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1.
Diabetes ; 71(12): 2557-2571, 2022 12 01.
Article in English | MEDLINE | ID: mdl-36170666

ABSTRACT

The phenotypic and functional plasticity of adipose tissue macrophages (ATMs) during obesity plays a crucial role in orchestration of adipose and systemic inflammation. Tonicity-responsive enhancer binding protein (TonEBP) (also called NFAT5) is a stress protein that mediates cellular responses to a range of metabolic insults. Here, we show that myeloid cell-specific TonEBP depletion reduced inflammation and insulin resistance in mice with high-fat diet-induced obesity but did not affect adiposity. This phenotype was associated with a reduced accumulation and a reduced proinflammatory phenotype of metabolically activated macrophages, decreased expression of inflammatory factors related to insulin resistance, and enhanced insulin sensitivity. TonEBP expression was elevated in the ATMs of obese mice, and Sp1 was identified as a central regulator of TonEBP induction. TonEBP depletion in macrophages decreased induction of insulin resistance-related genes and promoted induction of insulin sensitivity-related genes under obesity-mimicking conditions and thereby improved insulin signaling and glucose uptake in adipocytes. mRNA expression of TonEBP in peripheral blood mononuclear cells was positively correlated with blood glucose levels in mice and humans. These findings suggest that TonEBP in macrophages promotes obesity-associated systemic insulin resistance and inflammation, and downregulation of TonEBP may induce a healthy metabolic state during obesity.


Subject(s)
Insulin Resistance , Humans , Mice , Animals , Insulin Resistance/genetics , NFATC Transcription Factors/metabolism , Leukocytes, Mononuclear/metabolism , Adipose Tissue/metabolism , Obesity/metabolism , Inflammation/metabolism , Mice, Obese , Myeloid Cells/metabolism , Insulin/metabolism , Mice, Inbred C57BL
2.
Aust N Z J Psychiatry ; 54(9): 883-891, 2020 09.
Article in English | MEDLINE | ID: mdl-32436738

ABSTRACT

OBJECTIVE: We evaluated the effects of bone marrow-derived mesenchymal stem cells in a model of Alzheimer's disease using serial [18F]Florbetaben positron emission tomography. METHODS: 3xTg Alzheimer's disease mice were treated with intravenously injected bone marrow-derived mesenchymal stem cells, and animals without stem cell therapy were used as controls. Serial [18F]Florbetaben positron emission tomography was performed after therapy. The standardized uptake value ratio was measured as the cortex standardized uptake value divided by the cerebellum standardized uptake value. Memory function and histological changes were observed using the Barnes maze test and ß-amyloid-reactive cells. RESULTS: Standardized uptake value ratio decreased significantly from day 14 after stem cell administration in the bone marrow-derived mesenchymal stem cells-treated group (n = 28). In contrast, there was no change in the ratio in control mice (n = 25) at any time point. In addition, mice that received bone marrow-derived mesenchymal stem cell therapy also exhibited significantly better memory function and less ß-amyloid-immunopositive plaques compared to controls. CONCLUSION: The therapeutic effect of intravenously injected bone marrow-derived mesenchymal stem cells in a mouse model of Alzheimer's disease was confirmed by ß-amyloid positron emission tomography imaging, memory functional studies and histopathological evaluation.


Subject(s)
Alzheimer Disease , Mesenchymal Stem Cells , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/therapy , Amyloid beta-Peptides/metabolism , Animals , Brain , Disease Models, Animal , Humans , Mesenchymal Stem Cells/metabolism , Mice , Positron-Emission Tomography
3.
Exp Neurobiol ; 29(1): 70-79, 2020 Feb 29.
Article in English | MEDLINE | ID: mdl-32122109

ABSTRACT

Many previous studies have shown reduced glucose uptake in the ischemic brain. In contrast, in a permanent unilateral common carotid artery occlusion (UCCAO) mouse model, our pilot experiments using 18F-fluorodeoxyglucose positron emission tomography (FDG PET) revealed that a subset of mice exhibited conspicuously high uptake of glucose in the ipsilateral hemisphere at 1 week post-occlusion (asymmetric group), whereas other mice showed symmetric uptake in both hemispheres (symmetric group). Thus, we aimed to understand the discrepancy between the two groups. Cerebral blood flow and histological/metabolic changes were analyzed using laser Doppler flowmetry and immunohistochemistry/Western blotting, respectively. Contrary to the increased glucose uptake observed in the ischemic cerebral hemisphere on FDG PET (p<0.001), cerebral blood flow tended to be lower in the asymmetric group than in the symmetric group (right to left ratio [%], 36.4±21.8 vs. 58.0±24.8, p=0.059). Neuronal death was observed only in the ischemic hemisphere of the asymmetric group. In contrast, astrocytes were more activated in the asymmetric group than in the symmetric group (p<0.05). Glucose transporter-1, and monocarboxylate transporter-1 were also upregulated in the asymmetric group, compared with the symmetric group (p<0.05, respectively). These results suggest that the increased FDG uptake was associated with relatively severe ischemia, and glucose transporter-1 upregulation and astrocyte activation. Glucose metabolism may thus be a compensatory mechanism in the moderately severe ischemic brain.

4.
J Stroke Cerebrovasc Dis ; 27(12): 3549-3554, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30195698

ABSTRACT

BACKGROUND: The role of sex hormones in poststroke mood and emotional disturbances is unclear. We aimed to evaluate the impact of sex hormones on poststroke emotional disturbance, especially anger proneness (AP) and emotional incontinence (EI). We also investigated whether statins, which are widely used for stroke prevention, affect sex hormone levels or the presence of poststroke AP/EI based on the hypothesis that intensive treatment with statins would inhibit the synthesis of cholesterol, the preferred substrate of testosterone. METHODS: We prospectively enrolled 40 patients who experienced ischemic stroke at least 3 months prior to study enrollment. We performed clinical and laboratory evaluations, including hormone-level measurements and neuropsychological tests. Poststroke AP and EI were assessed using interviews, then patients were divided into 2 groups: AP/EI-present or absent. RESULTS: Of the 40 patients (30 men, mean age 58.8 years), 16 (40.0%) were classified as AP/EI-present group. AP/EI were not related to stroke severity or location; however, the testosterone level was significantly lower in patients with AP/EI than in those without AP/EI (2.1 ± 1.7 vs. 3.9 ± 2.5 ng/mL, P = .023). After adjusting for potential confounding variables, low testosterone levels were a significant independent predictor of AP/EI (odds ratio .68, 95% confidence interval .49-.96, P = .027). In contrast, sex hormone levels and AP/EI prevalence did not differ between statin users and nonusers. CONCLUSIONS: AP/EI were associated with low testosterone levels in patients with previous ischemic stroke, but statin use did not affect AP/EI prevalence.


Subject(s)
Brain Ischemia/blood , Brain Ischemia/psychology , Stroke/blood , Stroke/psychology , Testosterone/blood , Anger , Brain Ischemia/complications , Brain Ischemia/drug therapy , Female , Follow-Up Studies , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Male , Middle Aged , Mood Disorders/blood , Mood Disorders/diagnosis , Mood Disorders/epidemiology , Mood Disorders/etiology , Pilot Projects , Prevalence , Prognosis , Prospective Studies , Stroke/complications , Stroke/drug therapy
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