Clr-f expression regulates kidney immune and metabolic homeostasis
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ABSTRACT:
PROVIDER: PRJNA816926 | ENA |
REPOSITORIES: ENA
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Project description:The C-type lectin-related protein, Clr-f, encoded by Clec2h in the mouse NK gene complex (NKC), is a member of a family of immune regulatory lectins that guide immune responses at distinct tissues of the body. Clr-f is highly expressed in the kidney; however, its activity in this organ is unknown. To assess the requirement for Clr-f in kidney health and function, we generated a Clr-f-deficient mouse (Clr-f−/−) by targeted deletions in the Clec2h gene. Mice lacking Clr-f exhibited glomerular and tubular lesions, immunoglobulin and C3 complement protein renal deposits, and significant abdominal and ectopic lipid accumulation. Whole kidney transcriptional profile analysis of Clr-f−/− mice at 7, 13, and 24 weeks of age revealed a dynamic dysregulation in lipid metabolic processes, stress responses, and inflammatory mediators. Examination of the immune contribution to the pathologies of Clr-f−/− mouse kidneys identified elevated IL-12 and IFNγ in cells of the tubulointerstitium, and an infiltrating population of neutrophils and T and B lymphocytes. The presence of these insults in a Rag1−/−Clr-f−/− background reveals that Clr-f−/− mice are susceptible to a T and B lymphocyte-independent renal pathogenesis. Our data reveal a role for Clr-f in the maintenance of kidney immune and metabolic homeostasis.
2022-03-19 | GSE198814 | GEO
Project description:Integration of metabolic, stress and immune responses plays a fundamental role during animal development to maintain energy homeostasis while ensuring growth and proper developmental timing. Perturbation of metabolic and immune signaling circuits has detrimental consequences to animal development including growth retardation, organ malfunction and emergence of the metabolic syndrome. Here, we demonstrate that the Drosophila basic region-leucine zipper (bZIP) protein, Activating transcription factor 3 (Atf3), safeguards a balance of metabolic and immune system responses during fly development. Loss of Atf3 function results in lethality during late-larval and pupal stages. Atf3-deficient larvae exhibit phenotypes resembling the metabolic syndrome in mammals. Excessive accumulation of lipids in the larval fat body and gut is accompanied by altered expression of genes involved in lipid metabolism. Moreover, the fat body of atf3 mutants becomes infiltrated by hemocytes. The major pro-inflammatory pathways signaling through JNK and Imd are hyperactivated in atf3 mutants, causing ectopic expression of antimicrobial peptide genes. Suppression of the immune response, achieved by reducing the gene dose of the transcription factors FOXO or NF-kappaB/Relish, significantly improves lipid metabolism and normalizes gene expression profile of atf3 mutants. In addition, heterozygosity of relish partially rescues lethality of the atf3 mutants. Our data thus identify Atf3 as an essential player that links metabolic and immune system homeostasis during animal development. Examination of mRNA levels from four genotypes of male, 3rd instar Drosophila melanogaster larvae. mRNA levels from four genotypes relative to y w control were determined using two biological replicates per genotype. Genome build: BDGP R5/dm3, April 2006
2012-11-05 | E-GEOD-36377 | biostudies-arrayexpress
Project description:Integration of metabolic, stress and immune responses plays a fundamental role during animal development to maintain energy homeostasis while ensuring growth and proper developmental timing. Perturbation of metabolic and immune signaling circuits has detrimental consequences to animal development including growth retardation, organ malfunction and emergence of the metabolic syndrome. Here, we demonstrate that the Drosophila basic region-leucine zipper (bZIP) protein, Activating transcription factor 3 (Atf3), safeguards a balance of metabolic and immune system responses during fly development. Loss of Atf3 function results in lethality during late-larval and pupal stages. Atf3-deficient larvae exhibit phenotypes resembling the metabolic syndrome in mammals. Excessive accumulation of lipids in the larval fat body and gut is accompanied by altered expression of genes involved in lipid metabolism. Moreover, the fat body of atf3 mutants becomes infiltrated by hemocytes. The major pro-inflammatory pathways signaling through JNK and Imd are hyperactivated in atf3 mutants, causing ectopic expression of antimicrobial peptide genes. Suppression of the immune response, achieved by reducing the gene dose of the transcription factors FOXO or NF-kappaB/Relish, significantly improves lipid metabolism and normalizes gene expression profile of atf3 mutants. In addition, heterozygosity of relish partially rescues lethality of the atf3 mutants. Our data thus identify Atf3 as an essential player that links metabolic and immune system homeostasis during animal development.
2012-11-05 | GSE36377 | GEO
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2012-01-23 | E-GEOD-34417 | biostudies-arrayexpress
Project description:Mitochondria are known to be functional organelles, but their role as a signaling unit is increasingly being appreciated. The recent identification of a short open reading frame (sORF) in the mitochondrial DNA (mtDNA) that encodes a signaling peptide, humanin, suggests the possible existence of additional sORFs in the mtDNA that yield bioactive peptides. Here we report the identification of a sORF within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide named MOTS-c (mitochondrial open-reading-frame of the twelve S rRNA -c) that regulates insulin sensitivity and metabolic homeostasis. MOTS-c is detected in various tissues and in circulation in an age-dependent manner. Its primary target organ appears to be the skeletal muscle and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, causing a significant accumulation of AICAR levels concomitantly with AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat diet-induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may be more actively engaged in regulating metabolic homeostasis than previously recognized, through the production of peptides encoded within its genome that act at the cellular and organismal level. Human embryonic kidney cells (HEK293 cell line) were cultured in 10-cm dishes in 7 mL of phenol-free DMEM supplemented with 10% FBS and incubated with water (controls) or the 16-amino-acid peptide mitochondrial open-reading-frame of the twelve S rRNA-c (MOTS-c, 10 uM) for 4 or 72 hours prior to RNA extraction.
2015-03-07 | E-GEOD-65068 | biostudies-arrayexpress
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2023-09-07 | GSE233859 | GEO
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| S-EPMC3457521 | biostudies-literature
Project description:The Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) is a nuclear corepressor that regulates the transcriptional activity of many transcription factors critical for metabolic processes. While the importance of SMRT’s role in the adipocyte has been well-established, prior mouse models have yielded contradictory phenotypes, limiting our understanding of its in vivo function in the context of homeostatic maintenance. Multiple models suggest that SMRT deficiency leads to increased adiposity, though the effects of SMRT loss on glucose tolerance and insulin sensitivity have been variable. We therefore generated an adipocyte-specific SMRT knockout (adSMRT-/-) mouse to more clearly define SMRT’s metabolic contributions. In doing so, we found that SMRT deletion in the adipocyte does not, in fact, lead to obesity, despite increased food consumption in knockouts – even when mice are challenged with a high-fat diet. This suggests that prior adiposity phenotypes described in generalized models were due to effects beyond the adipocyte. However, an adipocyte-specific SMRT deficiency still led to dramatic effects on systemic glucose tolerance and adipocyte insulin sensitivity, impairing both. This metabolically deleterious effect was coupled with a surprising immune phenotype, wherein most genes differentially expressed in the adipose tissue of adSMRT-/- mice were upregulated in pro-inflammatory pathways. Flow cytometry and conditioned media experiments demonstrated that secreted factors from knockout adipose tissue strongly informed resident macrophages to develop a pro-inflammatory, MMe (metabolically activated) phenotype. Taken together, these studies suggest a novel role for SMRT as an integrator of metabolic and inflammatory signals to effectively maintain physiological homeostasis.
2019-07-05 | GSE129369 | GEO