scholarly journals PGC-1α Signaling Increases GABA(A) Receptor Subunit α2 Expression, GABAergic Neurotransmission and Anxiety-Like Behavior in Mice

2021 ◽  
Vol 14 ◽  
Author(s):  
Taavi Vanaveski ◽  
Svetlana Molchanova ◽  
Dan Duc Pham ◽  
Annika Schäfer ◽  
Ceren Pajanoja ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Gabaergic Neurotransmission ◽  
Gaba A ◽  
Protein Levels ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Hippocampal Ca1 ◽  
Pparγ Agonist

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondria biogenesis and cell stress playing a role in metabolic and degenerative diseases. In the brain PGC-1α expression has been localized mainly to GABAergic interneurons but its overall role is not fully understood. We observed here that the protein levels of γ-aminobutyric acid (GABA) type A receptor-α2 subunit (GABARα2) were increased in hippocampus and brain cortex in transgenic (Tg) mice overexpressing PGC-1α in neurons. Along with this, GABARα2 expression was enhanced in the hippocampus of the PGC-1α Tg mice, as shown by quantitative PCR. Double immunostaining revealed that GABARα2 co-localized with the synaptic protein gephyrin in higher amounts in the striatum radiatum layer of the hippocampal CA1 region in the Tg compared with Wt mice. Electrophysiology revealed that the frequency of spontaneous and miniature inhibitory postsynaptic currents (mIPSCs) was increased in the CA1 region in the Tg mice, indicative of an augmented GABAergic transmission. Behavioral tests revealed an increase for anxiety-like behavior in the PGC-1α Tg mice compared with controls. To study whether drugs acting on PPARγ can affect GABARα2, we employed pioglitazone that elevated GABARα2 expression in primary cultured neurons. Similar results were obtained using the specific PPARγ agonist, N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino) ethyl]-L-tyrosine hydrate (GW1929). These results demonstrate that PGC-1α regulates GABARα2 subunits and GABAergic neurotransmission in the hippocampus with behavioral consequences. This indicates further that drugs like pioglitazone, widely used in the treatment of type 2 diabetes, can influence GABARα2 expression via the PPARγ/PGC-1α system.

scholarly journals Effects of Caloric Intake on Learning and Memory Function in Juvenile C57BL/6J Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Bao-Lei Xu ◽  
Rong Wang ◽  
Li-Na Ma ◽  
Wen Dong ◽  
Zhi-Wei Zhao ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Memory Function ◽  
Caloric Intake ◽  
Camp Response Element Binding ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Downstream Effectors ◽  
Element Binding Protein

Dietary composition may influence neuronal function as well as processes underlying synaptic plasticity. In this study, we aimed to determine the effect of high and low caloric diets on a mouse model of learning and memory and to explore mechanisms underlying this process. Mice were divided into three different dietary groups: normal control(n=12), high-caloric (HC) diet(n=12), and low-caloric (LC) diet(n=12). After 6 months, mice were evaluated on the Morris water maze to assess spatial memory ability. We found that HC diet impaired learning and memory function relative to both control and LC diet. The levels of SIRT1 as well as its downstream effectors p53, p16, and peroxisome proliferator-activated receptorγ(PPARγ) were decreased in brain tissues obtained from HC mice. LC upregulated SIRT1 but downregulated p53, p16, and PPARγ. The expressions of PI3K and Akt were not altered after HC or LC diet treatment, but both LC and HC elevated the levels of phosphorylated-cAMP response element-binding protein (p-CREB) and IGF-1 in hippocampal CA1 region. Therefore, HC diet-induced dysfunction in learning and memory may be prevented by caloric restriction via regulation of the SIRT1-p53 or IGF-1 signaling pathways and phosphorylation of CREB.

Pioglitazone prevents cardiac remodeling in high-fat, high-calorie-induced Type 2 diabetes mellitus

2006 ◽  
Vol 291 (1) ◽  
pp. H81-H87 ◽  
Author(s):  
Walter E. Rodriguez ◽  
Irving G. Joshua ◽  
Jeff C. Falcone ◽  
Suresh C. Tyagi
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Left Ventricular ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Calorie Diet

The agonists of peroxisome proliferator-activated receptor-γ (PPARγ) ameliorate cardiovascular complications associated with diabetes mellitus. We tested the hypothesis that recovery from ailing to failing myocardium in diabetes by PPARγ agonist is in part due to decreased matrix metalloproteinase-9 (MMP-9) activation and left ventricular (LV) tissue levels of homocysteine (Hcy). C57BL/6J mice were made diabetic (D) by feeding them a high-fat calorie diet. PPARγ was activated by adding pioglitazone (Pi) to the diet. After 6 wk, mice were grouped into: normal calorie diet (N), D, N + Pi and D + Pi ( n = 6 in each group). LV variables were measured by echocardiography, endothelial-myocyte (E-M) coupling was measured in cardiac rings, and MMP-9 activation was measured by zymography. Blood glucose levels were twofold higher in D mice compared with N mice. Pi decreased the levels of glucose in D mice to the levels in N mice. LV Hcy levels were 3.5 ± 0.5 μM in N groups compared with 12.4 ± 0.6 μM in D groups. Treatment with Pi normalized the LV levels of Hcy but had no effect on plasma levels of Hcy. In the D group, LV contraction was reduced compared with that of the N group and was ameliorated by treatment with Pi. LV wall thickness was reduced to 0.25 ± 0.02 mm in the D group compared with 0.42 ± 0.01 mm in the N group. LV diastolic diameter was 3.05 ± 0.01 mm in the D group compared with 2.20 ± 0.02 mm in the N group. LV systolic diameter was 1.19 ± 0.02 mm in the D group and 0.59 ± 0.01 mm in the N group. Pi normalized the LV variables in D mice. The responses to ACh and nitroprusside were attenuated in diabetic hearts, suggesting that there was E-M uncoupling in the D group compared with the N group, which was ameliorated by Pi. Plasma and LV levels of MMP-2 and -9 activities were higher in the D group than in the N group but normalized after Pi treatment. These results suggest that E-M uncoupling in the myocardium, in part, is due to increased MMP activities secondary to suppressing PPARγ activity in high-fat, calorie-induced Type 2 diabetes mellitus.

scholarly journals RAPID COMMUNICATION: Inhibitory Effect of Pioglitazone on Carotid Arterial Wall Thickness in Type 2 Diabetes

2001 ◽  
Vol 86 (7) ◽  
pp. 3452-3452 ◽  
Author(s):  
Hiroyuki Koshiyama ◽  
Dai Shimono ◽  
Naomitsu Kuwamura ◽  
Jun Minamikawa ◽  
Yoshio Nakamura
Keyword(s):  
Type 2 Diabetes ◽  
Statistical Significance ◽  
Intima Media Thickness ◽  
Inhibitory Effect ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Carotid Arterial

There have been increasing evidences that thiazolidinediones, peroxisome proliferator-activated receptor γ (PPARγ) agonists, may have some antiatherogenic actions. We have previously reported that troglitazone has a potent inhibitory effect on common carotid arterial intima-media thickness (IMT) in subjects with type 2 diabetes. However, some studies suggested a possibility that PPARγ activators may have protoatherogenic actions, raising concern about their detrimental effects in diabetic subjects. In the present study, we investigated the effect of treatment with pioglitazone, another PPARγ agonist, on IMT in a total of 106 Japanese subjects with type 2 diabetes. Pioglitazone (30 mg daily) was administered for 6 months in 53 patients. Compared to control group (n = 53), the group given pioglitazone showed a significant decrease in IMT as early as 3 months after the administration. The decrease in IMT was also found after 6 months (IMT change: −0.084[SE 0.023] mm vs. control 0.022[SE 0.006] mm, P < 0.001), although the difference between those after 3 and 6 months did not reach any statistical significance. These findings indicate that thiazolidinediones cause an inhibition of early atherosclerotic process PPARγ activation.

Pioglitazone mitigates renal glomerular vascular changes in high-fat, high-calorie-induced type 2 diabetes mellitus

2006 ◽  
Vol 291 (3) ◽  
pp. F694-F701 ◽  
Author(s):  
Walter E. Rodriguez ◽  
Neetu Tyagi ◽  
Irving G. Joshua ◽  
John C. Passmore ◽  
John T. Fleming ◽  
...  
Keyword(s):  
Renal Artery ◽  
Matrix Metalloproteinase 2 ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Calorie Diet ◽  
Contraction And Relaxation ◽  
High Calorie

Our hypothesis is that impairment of peroxisome proliferator-activated receptor-γ (PPARγ) initiates renal dysfunction by increasing renal glomerular matrix metalloproteinase-2 (MMP-2) activity because of increased renal homocysteine (Hcy) and decreased nitric oxide (NO) levels. C57BL/6J mice were made diabetic (D) by being fed a high-fat-calorie diet, and an increase in PPARγ activity was induced by adding pioglitazone (Pi) to the diet. Mice were grouped as follows: normal calorie diet (N), D, N+Pi, and D+Pi ( n = 6/group). The glomerular filtration rate (GFR), renal artery blood flow and pressure, and plasma glucose were measured. Renal glomeruli and preglomerular arterioles were isolated. Plasma and glomerular levels of NO, Hcy, and MMP activity were measured. The contractile response to phenylephrine and the dilatation response to acetylcholine in renal arteriolar rings were measured in a tissue myobath. In N, D, N+Pi, and D+Pi groups, respectively, GFR was 9.4 ± 1.2, 3.9 ± 1.1, 9.2 ± 1.6, and 8.4 ± 1.4 μl·min−1·g body wt−1. Renovascular resistance was 140 ± 3, 367 ± 21, 161 ± 9, and 153 ± 10 mmHg·ml·min−1. Levels of Hcy were increased from 5.8 ± 1.5 in the N to 18.0 ± 4.0 μmol/l in the D group. Glomerular levels of MMP-2 were increased in D mice compared with N mice, and there was no change in levels of MMP-9. Treatment with Pi ameliorated glomerular levels of MMP-2 and Hcy in the D group. Renal artery ring contraction and relaxation by phenylephrine and acetylcholine, respectively, were attenuated in the D groups compared with the N groups. Results suggest that a PPARγ agonist ameliorates preglomerular arteriole remodeling in diabetes by decreasing tissue levels of Hcy and MMP-2 activity and increasing NO.

Comparative study on Cu,Zn-SOD immunoreactivity and protein levels in the adult and aged hippocampal CA1 region after ischemia–reperfusion

2006 ◽  
Vol 1092 (1) ◽  
pp. 214-219 ◽  
Author(s):  
Dae-Kun Yoon ◽  
Ki-Yeon Yoo ◽  
In Koo Hwang ◽  
Jae-Jung Lee ◽  
Jong-Hyun Kim ◽  
...  
Keyword(s):  
Comparative Study ◽  
Ischemia Reperfusion ◽  
Protein Levels ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Hippocampal Ca1

The PROactive and DREAM Studies

2006 ◽  
Vol 00 (02) ◽  
Author(s):  
Roy Taylor
Keyword(s):  
Type 2 Diabetes ◽  
Ace Inhibitor ◽  
Preventive Treatment ◽  
Peroxisome Proliferator ◽  
Converting Enzyme ◽  
Abnormal Glucose Tolerance ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Rate Of Progression

These two large studies, PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) and Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM), had very different aims. PROactive asked whether the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone could decrease macrovascular morbidity and mortality in people with type 2 diabetes who were already taking maximum preventive treatment.1DREAM asked whether rosiglitazone and ramipril (PPARγ agonist and angiotensin-converting enzyme (ACE) inhibitor, respectively), either in combination or individually, could decrease the rate of progression to diabetes in people with abnormal glucose tolerance.2,3

scholarly journals miR-27b promotes type II collagen expression by targetting peroxisome proliferator-activated receptor-γ2 during rat articular chondrocyte differentiation

2018 ◽  
Vol 38 (1) ◽  
Author(s):  
Jinying Xu ◽  
Shuang Lv ◽  
Yi Hou ◽  
Kan Xu ◽  
Dongjie Sun ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Type Ii Collagen ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Type Ii ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Pparγ Agonist ◽  
Gene Assay

MicroRNAs (miRNAs) play an essential role in articular cartilage development and growth. However, the exact mechanisms involved in this process remain unknown. In the present study, we investigated the biological functions of miR-27b during hypertrophic differentiation of rat articular chondrocytes. Based on in situ hybridization and immunohistochemistry, we report that miR-27b expression is reduced in the hypertrophic zone of articular cartilage, but expression of peroxisome proliferator-activated receptor γ (Pparγ) is increased. Dual-luciferase reporter gene assay and Western blot analysis demonstrated that Pparγ2 is a target of miR-27b. Overexpression of miR-27b inhibited expression of Pparγ2, as well as type X collagen (Col10a1) and matrix metalloproteinase 13 (Mmp13), while significantly promoting the expression of Sex-determining Region-box 9 (Sox9) and type II collagen (Col2a1) at both the mRNA and protein levels. Rosiglitazone, a Pparγ agonist, suppressed Col2a1 expression, while promoting expression of runt-related transcription factor 2 (Runx2) and Col10a1 in a concentration-dependent manner. siRNA-mediated knockdown of Pparγ2 caused an increase in protein levels of Col2a1. The present study demonstrates that miR-27b regulates chondrocyte hypertrophy in part by targetting Pparγ2, and that miR-27b may have important therapeutic implications in cartilage diseases.

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