Insulin-like 3 Affects Zebrafish Spermatogenic Cells Directly and via Sertoli Cells

Abstract Pituitary hormones can use local signaling molecules to regulate target tissue functions. In adult zebrafish testes, follicle-stimulating hormone (Fsh) strongly increases the production of insulin-like 3 (Insl3), a Leydig cell-derived growth factor found in all vertebrates. Little information is available regarding Insl3 function in adult spermatogenesis. The Insl3 receptors Rxfp2a and 2b were expressed by type A spermatogonia and Sertoli and myoid cells, respectively, in zebrafish testis tissue. Loss of insl3 increased germ cell apoptosis in males starting at 9 months of age, but spermatogenesis appeared normal in fully fertile, younger adults. Insl3 changed the expression of 409 testicular genes. Among others, retinoic acid (RA) signaling was up- and peroxisome proliferator-activated receptor gamma (Pparg) signaling was down-regulated. Follow-up studies showed that RA and Pparg signaling mediated Insl3 effects, resulting in the increased production of differentiating spermatogonia. This suggests that Insl3 recruits two locally active nuclear receptor pathways to implement pituitary (Fsh) stimulation of spermatogenesis.

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Insulin-like 3 affects zebrafish spermatogenic cells directly and via Sertoli cells

Communications Biology ◽

10.1038/s42003-021-01708-y ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Diego Crespo ◽

Luiz H. C. Assis ◽

Yu Ting Zhang ◽

Diego Safian ◽

Tomasz Furmanek ◽

...

Keyword(s):

Pituitary Hormones ◽

Tissue Loss ◽

Peroxisome Proliferator ◽

Target Tissue ◽

Younger Adults ◽

Peroxisome Proliferator Activated Receptor ◽

Local Signaling ◽

Testis Tissue ◽

Type A Spermatogonia

AbstractPituitary hormones can use local signaling molecules to regulate target tissue functions. In adult zebrafish testes, follicle-stimulating hormone (Fsh) strongly increases the production of insulin-like 3 (Insl3), a Leydig cell-derived growth factor found in all vertebrates. Little information is available regarding Insl3 function in adult spermatogenesis. The Insl3 receptors Rxfp2a and 2b were expressed by type A spermatogonia and Sertoli and myoid cells, respectively, in zebrafish testis tissue. Loss of insl3 increased germ cell apoptosis in males starting at 9 months of age, but spermatogenesis appeared normal in fully fertile, younger adults. Insl3 changed the expression of 409 testicular genes. Among others, retinoic acid (RA) signaling was up- and peroxisome proliferator-activated receptor gamma (Pparg) signaling was down-regulated. Follow-up studies showed that RA and Pparg signaling mediated Insl3 effects, resulting in the increased production of differentiating spermatogonia. This suggests that Insl3 recruits two locally active nuclear receptor pathways to implement pituitary (Fsh) stimulation of spermatogenesis.

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The Ala/Ala genotype of PPARY Pro12 Ala polymorphism is associated with late onset of multiple sclerosis

Archives of Biological Sciences ◽

10.2298/abs1302447l ◽

2013 ◽

Vol 65 (2) ◽

pp. 447-453

Author(s):

N. Lukic ◽

A. Stankovic ◽

E. Dincic ◽

M. Bundalo ◽

Z. Krsmanovic ◽

...

Keyword(s):

Multiple Sclerosis ◽

Late Onset ◽

Age At Onset ◽

Peroxisome Proliferator ◽

Pro12ala Polymorphism ◽

Peroxisome Proliferator Activated Receptor ◽

Post Hoc ◽

Genotype And Allele Frequencies

The function of peroxisome proliferator-activated receptor ? (PPAR?) in immune regulation, as well as in antiinflammatory and anti-proliferative actions towards T lymphocytes, has been reported. A potential role of PPARs in multiple sclerosis (MS) was suggested. The aim of this study was to investigate if there is an association of PPAR?-2 Pro12Ala polymorphism with MS in 361 patients from Serbia. The genotype and allele frequencies of Pro12Ala polymorphism were not significantly different between controls and patients, or between females and males. In contrast to controls, we detected a rare Ala/Ala genotype in patients with MS. We found that there is a significant association of Ala/Ala genotype with older age at onset (ANOVA, p=0.07; LSD post-hoc, Ala/Ala vs. Pro/Ala, p=0.03, Ala/Ala vs. Pro/Pro p=0.02). It would be useful to validate our results in other populations, as well as to perform follow-up of the disease progression in regard to PPAR? genotypes.

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Increased Body Mass Index but Not Common Vitamin D Receptor, Peroxisome Proliferator–Activated Receptor γ, or Cytokine Polymorphisms Confers Predisposition to Posttransplant Diabetes

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2011-0160-oa ◽

2011 ◽

Vol 135 (12) ◽

pp. 1581-1584 ◽

Cited By ~ 2

Author(s):

Ping Wang ◽

Elissa Hudspeth

Keyword(s):

Body Mass Index ◽

Vitamin D ◽

Body Mass ◽

Vitamin D Receptor ◽

Solid Organ Transplantation ◽

Significant Risk ◽

Peroxisome Proliferator ◽

Solid Organ ◽

Peroxisome Proliferator Activated Receptor

Context.—Posttransplant diabetes mellitus (PTDM) is a major complication after solid organ transplantation. The use of corticosteroids and calcineurin inhibitors, especially tacrolimus, are significant risk factors. However, it is not clear what genetic factors modify the risk. Evidence suggests vitamin D deficiency, perturbed glucose homeostasis, and increased inflammation all play roles in the development of diabetes. Objective.—To investigate whether common vitamin D receptor (VDR), cytokine, and peroxisome proliferator–activated receptor γ (PPARγ) polymorphisms are correlated with the development of PTDM. Design.—DNA was isolated from the peripheral blood of 51 kidney transplant recipients with PTDM and 72 patients without diabetes pretransplant or posttransplant at the time of follow-up. The genotypes for 5 polymorphisms, 1 each in VDR, PPARγ, INFγ, TGFβ1, and TNF, were determined using direct sequencing. Age, sex, number of acute rejection episodes, follow-up length, ethnicity, body mass index, and the frequency of alleles and genotypes for each polymorphism were compared between the 2 groups. Results.—Body mass index was the only factor that was statistically different between the 2 groups (P = .001). The frequency of different alleles and genotypes for each of the 5 polymorphisms did not differ between the 2 groups. Conclusions.—These results indicate that increased body mass index is a significant risk factor for the development of PTDM. However, none of the genetic polymorphisms studied confer predisposition to PTDM with the current sample size.

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Prognostic Significance of the Fission1/Parkin Ratio for Sepsis: A Prospective Cohort Study

Frontiers in Medicine ◽

10.3389/fmed.2021.642749 ◽

2021 ◽

Vol 8 ◽

Author(s):

Wei Huang ◽

Xiaoting Wang ◽

Hongmin Zhang ◽

Guangjian Wang ◽

Dawei Liu

Keyword(s):

Operating Characteristic ◽

Independent Predictor ◽

Mitochondrial Fission ◽

Prognostic Significance ◽

Serum Levels ◽

Enzyme Linked Immunosorbent Assay ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Icu Admission

Introduction: Fission1 (Fis1) and parkin are key proteins related to mitochondrial fission and mitophagy, respectively. This study aimed to assess the prognostic value of the Fis1/parkin ratio as a biomarker in patients with sepsis.Methods: Consecutive patients with sepsis (n = 133) or simple infection (n = 24) were enrolled within 24 h of arrival at the intensive care unit (ICU). Serum levels of Fis1, parkin, mitofusin2 (Mfn2), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) were measured by enzyme-linked immunosorbent assay (ELISA) upon ICU admission. Clinical parameters and standard laboratory test data were also collected. All patients received follow-up for at least 28 days.Results: Patients with sepsis presented with significantly decreased serum levels of parkin, Mfn2, and PGC-1α, but an increased serum Fis1 level and Fis1/parkin, Fis1/Mfn2, and Fis1/PGC-1α ratios at ICU admission. Relative to patients with simple infections, the ratios were remarkably elevated in septic patients—particularly septic shock patients. The area under the receiver operating characteristic (ROC) curve of the Fis1/parkin ratio was greater than that of Fis1, parkin, Mfn2, and PGC-1α levels as well as that of the Fis1/Mfn2 and Fis1/PGC-1α ratios for prediction of 28-day mortality due to sepsis. All of the ratios were significantly higher in non-survivors than survivors at the 28-day follow-up examination. Fis1/parkin ratio was found to be an independent predictor of 28-day mortality in patients with sepsis.Conclusions: The Fis1/parkin ratio is valuable for risk stratification in patients with sepsis and is associated with poor clinical outcomes for sepsis in the ICU.

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Peroxisome Proliferator-Activated Receptor-δ Deficiency in Microglia Results in Exacerbated Axonal Injury and Tissue Loss in Experimental Autoimmune Encephalomyelitis

Frontiers in Immunology ◽

10.3389/fimmu.2021.570425 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ellinore R. Doroshenko ◽

Paulina C. Drohomyrecky ◽

Annette Gower ◽

Heather Whetstone ◽

Lindsay S. Cahill ◽

...

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Axonal Injury ◽

Reactive Oxygen Species Generation ◽

Tissue Loss ◽

Peroxisome Proliferator ◽

Autoimmune Encephalomyelitis ◽

Peroxisome Proliferator Activated Receptor ◽

Expression Of Genes ◽

Deficient Mice ◽

Experimental Autoimmune

Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear receptor that functions to maintain metabolic homeostasis, regulate cell growth, and limit the development of excessive inflammation during immune responses. Previously, we reported that PPAR-δ-deficient mice develop a more severe clinical course of experimental autoimmune encephalomyelitis (EAE); however, it was difficult to delineate the role that microglia played in this disease phenotype since PPAR-δ-deficient mice exhibited a number of immune defects that enhanced CNS inflammation upstream of microglia activation. Here, we specifically investigated the role of PPAR-δ in microglia during EAE by using mice where excision of a floxed Ppard allele was driven by expression of a tamoxifen (TAM)-inducible CX3C chemokine receptor 1 promoter-Cre recombinase transgene (Cx3cr1CreERT2: Ppardfl/fl). We observed that by 30 days of TAM treatment, Cx3cr1CreERT2: Ppardfl/fl mice exhibited Cre-mediated deletion primarily in microglia and this was accompanied by efficient knockdown of Ppard expression in these cells. Upon induction of EAE, TAM-treated Cx3cr1CreERT2: Ppardfl/fl mice presented with an exacerbated course of disease compared to TAM-treated Ppardfl/fl controls. Histopathological and magnetic resonance (MR) studies on the spinal cord and brains of EAE mice revealed increased Iba-1 immunoreactivity, axonal injury and CNS tissue loss in the TAM-treated Cx3cr1CreERT2: Ppardfl/fl group compared to controls. In early EAE, a time when clinical scores and the infiltration of CD45+ leukocytes was equivalent between Cx3cr1CreERT2: Ppardfl/fl and Ppardfl/fl mice, Ppard-deficient microglia exhibited a more reactive phenotype as evidenced by a shorter maximum process length and lower expression of genes associated with a homeostatic microglia gene signature. In addition, Ppard-deficient microglia exhibited increased expression of genes associated with reactive oxygen species generation, phagocytosis and lipid clearance, M2-activation, and promotion of inflammation. Our results therefore suggest that PPAR-δ has an important role in microglia in limiting bystander tissue damage during neuroinflammation.

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Reduced Gene Expression of Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α in Whole Blood in Euthyroid Patients One Year After Hemithyroidectomy for Benign Euthyroid Goiter

Hormone and Metabolic Research ◽

10.1055/a-0822-3066 ◽

2019 ◽

Vol 51 (02) ◽

pp. 127-133

Author(s):

Tina Kristensen ◽

Palle Pedersen ◽

Jacob Larsen ◽

Anne-Dorthe Feldthusen ◽

Søren Jelstrup ◽

...

Keyword(s):

Gene Expression ◽

Mitochondrial Function ◽

Whole Blood ◽

Reference Range ◽

Quantitative Polymerase Chain Reaction ◽

Peroxisome Proliferator ◽

Mixed Effect ◽

Peroxisome Proliferator Activated Receptor ◽

One Year

AbstractWe have previously reported decreased thyroid function within the laboratory reference range and changes in mitochondrial function after hemithyroidectomy. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and coactivator-1β (PGC-1β) are key regulators of mitochondrial biogenesis and function. The aim was to examine the influence of hemithyroidectomy on the longitudinal change in mRNA expression of these genes. In addition, we measured longitudinal changes in mRNA expressions of the mitochoncrial-related genes nuclear factor erythroid-derived 2-like 2 (NFE2L2), mitochondrial transcription factor A (TFAM), and sodium dismutase 2 (SOD2). Twenty-eight patients were examined before and 1, 3, 6, and 12 months after hemithyroidectomy for benign euthyroid goiter. Thyroid stimulating hormone (TSH) and thyroid hormones were measured, and whole blood gene expression of PGC-1α, PGC-1β, NFE2L2, TFAM, and SOD2 was examined by reverse transcription quantitative Polymerase Chain Reaction. We used mixed effect regression models to investigate changes in gene expression with time. Averaged over all follow-up visits, TSH increased (p=0.001), tT3 declined (p=0.01), and fT4/tT3 ratio increased (p=0.03) over one-year follow-up, but fT4 remained unchanged. Averaged over all follow-up visits, whole blood PGC-1α levels (p<0.001) and SOD2 (p=0.009) levels declined, but PGC-1β, TFAM, and NFE2L2 did not change over one-year follow-up. The study demonstrates significant downregulation of whole blood PGC-1α and SOD2 gene expressions in hemithyroidectomized patients with a concomitant increase in TSH concentration within the reference range. Thus, hemithyroidectomized patients may likely have impaired mitochondrial function.

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