Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA394076 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Adult pancreatic β cells are refractory to proliferation, a roadblock for the treatment of insulin-deficient diabetes. Consumption of energy-dense Western or high-fat diet (HFD) triggers mild adaptive β cell mass expansion to compensate for peripheral insulin resistance; however, the underlying molecular mechanism remains unclear. Here we show that Toll-like receptors (TLR) 2/TLR4 act as molecular “brakes” for diet-induced β cell replication in both mice and humans. The combined loss of TLR2/TLR4, but not individually, dramatically increases facultative β, not α, cell replication, leading to progressively enlarged islet mass and hyperinsulinemia in diet-induced obesity. Mechanistically, loss of TLR2/TLR4 increases β cell proliferation and nuclear abundance of Cyclin D2 and CDK4 in an extracellular signal-regulated kinase (ERK)-dependent manner. These data reveal a novel mechanism governing adaptive β cell mass expansion in diet-induced obesity and suggest that selective targeting of TLR2/TLR4 pathways may hold promise for reversing β cell failure in diabetic patients.
2019-03-21 | GSE101392 | GEO
Project description:Toll-like receptors/Interleukin-1 receptor (IL-1R) signaling plays an important role in High-fat diet (HFD)-induced adipose tissue dysfunction contributing to obesity-associated metabolic syndromes. Here, we show an unconventional IL-1R-IRAKM (IL-1R-associated kinase M)-Slc25a1 signaling axis in adipocytes that reprograms lipogenesis to promote diet-induced obesity. Adipocyte-specific deficiency of IRAKM reduced HFD-induced body weight gain, increased whole body energy expenditure and improved insulin resistance, associated with decreased lipid accumulation and adipocyte cell sizes. IL-1β stimulation induced the translocation of IRAKM Myddosome to mitochondria to promote de novo lipogenesis in adipocytes. Mechanistically, IRAKM interacts with and phosphorylates mitochondrial citrate carrier Slc25a1 to promote IL-1β-induced mitochondrial citrate transport to cytosol and de novo lipogenesis. Moreover, IRAKM-Slc25a1 axis mediates IL-1β induced Pgc1a acetylation to regulate thermogenic gene expression in adipocytes. IRAKM kinase-inactivation also attenuated HFD-induced obesity. Taken together, our study suggests that the IL-1R-IRAKM-Slc25a1 signaling axis tightly links inflammation and adipocyte metabolism, indicating a novel therapeutic target for obesity.
2022-06-09 | PXD031934 | Pride
Project description:White adipose tissue (WAT) is a highly active metabolic and endocrine organ, and its dysfunction links obesity to a variety of diseases, ranging from type 2 diabetes to cancer. The function of WAT is under the control of multiple cell signaling systems, including that of G protein-coupled receptors (GPCRs). Gαs- and Gαi-coupled receptors have been reported to regulate lipolysis, and Gαq-coupled receptors stimulate glucose uptake in adipocytes. However, the roles of Gα12/13-coupled receptors in WAT are totally unknown. Here we show that lysophosphatidic acid receptor 4 (LPA4), an adipose cluster GPCR, selectively activates Gα12/13 proteins in adipocytes, and limits continuous remodeling and healthy expansion of WAT in mice. Under standard diet conditions, LPA4-knockout mice showed higher expression levels of mitochondrial biogenesis-related genes in WAT, along with higher production of adiponectin than control mice. In vitro studies have consistently demonstrated that the LPA4/Rho/Rho-kinase signaling pathway suppresses mRNA expression of mitochondrial biogenesis-related genes in adipocytes. In a diet-induced obesity model, LPA4-deficient mice showed “metabolically healthy obese” phenotypes, with continuous WAT expansion, and protection from WAT inflammation, hepatosteatosis, and insulin resistance. Given that GPCRs comprise the most successful class of drug targets, LPA4 would be a promising therapeutic target for obesity-related metabolic disorders.
2018-12-23 | GSE66131 | GEO
Project description:White adipose tissue (WAT) is a highly active metabolic and endocrine organ, and its dysfunction links obesity to a variety of diseases, ranging from type 2 diabetes to cancer. The function of WAT is under the control of multiple cell signaling systems, including that of G protein-coupled receptors (GPCRs). Gαs- and Gαi-coupled receptors have been reported to regulate lipolysis, and Gαq-coupled receptors stimulate glucose uptake in adipocytes. However, the roles of Gα12/13-coupled receptors in WAT are totally unknown. Here we show that lysophosphatidic acid receptor 4 (LPA4), an adipose cluster GPCR, selectively activates Gα12/13 proteins in adipocytes, and limits continuous remodeling and healthy expansion of WAT in mice. Under standard diet conditions, LPA4-knockout mice showed higher expression levels of mitochondrial biogenesis-related genes in WAT, along with higher production of adiponectin than control mice. In vitro studies have consistently demonstrated that the LPA4/Rho/Rho-kinase signaling pathway suppresses mRNA expression of mitochondrial biogenesis-related genes in adipocytes. In a diet-induced obesity model, LPA4-deficient mice showed “metabolically healthy obese” phenotypes, with continuous WAT expansion, and protection from WAT inflammation, hepatosteatosis, and insulin resistance. Given that GPCRs comprise the most successful class of drug targets, LPA4 would be a promising therapeutic target for obesity-related metabolic disorders.
2018-12-23 | GSE66130 | GEO
Project description:The aim of this study is to investigate the interaction between diet - primary meat and fiber - and polymorphisms in Toll-like receptors in relation to risk of colorectal cancer in a Danish prospective cohort.
| 2251863 | ecrin-mdr-crc
Project description:Inflammation is a key component of the pathogenesis of obesity-associated type 2 diabetes (T2D). However, the nature of T2D-associated islet inflammation and its impacts on T2D-associated beta cell abnormalities remain poorly defined. Using both diet-induced and genetically modified T2D animal models, we explore immune components of islet inflammation and define their roles in regulating beta cell function and proliferation. Our studies show that T2D-associated islet inflammation is uniquely dominated by macrophages, without the involvement of adaptive immune cells. We identify two islet macrophage populations, characterized by their distinct phenotypes, anatomical distributions and functional properties. Obesity induces a local expansion of intra-islet macrophages, independent of the replenishment from circulating monocytes. In contrast, the abundance of peri-islet macrophages is negligibly affected by obesity. Functionally, intra-islet macrophages impair beta cell function in a cell-cell contact dependent manner. In contrast, both intra- and peri-islet macrophage populations are able to promote beta cell proliferation. Together, these data provide a definitive view of the genesis of T2D-associated islet inflammation and define specific roles of islet macrophages in regulating beta cell function and proliferation.
2019-01-02 | GSE112002 | GEO
Project description:Efficient collagen degradation is essential for adaptive subcutaneous adipose tissue (SAT) expansion that protects against ectopic lipid deposition during weight gain. Here, we aimed to further define the mechanism for this collagenolytic process. We show that loss of collagen type-1 (CT1) and increased CT1-fragment levels in expanding SAT are associated with proliferation of resident M2-like macrophages that display increased CD206-mediated engagement in collagen endocytosis compared to chow-fed controls. Blockage of CD206 during acute diet-induced weight gain leads to SAT CT1-fragment accumulation associated with elevated inflammation and fibrosis markers. Moreover, the collagen endocytosis engagement of SAT macrophages is dramatically reduced in obesity along with elevated levels of short collagen fragments. Finally, we show that such fragments provoke M2-macrophage proliferation and fibroinflammatory changes in vitro. Thus, our data delineate the importance of a macrophage-collagen axis in physiological SAT expansion. Further understanding of this process can define novel targets in obesity-related disorders.
2024-06-16 | PXD043721 | Pride
Project description:Changes in the secretion profile of visceral-pancreatic white adipose tissue (pWAT) due to diet-induced obesity are partially responsible for increased beta cell replication, suggesting that a crosstalk between pWAT and beta cells may play a role in regulating beta cell plasticity. The molecular mechanisms underlying this cross-talk are still not fully understood. The aim of this study was to integrate transcriptomic, proteomic and metabolomic data to unravel the cross-talk between adipose tissue and pancreatic islets during evolution of obesity. Pancreatic islets from control lean and cafeteria diet fed obese rats were obtained. RNA was extracted and processed for further hybridization on Affymetrix microarrays (GeneChip Rat Genome 230 2.0 (Affymetrix, Santa Clara, CA)).
2014-02-15 | E-GEOD-44373 | biostudies-arrayexpress