Lepr+ mesenchymal cells sense diet to modulate intestinal stem cells via the Leptin-Igf1-Igf1r axis
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PROVIDER: PRJNA697948 | ENA |
REPOSITORIES: ENA
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Project description:We demonstrated that Lepr+ mesenchymal cells surround intestinal crypts where ISCs and transit-amplifying (TA) cells localize. The abundance of these cells increased upon administration of a high-fat diet (HFD) but dramatically decreased upon fasting. Depletion of Lepr+ mesenchymal cells resulted in fewer ISCs, compromised architecture of crypt-villi axis and impaired intestinal regeneration. Furthermore, Lepr+ cell-derived Igf1 has been identified as an important effector that promotes the proliferation of ISCs and TA cells. Deletion of Igf1 in Lepr+ cells partially recapitulated Lepr+ cell-ablated intestinal phenotypes during both homeostasis and regeneration. Overall, Lepr+ mesenchymal cells sense diet alteration and function as a novel niche for ISCs via the stromal Igf1 - epithelial Igf1r axis, which is critical for intestinal homeostasis and regeneration. These findings revealed that Lepr+ mesenchymal cells are an important mediator that links diet to ISC function and might provide a novel therapeutic target for gut diseases.
2022-03-07 | GSE165806 | GEO
Project description:IGF1 and IGF1 receptors (IGF1R) are present in the adult heart and have been shown to be essential for myocardial performance. Insulin-like growth factor 1 (IGF1) is produced in numerous tissues particularly by the liver in response to growth hormone stimulation and is an important factor in the regulation of post-natal growth and development. We have generated and characterized transgenic mice over-expressing the IGF1R. We crossed IGF1R transgenic mice with dominant negative (dn)PI3K (p110) and with constitutively active (ca)PI3K(p110) transgenic mice. Expression profiling was performed on the ventricles of IGF1R, IGF1R-caPI3K, IGF1R-dnPI3K, caPI3K, dnPI3K transgenic female mice at 3 months of age. Non-transgenic littermates were used as controls.
2007-09-29 | E-GEOD-1143 | biostudies-arrayexpress
Project description:Leptin receptors (Lepr) are expressed by various types of stem cells including mesenchymal stem cells, hematopoietic stem cells, embryonic stem cells, and induced pluripotent stem cells. Leptin/lepr signaling is also a central regulator of metabolism. However, the role of Lepr in pluripotency, metabolic disease progression and growth development is still controversial and poorly understood. In the present study, we explored the Lepr function in disease progression, pluripotency and metabolism using day 14.5 mouse embryonic fibroblasts (MEFs) and their reprogrammed induced pluripotent stem cells (iPSCs) as model system. We successfully reprogrammed mouse embryonic fibroblasts into iPSCs from control and db/db (Lepr deficient) mice. Using a global quantitative proteomic approach, we identified key pathways regulating pluripotency, metabolic homeostasis and protein synthesis during fetal growth and development. The Lepr MEFs show abnormal metabolic abnormalities and mitochondrial dysfunction as compared to control MEFs, while Lepr iPSCs show upregulated elongated factor 4 e (eIF4e) protein synthesis pathway and altered Oct4 and Stat3 pathways which are involved in normal fetal growth development. Furthermore, chip analysis revealed that higher Stat3 binding on the promoter of eIF4e in Lepr iPSCs leads to higher protein synthesis in these cell types as compared to control iPSCs. Finally, point mutation corrected Lepr iPSCs using CRISPR/Cas9 gene editing method showed recovered pluripotency, metabolic and protein synthesis pathways. In conclusion, we have shown that Lepr signaling is involved in the regulation of the metabolic properties and key developmental pathways in MEFs and stemness of pluripotent stem cells. Disruption of Lepr signaling has been shown to involve in the pathophysiology of various diseases including obesity and diabetes. The generated MEFs and iPSCs in this present study provide valuable tools to explore the role of Lepr in the progression of obesity, diabetes and metabolic abnormalities, and to find the putative targets of Lepr signaling during the development of these diseases.
2021-09-09 | PXD020959 | Pride
Project description:IGF1 and IGF1 receptors (IGF1R) are present in the adult heart and have been shown to be essential for myocardial performance. Insulin-like growth factor 1 (IGF1) is produced in numerous tissues particularly by the liver in response to growth hormone stimulation and is an important factor in the regulation of post-natal growth and development. We have generated and characterized transgenic mice over-expressing the IGF1R. We crossed IGF1R transgenic mice with dominant negative (dn)PI3K (p110) and with constitutively active (ca)PI3K(p110) transgenic mice. Expression profiling was performed on the ventricles of IGF1R, IGF1R-caPI3K, IGF1R-dnPI3K, caPI3K, dnPI3K transgenic female mice at 3 months of age. Non-transgenic littermates were used as controls. Keywords = http://cardiogenomics.med.harvard.edu/groups/proj1/pages/igfr1_home.html Keywords: other
2004-03-24 | GSE1143 | GEO
Project description:In a prospective clinical study, we show that increased serum IGF1 levels in a patient may be a predictive marker of melanoma escape to therapies targeting MAPK pathway (BRAFi/MEKi). In addition, our in vitro and in vivo studies suggest that the response of targeted therapies-resistant melanoma cells to IGF1R inhibitor appears to correlate with the level of IGF1 secretion. Overall, our results suggest that monitoring serum IGF1 levels would individually identify melanoma patients who escape BRAFi/MEKi treatment and may benefit from a combination of targeted therapies and IGF1 signaling inhibition to overcome resistance.
2023-10-30 | GSE239284 | GEO
Project description:Leptin receptor (LEPR) identifies a subpopulation of hematopoietic stem cells (HSCs) with high repopulating potential. In this study, we demonstrated that LEPR-expressing HSCs while exhibiting significantly higher engrafting potential and self-renewing capacity in young mice showed early age-associated decline in these functions as compared to the LEPR- HSCs. LEPR+ HSCs have transcriptomic profiles significantly different from LEPR- HSCs in young mouse bone marrow, but middle-aged HSCs do not have distinct transcriptomic profiles based on LEPR status. The age-related phenotypes were associated with a proinflammatory transcriptomic profile at baseline in young LEPR+ HSCs, which was further exacerbated by age. In contrast, LEPR- HSCs did not show age-associated functional impairment at the ages tested. This suggested that subsets of HSCs are susceptible to age-related decline in function at varying ages and that LEPR+ HSCs are a potential target for early cellular therapeutic interventions in delaying the detrimental effects of aging in hematopoiesis.
2023-02-18 | GSE221126 | GEO
Project description:Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor (LepR)-expressing barrier cells which ensheath sympathetic axon bundles in adipose tissues. These LepR-expressing Sympathetic Perineurial Cells (SPCs) produce IL33, a factor for maintenance and recruitment of regulatory T cell (Treg) and eosinophils in AT. Brown adipose tissues (BAT) of mice lacking IL33 in SPCs (SPCIL33cKO) have fewer Treg and eosinophils, resulting in increased BAT inflammation. These SPCIL33cKO mice are more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCIL33cKO mice have impaired adaptive thermogenesis, and are unresponsive to leptin-induced rescue of metabolic adaptation. We, therefore, identify LepR-expressing SPCs as a source of IL33 which orchestrate an anti-inflammatory environment in BAT, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+ IL33+SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research.
2023-12-12 | GSE227493 | GEO
Project description:Insulin-like growth factor (IGF1R) signalling has been implicated to play an important role in regulation of cardiac growth, hypertrophy and contractile function, and has been linked to the development of age related congestive heart failure. Here we address the question to what extent cardiomyocyte specific IGF1 signalling is essential for maintenance of the structural and functional integrity of the adult murine heart. To investigate the effects of IGF1 signalling in the adult heart without confounding effects due to IGF1 over-expression or adaptation during embryonic and early post-natal development, we inactivated the IGF1R by a 4-hydroxy tamoxifen inducible Cre recombinase in adult cardiac myocytes. Efficient inactivation of the IGF1R (iCMIGF1RKO) as assessed by Western analysis and real-time PCR went along with reduced IGF1-dependent AKT and GSK3β-phosphorylation. Functional analysis by conductance manometry and magnetic resonance imaging (MRI) revealed no functional alterations in young adult iCMIGF1RKO mice (age 3 month). However, when induced in aged mice (11 month) diastolic cardiac function was depressed. To address the question if insulin signalling might compensate for the defective IGF1R signalling we inactivated β-cells by streptozotocin. However, the diabetes associated functional depression was similar in controls and iCMIGF1RKO mice. Similarly, analysis of the cardiac gene expression profile on 44K microarrays did not reveal activation of overt adaptive processes. Endogenous IGF1 receptor signalling is required for conservation of cardiac function of the aging heart, but not for the integrity of cardiac structure and function of young hearts. Four samples of each group: the control group, positive for Cre recombinase, but negative for the floxed IGF-1R and the experimental group with double transgenic mice (merCremer/+ IGFloxP/IGFloxP).
2012-07-31 | E-GEOD-32936 | biostudies-arrayexpress
Project description:In contrast to light-dependent entrainment of the central circadian pacemaker, the molecular and neural underpinnings of entrainment by non-photic cues, such as food, remain unclear. Using single-nucleus RNA-sequencing, we identified a leptin receptor (LepR) positive neuronal population in the dorsomedial hypothalamus (DMH) that is responsive to scheduled feeding (SF). During SF, DMH LepR neuron activity precedes an impending meal. Mis-timed exogenous leptin administration or chemogenetic activation of DMH LepR neurons inhibits both neuronal and behavioral food anticipatory activities. Further, repetitive chemogenetic activation of DMH LepR neurons partitions a secondary bout of circadian locomotor activity in phase with the stimulation. This work places DMH LepR neurons as an essential integrator of food entrainment, and positions leptin as a critical central mediator of this circadian response.
2023-06-14 | GSE211757 | GEO
Project description:Introduction: Leptin inhibits insulin secretion from isolated islets from multiple species, but the cell type that mediates this process remains elusive. Several mouse models have been used to explore this question. Ablation of the leptin receptor (Lepr) throughout the pancreatic epithelium results in altered glucose homeostasis and ex vivo insulin secretion and Ca2+ dynamics. However, Lepr removal from neither alpha nor beta cells mimics this result. Moreover, scRNAseq data has revealed an enrichment of LEPR in human islet delta cells. Methods: We confirmed LEPR upregulation in human delta cells by performing RNAseq on fixed, sorted beta and delta cells. We then used a mouse model to test whether delta cells mediate the diminished glucose-stimulated insulin secretion in response to leptin. Results: Ablation of Lepr within mouse delta cells did not change glucose homeostasis or insulin secretion, whether mice were fed a chow or high-fat diet. We further show, using a publicly available scRNAseq dataset, that islet cells expressing Lepr lie within endothelial cell clusters. Conclusions: In mice, leptin does not influence beta-cell function through delta cells.
2023-10-02 | GSE243984 | GEO