scholarly journals Lipin1 Regulation by Estrogen in Uterus and Liver: Implications for Diabetes and Fertility

Endocrinology ◽  
2007 ◽  
Vol 148 (8) ◽  
pp. 3685-3693 ◽  
Author(s):  
P. Mangala Gowri ◽  
Surojeet Sengupta ◽  
Suzanne Bertera ◽  
Benita S. Katzenellenbogen
Keyword(s):  
Metabolic Regulation ◽  
Energy Use ◽  
Nod Mice ◽  
Blood Levels ◽  
Estrogen Regulation ◽  
Nonobese Diabetic ◽  
Lipid Utilization ◽  
Phosphatidic Acid Phosphatase ◽  
Target Organs ◽  
Estrogen Administration

Estrogens are essential for fertility and also have important effects on regulation of adiposity and the euglycemic state. We report here that lipin1, a candidate gene for lipodystrophy and obesity that is a phosphatidic acid phosphatase critical in regulation of cellular levels of diacylglycerol and triacylglycerol and a key regulator of lipid utilization, is rapidly and robustly down-regulated in the uterus by estradiol via the estrogen receptor. Lipin1 is expressed predominantly in the uterine luminal and glandular epithelium, and during the estrous cycle, lipin1 is lowest when blood levels of estrogen are highest. Lipin1 is expressed throughout all cells in the liver of ovariectomized female mice, and a sustained down-regulation is observed at the mRNA, protein and immunohistochemical levels after estrogen administration. Because the coupling of proper energy use and availability is central to reproduction, we also investigated expression of lipin1 in the uterus and liver of several mouse models of diabetes. Nonobese diabetic (NOD) mice, which have high blood levels of estrogen and impaired fertility, were severely deficient in lipin1 in the uterus and liver, which, interestingly, could be restored by insulin treatment. By contrast, nonobese diabetic/severe combined immunodeficient (NOD-SCID) mice, which do not develop diabetes, showed normal levels of lipin1. Our findings of lipin1 regulation by estrogen in two key target organs suggest a new role for this lipid-regulating phosphatase not only in central metabolic regulation but also in uterine function and reproductive biology. Estrogen regulation of lipin1 may provide a mechanistic link between estrogens, lipid metabolism, and lipid signaling.

Preventive and therapeutic effects of large-dose nicotinamide injections on diabetes associated with insulitis. An observation in nonobese diabetic (NOD) mice

Diabetes ◽  
1982 ◽  
Vol 31 (9) ◽  
pp. 749-753 ◽  
Author(s):  
K. Yamada ◽  
K. Nonaka ◽  
T. Hanafusa ◽  
A. Miyazaki ◽  
H. Toyoshima ◽  
...  
Keyword(s):  
Large Dose ◽  
Nod Mice ◽  
Therapeutic Effects ◽  
Nonobese Diabetic

Prevention of Autoimmunity in Nonobese Diabetic (NOD) Mice by Neonatal Transfer of Allogeneic Thymic Macrophages

Autoimmunity ◽  
1995 ◽  
Vol 21 (2) ◽  
pp. 89-97 ◽  
Author(s):  
Harry M. Georgiou ◽  
Dora Constantinou ◽  
Thomas E. Mandel
Keyword(s):  
Nod Mice ◽  
Nonobese Diabetic

scholarly journals T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice.

1989 ◽  
Vol 169 (5) ◽  
pp. 1669-1680 ◽  
Author(s):  
C Boitard ◽  
R Yasunami ◽  
M Dardenne ◽  
J F Bach
Keyword(s):  
T Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Insulin Dependent Diabetes Mellitus ◽  
Lymphoid Cells ◽  
Dependent Diabetes Mellitus ◽  
Spleen Cells ◽  
Nonobese Diabetic ◽  
Insulin Dependent ◽  
Onset Of Diabetes

The nonobese diabetic (NOD) mouse has recently been introduced as a model for insulin-dependent diabetes mellitus. The role of regulatory T cells in the development of antipancreatic autoimmunity in this model remains unclear. To evaluate the presence of suppressive phenomena, we used disease transfer by spleen cells from diabetic NOD mice into preirradiated adult recipients as a model for accelerated disease. Suppressor phenomena were detected by testing the protection afforded by lymphoid cells from nondiabetic NOD mice against diabetes transfer in irradiated recipients. Transfer of diabetes was delayed by reconstituting recipients with spleen cells from nondiabetic NOD donors. The greatest protection against diabetes transfer was conferred by spleen cells from 8-wk-old nondiabetic female NOD mice. Depletion experiments showed that the protection was dependent on CD4+ cells. Protection was also detected within thymic cells from nondiabetic NOD mice and protection conferred by spleen cells was abrogated by thymectomy of nondiabetic female, but not male, NOD donors at 3 wk of age. These findings indicate that suppressive CD4+ T cells that are dependent on the presence of the thymus may delay the onset of diabetes in female diabetes-prone NOD mice.

scholarly journals Normal Incidence of Diabetes in NOD Mice Tolerant to Glutamic Acid Decarboxylase

2003 ◽  
Vol 197 (12) ◽  
pp. 1635-1644 ◽  
Author(s):  
Elmar Jaeckel ◽  
Ludger Klein ◽  
Natalia Martin-Orozco ◽  
Harald von Boehmer
Keyword(s):  
Glutamic Acid ◽  
Glutamic Acid Decarboxylase ◽  
Tolerance Induction ◽  
Nod Mice ◽  
Normal Incidence ◽  
Invariant Chain ◽  
Acid Decarboxylase ◽  
Β Cells ◽  
Nonobese Diabetic ◽  
Specific Tolerance

Experiments in nonobese diabetic (NOD) mice that lacked expression of glutamic acid decarboxylase (GAD) in β cells have suggested that GAD represents an autoantigen essential for initiating and maintaining the diabetogenic immune response. Several attempts of inducing GAD-specific recessive tolerance to support this hypothesis have failed. Here we report on successful tolerance induction by expressing a modified form of GAD under control of the invariant chain promoter resulting in efficient epitope display. In spite of specific tolerance insulitis and diabetes occurred with normal kinetics indicating that GAD is not an essential autoantigen in the pathogenesis of diabetes.

scholarly journals Clostridial Butyrate Biosynthesis Enzymes Are Significantly Depleted in the Gut Microbiota of Nonobese Diabetic Mice

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Alessandro Tanca ◽  
Antonio Palomba ◽  
Cristina Fraumene ◽  
Valeria Manghina ◽  
Michael Silverman ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Intestinal Microbiota ◽  
Time Window ◽  
High Resolution Mass Spectrometry ◽  
Nod Mice ◽  
16S Rrna Gene Sequencing ◽  
Rrna Gene ◽  
Diabetic Mice ◽  
Nonobese Diabetic ◽  
Nonobese Diabetic Mice

ABSTRACT Increasing evidence suggests that the intestinal microbiota is involved in the pathogenesis of type 1 diabetes (T1D). Here we sought to determine which gut microbial taxa and functions vary between nonobese diabetic (NOD) mice and genetically modified NOD mice protected from T1D (Eα16/NOD) at 10 weeks of age in the time window between insulitis development and T1D onset. The gut microbiota of NOD mice were investigated by analyzing stool samples with a metaproteogenomic approach, comprising both 16S rRNA gene sequencing and microbial proteome profiling through high-resolution mass spectrometry. A depletion of Firmicutes (particularly, several members of Lachnospiraceae) in the NOD gut microbiota was observed compared to the level in the Eα16/NOD mice microbiota. Moreover, the analysis of proteins actively produced by the gut microbiota revealed different profiles between NOD and Eα16/NOD mice, with the production of butyrate biosynthesis enzymes being significantly reduced in diabetic mice. Our results support a model for gut microbiota influence on T1D development involving bacterium-produced metabolites as butyrate. IMPORTANCE Alterations of the gut microbiota early in age have been hypothesized to impact T1D autoimmune pathogenesis. In the NOD mouse model, protection from T1D has been found to operate via modulation of the composition of the intestinal microbiota during a critical early window of ontogeny, although little is known about microbiota functions related to T1D development. Here, we show which gut microbial functions are specifically associated with protection from T1D in the time window between insulitis development and T1D onset. In particular, we describe that production of butyrate biosynthesis enzymes is significantly reduced in NOD mice, supporting the hypothesis that modulating the gut microbiota butyrate production may influence T1D development.

scholarly journals Rodent Models for Investigating the Dysregulation of Immune Responses in Type 1 Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Feng-Cheng Chou ◽  
Heng-Yi Chen ◽  
Shyi-Jou Chen ◽  
Mei-Cho Fang ◽  
Huey-Kang Sytwu
Keyword(s):  
Type 1 Diabetes ◽  
Animal Studies ◽  
Genetic Manipulation ◽  
Nod Mice ◽  
Environmental Parameters ◽  
Conditional Knockout ◽  
Therapeutic Approaches ◽  
Nonobese Diabetic ◽  
Genetically Manipulated

Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells that selectively destroy the insulin-producingβcells. Previous reports based on epidemiological and animal studies have demonstrated that both genetic factors and environmental parameters can either promote or attenuate the progression of autoimmunity. In recent decades, several inbred rodent strains that spontaneously develop diabetes have been applied to the investigation of the pathogenesis of T1D. Because the genetic manipulation of mice is well developed (transgenic, knockout, and conditional knockout/transgenic), most studies are performed using the nonobese diabetic (NOD) mouse model. This paper will focus on the use of genetically manipulated NOD mice to explore the pathogenesis of T1D and to develop potential therapeutic approaches.

scholarly journals Gene Transfection and Expression of Transforming Growth Factor-β1 in Nonobese Diabetic Mouse Islets Protects β-Cells in Syngeneic Islet Grafts from Autoimmune Destruction

2002 ◽  
Vol 11 (6) ◽  
pp. 519-528 ◽  
Author(s):  
Wilma L. Suarez-Pinzon ◽  
Yvonne Marcoux ◽  
Aziz Ghahary ◽  
Alex Rabinovitch
Keyword(s):  
Transforming Growth Factor ◽  
Islet Cells ◽  
Gene Transfection ◽  
Nod Mice ◽  
Nod Mouse ◽  
Β Cells ◽  
Nonobese Diabetic ◽  
Autoimmune Destruction ◽  
Mouse Islets ◽  
Tgf Β1

Nonobese diabetic (NOD) mice develop diabetes and destroy syngeneic islet grafts through an autoimmune response. Because transforming growth factor (TGF)-β1 downregulates immune responses, we tested whether overexpression of TGF-β1 by gene transfection of NOD mouse islets could protect β-cells in islet grafts from autoimmune destruction. NOD mouse islet cells were transfected with an adenoviral DNA expression vector encoding porcine latent TGF-β1 (Ad TGF- β1) or the adenoviral vector alone (control Ad vector). The frequency of total islet cells expressing TGF-1 protein was increased from 12±1% in control Ad vector-transfected cells to 89 ± 4% in Ad TGF-β1-transfected islet cells, and the frequency of β-cells that expressed TGF-β1 was increased from 12 ± 1% to 60 ± 7%. Also, secretion of TGF-β1 was significantly increased in islets that overexpressed TGF-β1. Ad TGF-β1-transfected NOD mouse islets that overexpressed TGF-β1 prevented diabetes recurrence after transplantation into diabetic NOD mice for a median of 22 days compared with only 7 days for control Ad vector-transfected islets (p = 0.001). Immunohistochemical examination of the islet grafts revealed significantly more TGF-β1+ cells and insulin+ cells and significantly fewer CD45+ leukocytes in Ad TGF-β1-transfected islet grafts. Also, islet β-cell apoptosis was significantly decreased whereas apoptosis of graft-infiltrating leukocytes was significantly increased in Ad TGF-β1-transfected islet grafts. These observations demonstrate that overexpression of TGF-β1, by gene transfection of NOD mouse islets, protects islet β-cells from apoptosis and autoimmune destruction and delays diabetes recurrence after islet transplantation.

scholarly journals Nonobese Diabetic (NOD) Mice Lack a Protective B-Cell Response against the “Nonlethal” Plasmodium yoelii 17XNL Malaria Protozoan

2016 ◽  
Vol 2016 ◽  
pp. 1-9
Author(s):  
Mirian Mendoza ◽  
Luis Pow Sang ◽  
Qi Qiu ◽  
Sofia Casares ◽  
Teodor-D. Brumeanu
Keyword(s):  
B Cell ◽  
Nod Mice ◽  
Treg Cells ◽  
Plasmodium Yoelii ◽  
Mouse Strains ◽  
Nonobese Diabetic ◽  
Blood Stage Infection ◽  
Protective Antibodies ◽  
Antibody Secretion

Background. Plasmodium yoelii 17XNL is a nonlethal malaria strain in mice of different genetic backgrounds including the C57BL/6 mice (I-Ab/I-Enull) used in this study as a control strain. We have compared the trends of blood stage infection with the nonlethal murine strain of P. yoelii 17XNL malaria protozoan in immunocompetent Nonobese Diabetic (NOD) mice prone to type 1 diabetes (T1D) and C57BL/6 mice (control mice) that are not prone to T1D and self-cure the P. yoelii 17XNL infection. Prediabetic NOD mice could not mount a protective antibody response to the P. yoelii 17XNL-infected red blood cells (iRBCs), and they all succumbed shortly after infection. Our data suggest that the lack of anti-P. yoelii 17XNL-iRBCs protective antibodies in NOD mice is a result of parasite-induced, Foxp3+ T regulatory (Treg) cells able to suppress the parasite-specific antibody secretion. Conclusions. The NOD mouse model may help in identifying new mechanisms of B-cell evasion by malaria parasites. It may also serve as a more accurate tool for testing antimalaria therapeutics due to the lack of interference with a preexistent self-curing mechanism present in other mouse strains.

scholarly journals Histidine Decarboxylase Deficiency Prevents Autoimmune Diabetes in NOD Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Manal Alkan ◽  
François Machavoine ◽  
Rachel Rignault ◽  
Julie Dam ◽  
Michel Dy ◽  
...  
Keyword(s):  
Histidine Decarboxylase ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Wild Type ◽  
Gene Encoding ◽  
Nonobese Diabetic ◽  
Endogenous Histamine ◽  
Wild Type Counterpart

Recent evidence has highlighted the role of histamine in inflammation. Since this monoamine has also been strongly implicated in the pathogenesis of type-1 diabetes, we assessed its effect in the nonobese diabetic (NOD) mouse model. To this end, we used mice (inactivated) knocked out for the gene encoding histidine decarboxylase, the unique histamine-forming enzyme, backcrossed on a NOD genetic background. We found that the lack of endogenous histamine in NOD HDC−/−mice decreased the incidence of diabetes in relation to their wild-type counterpart. Whereas the proportion of regulatory T and myeloid-derived suppressive cells was similar in both strains, histamine deficiency was associated with increased levels of immature macrophages, as compared with wild-type NOD mice. Concerning the cytokine pattern, we found a decrease in circulating IL-12 and IFN-γin HDC−/−mice, while IL-6 or leptin remained unchanged, suggesting that histamine primarily modulates the inflammatory environment. Paradoxically, exogenous histamine given to NOD HDC−/−mice provided also protection against T1D. Our study supports the notion that histamine is involved in the pathogenesis of diabetes, thus providing additional evidence for its role in the regulation of the immune response.

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