH organoid model was also employed. Although TSP1 deletion in platelets did not affect diet-induced steatosis, TSP1Δpf4 mice exhibited attenuated NASH and liver fibrosis, accompanied by improvements in plasma glucose and lipid homeostasis. Moreover, intrahepatic platelet accumulation, activation and chemokine production were reduced in TSP1Δpf4 mice, which was correlated with decreased immune cell infiltration into the liver. Consequently, this leads to diminished pro-inflammatory signaling in the liver and mitigated the progression of NAFLD. Moreover, in vitro data revealed that co-culturing TSP1-deficient platelets in a human liver NASH organoid model attenuated hepatic stellate cell activation and NASH progression. Additionally, TSP1 deficient platelets play a role in regulating brown fat endocrine function, specifically affecting Nrg4 production. Crosstalk between brown fat and the liver may also influence NAFLD progression. Conclusions: These data suggest that platelet α-granule-derived TSP1 is a significant contributor to diet-induced NASH and fibrosis, and may serve as a new therapeutic target for this severe liver disease.
2024-03-13 | GSE250004 | GEO
Project description:Resistin has been originally identified as an adipokine that links obesity to insulin resistance in mice. In our previous studies in spontaneously hypertensive rats (SHR) expressing a nonsecreted form of mouse resistin (Retn) transgene specifically in adipose tissue (SHR-Retn), we observed an increased lipolysis and serum free fatty acids, ectopic fat accumulation in muscles and insulin resistance. Recently, brown adipose tissue (BAT) has been suggested to play an important role in the pathogenesis of metabolic disturbances by its ability to dissipate energy excess. In the current study, we analyzed autocrine effects of transgenic resistin on BAT glucose and lipid metabolism and mitochondrial function in the SHR-Retn versus nontransgenic SHR controls. We observed that interscapular BAT isolated from SHR-Retn transgenic rats when compared to SHR controls showed a lower relative weight, significantly reduced both basal and insulin stimulated incorporation of palmitate into BAT lipids, and significantly decreased palmitate oxidation and glucose oxidation. In addition, in vivo microPET imaging revealed significantly reduced 18F-FDG uptake in BAT induced by exposure to cold in SHR-Retn versus control SHR. Gene expression profiles identified differentially expressed genes involved in skeletal muscle and connective tissue developmental and inflammation, as well as MAPK and insulin signaling. These results provide compelling evidence that autocrine effects of resisitin in BAT play an important role in the pathogenesis of insulin resistance in the rat.
2016-07-03 | E-MTAB-3787 | biostudies-arrayexpress