209-LB: RNA-Seq Analysis of Liver from Diabetic and NASH Model Mouse Treated with Streptozotocin, High-Fat Diet

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 209-LB
Author(s):  
LINH P. BUI ◽  
YUKI SAKAKIBARA ◽  
RYUTO TANAKA ◽  
ELIZABETH H. PIGNEY ◽  
TAISHI HASHIGUCHI
Keyword(s):  
High Fat Diet ◽  
Rna Seq ◽  
High Fat ◽  
Nash Model ◽  
Model Mouse

Abstract MP05: The Mechanism Of The Pvat Pro-inflammatory Micro-environment Formation During The Development Of High Fat Diet-induced Hypertension

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Yining Jin ◽  
Omar Kana ◽  
Ramya Kumar ◽  
Rance Nault ◽  
Hannah Garver ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
High Fat Diet ◽  
Cell Activation ◽  
Control Diet ◽  
Rna Seq ◽  
High Fat ◽  
Induced Hypertension ◽  
Th17 Differentiation

There is considerable evidence for a causative role for T cells in hypertension, including studies with immunosuppressive drugs and T cell-deficient models. Our previous studies showed that soluble mediators from mesenteric perivascular adipose tissue (mPVAT) modulate T cell function. Specifically, conditioned media from mPVAT (mPVAT-CM) from Dahl S rats on a high fat diet (HFD) promoted expression of the pro-inflammatory cytokines, IFNg, IL-17a and GM-CSF, by activated T cells. Furthermore, the Dahl S rats on HFD will later develop hypertension. Hypothesis: mPVAT is stimulated to produce immunomodulatory mediators that promotes Th1/17 differentiation preceding the development of HFD-induced hypertension. We conducted bulk RNA-seq on activated splenocytes cultured in mPVAT-CM from Dahl S rats on either control or HFD for 10 weeks. In accordance with our previous studies, PVAT-CM from HFD-fed rats significantly upregulated many genes associated with IFNg/IL-17 induction, including Mpeg1, Lyz2 and Tnfsf4 (5.0±1.78, 3.70±0.53 and 1.78±0.42 fold over Control diet, respectively). In contrast, Th2/Treg-associated genes, such as Ctla2a (-0.27±0.02) and Ccr4 (-0.41±0.03) were downregulated. We also performed single cell (sc) RNA-seq on the PVAT stromal vascular fraction (SVF) and found that acute inflammatory genes were enriched in the HFD group. Together with the bulk RNA-seq on mPVAT, these data strongly suggest that the pro-inflammatory mPVAT micro-environment may promote Th1/Th17 differentiation. To identify mediators in PVAT-CM that may induce Th1/Th17 differentiation, we compared the bulk RNA-seq on splenocytes cultured in PVAT-CM with bulk RNA-seq conducted on the whole mPVAT itself. We found that a T cell co-stimulatory receptor DPP4 (CD26), which is closely associated with T cell activation was significantly increased in mPVAT from HFD-fed rats (33.4±2.3 HFD vs. 15.3±1.8 Control diet). We also observed an increase in DPP4 global expression from mPVAT SVF in HFD-fed rats, as determined by scRNA-seq. Conclusion: The data suggest that HFD promotes the IFNg and IL-17a pathways in PVAT, which precedes hypertension in Dahl S rats and correlates with an increase in expression of DPP-4, a gene that promotes T cell activation. (NIH P01 HL070687).

Tu1818 The Chemical Chaperon 4-Phenylbutyrate Inhibits Liver Fibrosis and Tumorgenesis in High-Fat Diet With N-Acetyl-ß-D-Glucosaminedase Inhibitor-Induced NASH Model Mice

2012 ◽  
Vol 142 (5) ◽  
pp. S-1024-S-1025
Author(s):  
Kazuyoshi Kon ◽  
Kenichi Ikejima ◽  
Takashi Miyaji ◽  
Satoko Hosoya ◽  
Kumiko Arai ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
High Fat Diet ◽  
High Fat ◽  
Nash Model

scholarly journals Distinct gene signatures predict insulin resistance in young mice with high fat diet-induced obesity

2018 ◽  
Vol 50 (3) ◽  
pp. 144-157 ◽  
Author(s):  
Katherine Chen ◽  
Alice Jih ◽  
Olivia Osborn ◽  
Sarah T. Kavaler ◽  
Wenxian Fu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Expression Patterns ◽  
Gene Families ◽  
Differentially Expressed ◽  
Rna Seq ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Before And After ◽  
Young Mice

Highly inbred C57BL/6 mice show wide variation in their degree of insulin resistance in response to diet-induced obesity even though they are almost genetically identical. Here we employed transcriptional profiling by RNA sequencing (RNA-Seq) of visceral adipose tissue (VAT) and liver in young mice to determine how gene expression patterns correlate with the later development of high-fat diet (HFD)-induced insulin resistance in adulthood. To accomplish this goal, we partially removed and banked tissues from pubertal mice. Mice subsequently received HFD followed by metabolic phenotyping to identify two well-defined groups of mice with either severe or mild insulin resistance. The remaining tissues were collected at study termination. We then applied RNA-Seq to generate transcriptome profiles associated with worsened insulin resistance before and after the initiation of HFD. We found 244 up- and 109 downregulated genes in VAT of the most insulin-resistant mice even before HFD exposure. Downregulated genes included serine protease inhibitor, major urinary protein, and complement genes; upregulated genes represented mostly muscle constituents. These gene families were also differentially expressed in VAT of mice with high or low insulin resistance after HFD. Inflammatory genes predicted insulin resistance in liver, but not in VAT. In contrast, when we compared VAT of all mice before and after HFD, differentially expressed genes were predominantly composed of immune response genes. These data show a distinct set of gene transcripts in young mice correlates with the severity of insulin resistance in adulthood, providing insight into the pathogenesis of insulin resistance in early life.

scholarly journals Alleviating the effect of quinoa and the underlying mechanism on hepatic steatosis in high-fat diet-fed rats

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Chenwei Song ◽  
Wei Lv ◽  
Yahui Li ◽  
Pan Nie ◽  
Jun Lu ◽  
...  
Keyword(s):  
Immune Response ◽  
Lipid Metabolism ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Metabolic Profile ◽  
Hepatic Tissue ◽  
Circulation System ◽  
Rna Seq ◽  
Rt Pcr ◽  
High Fat

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic component of metabolic syndrome and has attracted widespread attention due to its increased prevalence. Daily dietary management is an effective strategy for the prevention of NAFLD. Quinoa, a nutritious pseudocereal, is abundant in antioxidative bioactive phytochemicals. In the present study, the effects of different amounts of quinoa on the progression of NAFLD and the related molecular mechanism were investigated. Methods Male SD rats were simultaneously administered a high fat diet (HF) and different amounts of quinoa (equivalent to 100 g/day and 300 g/day of human intake, respectively). After 12 weeks of the intervention, hepatic TG (triglyceride) and TC (total cholesterol) as well as serum antioxidative parameters were determined, and hematoxylin–eosin staining (H&E) staining was used to evaluate hepatic steatosis. Differential metabolites in serum and hepatic tissue were identified using UPLC-QTOF-MSE. The mRNA expression profile was investigated using RNA-Seq and further verified using real-time polymerase chain reaction (RT-PCR). Results Low amounts of quinoa (equivalent to 100 g/d of human intake) effectively controlled the weight of rats fed a high-fat diet. In addition, quinoa effectively inhibited the increase in hepatic TG and TC levels, mitigated pathological injury, promoted the increase in SOD and GSH-Px activities, and decreased MDA levels. Nontarget metabolic profile analysis showed that quinoa regulated lipid metabolites in the circulation system and liver such as LysoPC and PC. RNA-Seq and RT-PCR verification revealed that a high amount of quinoa more effectively upregulated genes related to lipid metabolism [Apoa (apolipoprotein)5, Apoa4, Apoc2] and downregulated genes related to the immune response [lrf (interferon regulatory factor)5, Tlr6 (Toll-like receptor), Tlr10, Tlr11, Tlr12]. Conclusion Quinoa effectively prevented NAFLD by controlling body weight, mitigating oxidative stress, and regulating the lipid metabolic profile and the expression of genes related to lipid metabolism and the immune response.

Circulating pro fibrotic protein promotes fibrosis in liver

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Hsiao ◽  
I Shimizu ◽  
Y Yoshida ◽  
R Ikegami ◽  
Y Hayashi ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
High Fat Diet ◽  
In Vitro Studies ◽  
High Fat ◽  
Brown Adipocytes ◽  
Adipose Tissues ◽  
Nash Model ◽  
Brown Adipose

Abstract Background/Introduction Non-alcoholic steatohepatitis (NASH), driven by the obesity epidemic, has become the most common form of liver disease. Inflamed visceral adipose tissue secretes pro-inflammatory adipokines that are causal for systemic metabolic disorders. Role of adipokines in NASH, especially those from brown adipose tissues (BATokine) remain unclear. Purpose To show the pathogenic role of BATokine in NASH. Methods To identify and characterize the pathological roles of pro-fibrotic BATokine, we generated a murine obese NASH model by imposing a high fat diet in C57BL6/NCr mice, and murine systemic or BAT specific knockout (KO) models. We also conducted functional in-vitro studies with differentiated brown adipocytes. Results Analyzing two sets of DNA micro array data with bioinformatics, we identified a secreted form pro-fibrotic protein (sPFP) expressed in dysfunctional brown adipose tissues (BAT) in mice. Testing our biobank samples, we found this protein increased in plasma of NASH patients. We generated a murine obese NASH model by imposing a high fat diet in C57BL6/NCr mice for 9–10 months since 4 weeks of age, and found that sPFP is produced predominantly by BAT. In this model, we also found that sPFP increased in plasma. We generated a murine systemic or BAT specific sPFP knockout (KO) models and found that liver fibrosis ameliorated in these models. We also suppressed circulating sPFP with a peptide vaccine targeting this molecule, and found that sPFP vaccination therapy inhibited liver fibrosis. Next, we generated sPFP gain of function (GOF) model by the administration of plasmid encoding sPFP into skeletal muscle. Liver fibrosis augmented in sPFP-GOF model, and these results suggested that sPFP has causal role for the progression of fibrotic response in liver. In vitro studies with differentiated brown adipocytes showed that metabolic stress increased c-Fos in nuclear, and this was causal for an increase in sPFP level. Conclusions Our results suggest that one of the BATokines, sPFP, contributes for the progression of fibrotic responses in obese-NASH model. Inhibition of sPFP may become a therapy for NASH or obesity related fibrotic disorders. Funding Acknowledgement Type of funding source: None

scholarly journals Healthy aging interventions reduce repetitive element transcripts

2020 ◽  
Author(s):  
Devin Wahl ◽  
Alyssa N Cavalier ◽  
Meghan Smith ◽  
Douglas R Seals ◽  
Thomas J LaRocca
Keyword(s):  
Transgenic Mice ◽  
Aerobic Exercise ◽  
Calorie Restriction ◽  
High Fat Diet ◽  
Healthy Aging ◽  
Repetitive Element ◽  
Repetitive Elements ◽  
Rna Seq ◽  
High Fat ◽  
Physiological Processes

Abstract Background Transcripts from non-coding repetitive elements (RE) in the genome may be involved in aging. However, they are often ignored in transcriptome studies on healthspan and lifespan, and their role in healthy aging interventions has not been characterized. Methods We analyze RE in RNA-seq datasets from mice subjected to robust healthspan- and lifespan-increasing interventions including calorie restriction, rapamycin, acarbose, 17-⍺-estradiol, and Protandim. We also examine RE transcripts in long-lived transgenic mice, and in mice subjected to a high-fat diet, and we use RNA-seq to investigate the influence of aerobic exercise on RE transcripts with aging in humans. Results We find that: 1) healthy aging interventions/behaviors globally reduce RE transcripts, whereas aging and a high-fat diet increase RE expression; and 2) reduced RE expression with healthy aging interventions is associated with biological/physiological processes mechanistically linked with aging. Conclusions RE transcript dysregulation and suppression are likely novel mechanisms underlying aging and healthy aging interventions, respectively.

scholarly journals Validation of Antiobesity Effects of Black Soybean Seed Coat Powder Suitable as a Food Material: Comparisons with Conventional Yellow Soybean Seed Coat Powder

Foods ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 841
Author(s):  
Yuuki Moriyasu ◽  
Chiho Fukumoto ◽  
Maki Wada ◽  
Erika Yano ◽  
Hiroshi Murase ◽  
...  
Keyword(s):  
Seed Coat ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
Soybean Seed ◽  
High Fat ◽  
Food Material ◽  
Black Soybean ◽  
Diet Induced Obesity ◽  
Model Mouse ◽  
Soybean Seed Coat

In this study, we fed obese model mice black soybean seed coat powder (BSCP) and evaluated the antiobesity effects. As a control, normal yellow soybean seed coat powder (YSCP) was used. C57BL/6J, a high-fat diet-induced obesity model mouse, was fed a high-fat diet containing BSCP or YSCP (20% fat) to induce obesity. The results showed that in the BSCP group, it caused significant suppression of body weight gain and suppression of white adipose tissue weight compared with the YSCP group. Moreover, it significantly decreased serum leptin levels, which correlated with visceral fat mass, and increased antidiabetic adipocytokine and adiponectin levels. Therefore, this suggests the pigmented components contained in BSCP have an antiobesity effect in obese model mice. It is suggested that this material, which can be prepared without extraction with an organic solvent and is suitable for use as a food material, could be a functional food material with a practicable antiobesity effect.

scholarly journals Healthy aging interventions reduce non-coding repetitive element transcripts

2020 ◽  
Author(s):  
Devin Wahl ◽  
Alyssa N. Cavalier ◽  
Meghan Smith ◽  
Douglas R. Seals ◽  
Thomas J. LaRocca
Keyword(s):  
Transgenic Mice ◽  
Aerobic Exercise ◽  
Calorie Restriction ◽  
High Fat Diet ◽  
Healthy Aging ◽  
Repetitive Element ◽  
Repetitive Elements ◽  
Rna Seq ◽  
High Fat ◽  
Physiological Processes

ABSTRACTTranscripts from non-coding repetitive elements (RE) in the genome may be involved in aging. However, they are often ignored in transcriptome studies on healthspan and lifespan, and their role in healthy aging interventions has not been characterized. Here, we analyze RE in RNA-seq datasets from mice subjected to robust healthspan- and lifespan-increasing interventions including calorie restriction, rapamycin, acarbose, 17-α-estradiol, and Protandim. We also examine RE transcripts in long-lived transgenic mice, and in mice subjected to high-fat diet, and we use RNA-seq to investigate the influence of aerobic exercise on RE transcripts with aging in humans. We find that: 1) healthy aging interventions/behaviors globally reduce RE transcripts, whereas aging and age-accelerating treatments increase RE expression; and 2) reduced RE expression with healthy aging interventions is associated with biological/physiological processes mechanistically linked with aging. Thus, RE transcript dysregulation and suppression are likely novel mechanisms underlying aging and healthy aging interventions, respectively.

scholarly journals Caloric restriction improves diabetes-induced cognitive deficits by attenuating neurogranin-associated calcium signaling in high-fat diet-fed mice

2015 ◽  
Vol 36 (6) ◽  
pp. 1098-1110 ◽  
Author(s):  
Hwajin Kim ◽  
Heeyoung Kang ◽  
Rok Won Heo ◽  
Byeong Tak Jeon ◽  
Chin-ok Yi ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Caloric Restriction ◽  
Blood Brain Barrier ◽  
High Fat Diet ◽  
Memory Deficits ◽  
Glial Activation ◽  
Brain Barrier ◽  
Rna Seq ◽  
High Fat ◽  
Blood Brain

Diabetes-induced cognitive decline has been recognized in human patients of type 2 diabetes mellitus and mouse model of obesity, but the underlying mechanisms or therapeutic targets are not clearly identified. We investigated the effect of caloric restriction on diabetes-induced memory deficits and searched a molecular mechanism of caloric restriction-mediated neuroprotection. C57BL/6 mice were fed a high-fat diet for 40 weeks and RNA-seq analysis was performed in the hippocampus of high-fat diet-fed mice. To investigate caloric restriction effect on differential expression of genes, mice were fed high-fat diet for 20 weeks and continued on high-fat diet or subjected to caloric restriction (2 g/day) for 12 weeks. High-fat diet-fed mice exhibited insulin resistance, glial activation, blood–brain barrier leakage, and memory deficits, in that we identified neurogranin, a down-regulated gene in high-fat diet-fed mice using RNA-seq analysis; neurogranin regulates Ca2+/calmodulin-dependent synaptic function. Caloric restriction increased insulin sensitivity, reduced high-fat diet-induced blood–brain barrier leakage and glial activation, and improved memory deficit. Furthermore, caloric restriction reversed high-fat diet-induced expression of neurogranin and the activation of Ca2+/calmodulin-dependent protein kinase II and calpain as well as the downstream effectors. Our results suggest that neurogranin is an important factor of high-fat diet-induced memory deficits on which caloric restriction has a therapeutic effect by regulating neurogranin-associated calcium signaling.

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