SAT-326 INPP4B Suppresses Prostate Inflammation And Protects Mice Fed With High-fat Diet From The Development Of Prostate Intraepithelial Neoplasia

Metabolic syndrome (MetS) and benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) are often associated. One of their common denominators is hypogonadism. However, testosterone supplementation is limited by concerns for potential prostatic side effects. The objective was to determine whether MetS-associated prostate alterations are prevented by testosterone supplementation. We used a previously described animal model of MetS, obtained by feeding male rabbits a high-fat diet (HFD) for 12 weeks. Subsets of HFD rabbits were treated with testosterone or with the farnesoid X receptor agonist INT-747. Rabbits fed a standard diet were used as controls. HFD-animals develop hypogonadism and all the MetS features: hyperglycemia, glucose intolerance, dyslipidemia, hypertension, and visceral obesity. In addition, HFD-animals show a prostate inflammation. Immunohistochemical analysis demonstrated that HFD-induced prostate fibrosis, hypoxia, and inflammation. The mRNA expression of several proinflammatory (IL8, IL6, IL1β, and TNFα), T lymphocyte (CD4, CD8, Tbet, Gata3, and ROR γt), macrophage (TLR2, TLR4, and STAMP2), neutrophil (lactoferrin), inflammation (COX2 and RAGE), and fibrosis/myofibroblast activation (TGFβ, SM22α, αSMA, RhoA, and ROCK1/ROCK2) markers was significantly increased in HFD prostate. Testosterone, as well as INT-747, treatment prevented some MetS features, although only testosterone normalized all the HFD-induced prostate alterations. Interestingly, the ratio between testosterone and estradiol plasma level retains a significant, negative, association with all the fibrosis and the majority of inflammatory markers analyzed. These data highlight that testosterone protects rabbit prostate from MetS-induced prostatic hypoxia, fibrosis, and inflammation, which can play a role toward the development/progression of BPH/LUTS.

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Topographic and quantitative relationship between prostate inflammation, proliferative inflammatory atrophy and low-grade prostate intraepithelial neoplasia: A biopsy study in chronic prostatitis patients

International Journal of Oncology ◽

10.3892/ijo.2012.1646 ◽

2012 ◽

Vol 41 (6) ◽

pp. 1950-1958 ◽

Cited By ~ 23

Author(s):

A. VRAL ◽

V. MAGRI ◽

E. MONTANARI ◽

G. GAZZANO ◽

V. GOURVAS ◽

...

Keyword(s):

Chronic Prostatitis ◽

Quantitative Relationship ◽

Intraepithelial Neoplasia ◽

Low Grade ◽

Prostate Intraepithelial Neoplasia ◽

Proliferative Inflammatory Atrophy ◽

Prostate Inflammation

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INPP4B protects from metabolic syndrome and associated disorders

Communications Biology ◽

10.1038/s42003-021-01940-6 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Manqi Zhang ◽

Yasemin Ceyhan ◽

Elena M. Kaftanovskaya ◽

Judy L. Vasquez ◽

Jean Vacher ◽

...

Keyword(s):

High Fat Diet ◽

De Novo ◽

Intraepithelial Neoplasia ◽

Prostate Neoplasms ◽

De Novo Lipogenesis ◽

Metabolic Dysfunction ◽

Type Ii ◽

Inositol Polyphosphate ◽

High Fat ◽

Alcoholic Fatty Liver

AbstractA high fat diet and obesity have been linked to the development of metabolic dysfunction and the promotion of multiple cancers. The causative cellular signals are multifactorial and not yet completely understood. In this report, we show that Inositol Polyphosphate-4-Phosphatase Type II B (INPP4B) signaling protects mice from diet-induced metabolic dysfunction. INPP4B suppresses AKT and PKC signaling in the liver thereby improving insulin sensitivity. INPP4B loss results in the proteolytic cleavage and activation of a key regulator in de novo lipogenesis and lipid storage, SREBP1. In mice fed with the high fat diet, SREBP1 increases expression and activity of PPARG and other lipogenic pathways, leading to obesity and non-alcoholic fatty liver disease (NAFLD). Inpp4b−/− male mice have reduced energy expenditure and respiratory exchange ratio leading to increased adiposity and insulin resistance. When treated with high fat diet, Inpp4b−/− males develop type II diabetes and inflammation of adipose tissue and prostate. In turn, inflammation drives the development of high-grade prostatic intraepithelial neoplasia (PIN). Thus, INPP4B plays a crucial role in maintenance of overall metabolic health and protects from prostate neoplasms associated with metabolic dysfunction.

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Ppard Is Essential in Acceleration of Pancreatic Ductal Adenocarcinoma Development by High-Fat Diet in Mutant Kras Mice

10.1101/2020.12.04.412320 ◽

2020 ◽

Author(s):

Yi Liu ◽

Yasunori Deguchi ◽

Daoyan Wei ◽

Micheline J. Moussalli ◽

Donghui Li ◽

...

Keyword(s):

Epithelial Cells ◽

Pancreatic Ductal Adenocarcinoma ◽

High Fat Diet ◽

Suppressor Cells ◽

Intraepithelial Neoplasia ◽

Ductal Adenocarcinoma ◽

High Fat ◽

Pancreatic Cancers ◽

Genetic Deletion ◽

Targeted Inhibition

AbstractPro-obesity high-fat diet is linked with an increased incidence of pancreatic cancers, but the molecular underpinnings of this association remain poorly understood. Here, we report that PPARD is upregulated in pancreatic intraepithelial neoplasia lesions (PanINs) at early stages of pancreatic tumorigenesis in humans and mutant Kras mice. Transgenic overexpression of Ppard in pancreatic epithelial cells drastically accelerates the development and progression of pancreatic ductal adenocarcinoma in mutant Kras mice when activated by feeding the mice with a high-fat diet or a diet containing GW501516 (50 mg/kg), a selective PPARD agonist. In contrast, pancreatic Ppard genetic deletion significantly suppressed the promotion of pancreatic tumorigenesis by these diets. Mechanistically, we found that this Ppard hyperactivation in pancreatic epithelial cells of mutant Kras mice increased production of chemokines and cytokines (e.g., CcI2, CcI4-5, CxcI5 and II6), leading to the robustly increased recruitment of myeloid-derived suppressor cells and macrophages into pancreata, which fostered an immune suppressive microenvironment and subsequently accelerated pancreatic ductal adenocarcinoma development and progression. Our findings demonstrate that PPARD plays an essential role in the promotion of pancreatic tumorigenesis by a high-fat diet. Targeted inhibition of PPARD activation is a potential interventive strategy for pancreatic cancer prevention and therapy.

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Abstract # P-20: 11b-Hydroxysteroid Dehydrogenase 1 Regulation in High Fat Diet Induced Insulin Resistant Rats and Rats Treated with Sutherlandia Frutescens

Endocrine Practice ◽

10.1016/s1530-891x(20)43833-9 ◽

2016 ◽

Vol 22 ◽

pp. 23

Author(s):

Ngozi F. Nnolum-Orji ◽

Saartjie Roux ◽

Janine Mackenzie ◽

Disang Lekutlane

Keyword(s):

High Fat Diet ◽

Hydroxysteroid Dehydrogenase ◽

High Fat ◽

Insulin Resistant ◽

Sutherlandia Frutescens

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Effects of Maternal Flaxseed Supplementation on Female Offspring of Diabetic Rats in Serum Concentration of Glucose, Insulin, and Thyroid Hormones

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000259 ◽

2019 ◽

Vol 89 (1-2) ◽

pp. 45-54

Author(s):

Akemi Suzuki ◽

André Manoel Correia-Santos ◽

Gabriela Câmara Vicente ◽

Luiz Guillermo Coca Velarde ◽

Gilson Teles Boaventura

Keyword(s):

Thyroid Hormones ◽

High Fat Diet ◽

Female Offspring ◽

Flaxseed Oil ◽

Diabetic Rats ◽

High Fat ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Flaxseed Flour ◽

Maternal Consumption

Abstract. Objective: This study aimed to evaluate the effect of maternal consumption of flaxseed flour and oil on serum concentrations of glucose, insulin, and thyroid hormones of the adult female offspring of diabetic rats. Methods: Wistar rats were induced to diabetes by a high-fat diet (60%) and streptozotocin (35 mg/kg). Rats were mated and once pregnancy was confirmed, were divided into the following groups: Control Group (CG): casein-based diet; High-fat Group (HG): high-fat diet (49%); High-fat Flaxseed Group (HFG): high-fat diet supplemented with 25% flaxseed flour; High-fat Flaxseed Oil group (HOG): high-fat diet, where soya oil was replaced with flaxseed oil. After weaning, female pups (n = 6) from each group were separated, received a commercial rat diet and were sacrificed after 180 days. Serum insulin concentrations were determined by ELISA, the levels of triiodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone (TSH) were determined by chemiluminescence. Results: There was a significant reduction in body weight at weaning in HG (−31%), HFG (−33%) and HOG (44%) compared to CG (p = 0.002), which became similar by the end of 180 days. Blood glucose levels were reduced in HFG (−10%, p = 0.044) when compared to CG, and there was no significant difference between groups in relation to insulin, T3, T4, and TSH after 180 days. Conclusions: Maternal severe hyperglycemia during pregnancy and lactation resulted in a microsomal offspring. Maternal consumption of flaxseed reduces blood glucose levels in adult offspring without significant effects on insulin levels and thyroid hormones.

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