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Thyroid hormone (TH) and thyroid hormone receptor (THR) regulate stem cell proliferation and differentiation during development, as well as during tissue renewal and repair in the adult. THR undergoes posttranslational modification by small ubiquitin-like modifier (SUMO). We generated the THRA (K283Q/K288R)-/- mouse model for in vivo studies and used human primary preadipocytes expressing the THRA sumoylation mutant (K283R/K288R) and isolated preadipocytes from mutant mice for in vitro studies. THRA mutant mice had reduced white adipose stores and reduced adipocyte cell diameter on a chow diet, compared to wild-type, and these differences were further enhanced after a high fat diet. Reduced preadipocyte proliferation in mutant mice, compared to wt, was shown after in vivo labeling of preadipocytes with EdU and in preadipocytes isolated from mice fat stores and studied in vitro. Mice with the desumoylated THRA had disruptions in cell cycle G1/S transition and this was associated with a reduction in the availability of cyclin D2 and cyclin-dependent kinase 2. The genes coding for cyclin D1, cyclin D2, cyclin-dependent kinase 2 and Culin3 are stimulated by cAMP Response Element Binding Protein (CREB) and contain CREB Response Elements (CREs) in their regulatory regions. We demonstrate, by Chromatin Immunoprecipitation (ChIP) assay, that in mice with the THRA K283Q/K288R mutant there was reduced CREB binding to the CRE. Mice with a THRA sumoylation mutant had reduced fat stores on chow and high fat diets and reduced adipocyte diameter.

BackgroundRecurrent hypoglycemia (RH) is well known to impair awareness of hypoglycemia and increase the risk of severe hypoglycemia; the underlying mechanism requires further understanding. We aimed to investigate the metabolic characteristic profile for RH in type 2 diabetes mellitus (T2DM) patients and explore the potential metabolic mechanism and prevention strategies.MethodsWe screened 553 community-based T2DM patients. T2DM with RH (DH group, n=40) and T2DM without hypoglycemia (DC group, n=40) were assigned in the case-control study, matched by propensity score matching. Non-targeted, global metabolite profiling was conducted using ultra-high performance liquid chromatography-mass spectrometry. Principal component analysis and supervised projections to latent structures-discriminant analysis were constructed to evaluate the potential biomarkers. Metabolites with a fold change of >2.0 or 1 were identified as significantly differential metabolites. MetaboAnalyst was performed to analyze the related metabolic pathways.ResultsWe identified 12 significantly distinct metabolites as potential biomarkers of RH, which were enriched in five pathways; the caffeine metabolic pathway was the most dominant related one. Caffeine and its main downstream metabolites (theophylline and paraxanthine, all q

Objective. It remains unknown whether obesity has an effect on the pituitary-thyroid feedback control axis in subclinical hypothyroidism (SCH). We aimed to investigate the association of thyroid homeostasis with obesity in a SCH population. Methods. Our study consisted of a community-based and cross-sectional study from the Epidemiological Survey of Thyroid Diseases in Fujian Province, China. A total of 193 subjects with SCH (90 males and 103 females) without a history of treatment of thyroid disease, such as surgery, radiation, and thyroid hormone or antithyroid medication, were included in the present study. Indices of obesity, including body mass index (BMI), waist circumference (WC), and waist-height ratio (WHtR) were measured. Results. Our results showed that the secretory capacity of the thyroid gland (SPINA-GT) and Jostel's thyrotropin index (TSHI) were negatively correlated with BMI, WC, and WHtR, whereas the reciprocal of the thyrotroph thyroid hormone resistance index (TTSI-1) was positively correlated with BMI (all p < 0.05). After adjustment for age, sex, smoking, iodine status, and glucolipid metabolism, the associations between TSHI, TTSI (reciprocal transformation), and BMI still persisted (all p < 0.05). Conclusions. These results suggest that low levels of thyroid homeostasis indexes may be associated with overall obesity in SCH, rather than central adiposity. [ABSTRACT FROM AUTHOR]

Thyroid hormone plays an important role in brain development and adult brain function, and may influence neuronal recovery after Traumatic Brain Injury (TBI). We utilized both animal and cell culture models to determine the effects of thyroid hormone treatment, post TBI or during hypoxia, on genes important for neuronal survival and neurogenesis. We show that TBI in rats is associated with a reduction in serum thyroxine (T4) and triiodothyronine (T3). A single dose of levothyroxine (T4), one hour after injury, increased serum T4 and normalized serum T3 levels. Expression of genes important for thyroid hormone action in the brain, MCT8 and Type 2 deiodinase ( Dio2 ) mRNA, diminished after injury, but were partially restored with T4 treatment. mRNA from the Type 3 deiodinase ( Dio3 ) gene, which inactivates T4 to reverse T3 (rT3), was induced 2.7 fold by TBI, and further stimulated 6.7-fold by T4 treatment. T4 treatment significantly increased the expression of mRNA from Bcl2, VEGFA, Sox2 and neurotrophin , genes important for neuronal survival and recovery. The cortex, compared to the hippocampus and cerebellum, sustained the greatest injury and had the most significant change in gene expression as a result of injury and the greatest response to T4 treatment. We utilized hypoxia to study the effect of neuronal injury in vitro . Neuroblastoma cells were exposed to reduced oxygen tension, 0.2%, and were compared to cells grown at control oxygen levels of 21%. T3 treatment significantly increased hypoxia inducible factor (HIF)-2α protein, but not HIF-1α. In a hypoxia time course exposure, expression of hypoxia-mediated genes ( VEGF, Enolase, HIF2α, c-Jun ) peaked at least 8 h earlier with T3-treatment, compared to cells grown without T3. The early induction of these genes may promote cellular growth after injury. After hypoxic injury, T3 induced mRNA expression of the genes, KLF9 and hairless , important for T3-mediated brain function. The findings from both in vitro and in vivo studies support a role of thyroid hormone in activating pathways important for neuronal protection and promotion of neuronal recovery after injury. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the relationship between astrocytes and recurrent non-severe hypoglycemia (RH)2 -associated cognitive decline in diabetes. RH induced cognitive impairment and neuronal cell death in the cerebral cortex of diabetic mice, accompanied by excessive activation of astrocytes. Levels of the neurotrophins BDNF and GDNF, together with BDNF and GDNF- related signaling, were downregulated by RH. In vitro , recurrent low glucose (RLG)3 impaired cell viability and induced apoptosis of high-glucose cultured astrocytes. Accumulating mitochondrial ROS and dysregulated mitochondrial functions, including abnormal morphology, decreased membrane potential, downregulated ATP levels, and disrupted bioenergetic status, were observed in these cells. SS-31 mediated protection of mitochondrial functions reversed RLG-induced cell viability defects and neurotrophin production. These findings demonstrate that RH induced astrocyte overactivation and mitochondrial dysfunction, leading to astrocyte-derived neurotrophin disturbance, which might contribute to diabetic cognitive decline. Targeting astrocyte mitochondria might represent a neuroprotective therapy for hypoglycemia-associated neurodegeneration in diabetes. • RH induced neurodegeneration and excessive activation of the cortical astrocytes. • RH disrupted neurotrophin level and the related signaling in the cerebral cortex of diabetic mice. • RLG induced mitochondrial ROS accumulation in astrocytes in high glucose culture. • RLG impaired mitochondrial function of astrocytes in high glucose culture. • RLG-induced mitochondrial dysfunction reduced astrocytic neurotrophin synthesis and secretion. [ABSTRACT FROM AUTHOR]

• Exenatide improves spatial memory and learning ability in 5xFAD mice. • Exenatide reduces hippocampal A 1-42 deposits and synaptic degradation in 5xFAD mice. • Exenatide improves hippocampal mitochondrial morphology and dynamics in 5xFAD mice. • Exenatide reduces oxidative stress in the hippocampus of 5xFAD mice. • Exenatide is a promising agent for AD therapy via mitochondrial protection. The role of mitochondrial dysfunction has been well-documented in Alzheimer's disease (AD). Glucagon-like peptide 1 (GLP-1) receptor agonists are being utilized as neuroprotectants in the treatment of various neurological disorders, including AD. We conducted this study to explore the effects of exenatide (a GLP-1 receptor agonist) on β-amyloid plaque (Aβ)-induced cognitive impairment and mitochondrial dysfunction in 5xFAD transgenic mice. Spatial memory test showed that exenatide administration (100 μg/kg twice per day) prevented cognitive decline after 16 weeks of treatment. Aβ 1-42 deposition and synapse damage in the hippocampus was significantly alleviated. Furthermore, exenatide treatment can improve mitochondrial morphology, relieve oxidative damage, correct mitochondrial energy crisis, and normalize mitochondrial dynamics. These findings suggest that exenatide, which has already been applied in clinical medicine, may be a promising agent for AD therapy via mitochondrial protection. [ABSTRACT FROM AUTHOR]

Thyroid hormone receptor β (THRB) is posttranslationally modified by small ubiquitin-like modifier (SUMO). We generated a mouse model with a mutation that disrupted sumoylation at lysine 146 (K146Q) and resulted in desumoylated THRB as the predominant form in tissues. The THRB K146Q mutant mice had normal serum thyroxine (T4), markedly elevated serum thyrotropin-stimulating hormone (TSH; 81-fold above control), and enlargement of both the pituitary and the thyroid gland. The marked elevation in TSH, despite a normal serum T4, indicated blunted feedback regulation of TSH. The THRB K146Q mutation altered the recruitment of transcription factors to the TSHβ gene promoter, compared with WT, in hyperthyroidism and hypothyroidism. Thyroid hormone content (T4, T3, and rT3) in the thyroid gland of the THRB K146Q mice was 10-fold lower (per gram tissue) than control, despite normal TSH bioactivity. The expression of thyroglobulin and dual oxidase 2 genes in the thyroid was reduced and associated with modifications of cAMP response element-binding protein DNA binding and cofactor interactions in the presence of the desumoylated THRB. Therefore, thyroid hormone production had both TSH-dependent and TSH-independent components. We conclude that THRB sumoylation at K146 was required for normal TSH feedback regulation and TH synthesis in the thyroid gland, by a TSH-independent pathway.

Background: Metabolic associated fatty liver disease (MAFLD) refers to metabolic dysfunction associated with fatty liver disease, and liver fibrosis stage is closely connected with liver-related and all-cause mortality. This study aimed to explore the association of sleep duration with liver fibrosis in the diabetic subgroup of the MAFLD population., Methods: This retrospective study analyzed 342 patients with MAFLD. Anthropometric measurements, clinical and biochemical markers, and lifestyle parameters were collected. Fibrosis was defined as fibrosis-4 ⩾1.3. Propensity score matching (PSM) was performed to match cases. Student's t -test and chi-square tests were applied for group comparisons, and binary regression models were used to explore the independent risk factors of liver fibrosis., Results: Among the 342 subjects, 87 (25.4%) were diagnosed with fibrosis and 255 (74.6%) without. Baseline characteristic comparisons showed differences in age and diabetes duration between the two groups, and adjustment was made by PSM. Ultimately, the fibrosis group and nonfibrosis group each had 87 patients. The fibrosis group had shorter duration of nocturnal sleep (6.77 ± 1.59 h) than the nonfibrosis group (7.77 ± 1.92 h, p  < 0.001). More patients in the fibrosis group stayed up late at night (32.2% versus 14.9%, p  < 0.01). Visceral adipose tissue (VAT) areas were larger in the fibrosis group than in the nonfibrosis group ( p  < 0.001). Glycemic profile, lipid profile, gamma-glutamyl transferase level, and serum uric acid level were not significantly different between the two groups. In the multivariate regression analysis, nocturnal sleep and VAT areas were independently associated with liver fibrosis, with odds ratios of 0.694 [95% confidence interval (CI) 0.551-0.875, p  < 0.01] for nocturnal sleep and 1.031 (95% CI 1.014-1.048, p  < 0.001) for VAT areas., Conclusion: Insufficient nocturnal sleep was independently related to a higher risk of fibrosis. Sleep modification might be beneficial in promoting the health of patients with MAFLD., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Background: The hypertension cure rate of unilateral adrenalectomy in primary aldosteronism (PA) patients varies widely in existing studies., Methods: We conducted an observational meta-analysis to summarize the pooled hypertension cure rate of unilateral adrenalectomy in PA patients. Comprehensive electronic searches of PubMed, Embase, Cochrane, China National Knowledge Internet (CNKI), WanFang, SinoMed and Chongqing VIP databases were performed from initial state to May 20, 2016. We manually selected eligible studies from references in accordance with the inclusion criteria. The pooled hypertension cure rate of unilateral adrenalectomy in PA patients was calculated using the DerSimonian-Laird method to produce a random-effects model., Results: Forty-three studies comprising approximately 4000 PA patients were included. The pooled hypertension cure rate was 50.6% (95% CI: 42.9-58.2%) for unilateral adrenalectomy in PA. Subgroup analyses showed that the hypertension cure rate was 61.3% (95% CI: 49.4-73.3%) in Chinese studies and 43.7% (95% CI: 38.0-49.4%) for other countries. Furthermore, the hypertension cure rate at 6-month follow-up was 53.3% (95% CI: 36.0-70.5%) and 49.6% (95% CI: 40.9-58.3%) for follow-up exceeding 6 months. The pooled hypertension cure rate was 50.9% (95% CI: 40.5-61.3%) from 2001 to 2010 and 50.2% (95% CI: 39.0-61.5%) from 2011 to 2016., Conclusions: The hypertension cure rate for unilateral adrenalectomy in PA is not optimal. Large clinical trials are required to verify the utility of potential preoperative predictors in developing a novel and effective prediction model.

Objective: To investigate the protective effects of exendin-4 on vascular endothelial cells and explore the possible mechanism., Methods: Human umbilical vascular endothelial cells (HUVECs) were cultured in the presence of high glucose and tumor necrosis factor-α (TNF-α, 10 ng/ml) with or without exendin-4. The level of nitric oxide (NO) in the cell culture supernatant was measured using a nitrate reductase method. The expression of intercellular adhesion molecule-1 (ICAM-1) mRNA was measured by real-time PCR, and nuclear factor-κB (NF-κB) p65 translocation was detected using immunofluorescence assay. Western blotting was employed to measure the expression of p38 MAPK protein in the treated cells., Results: In the presence of high glucose and TNF-α, treatment of cells with exendin-4 did not obviously affect the cellular synthesis of NO, but significantly down-regulated the expression of ICAM-1 mRNA (P<0.01). The nuclear fluorescence intensity of NF-κB p65 and the expression level of p38 MAPK protein in the cells were significantly lowered by exendin-4 treatment (P<0.01)., Conclusion: Exendin-4 ameliorates high glucose- and TNF-α-induced HUVEC-12 cell damage by inhibiting the expression of p38 MAPK protein and translocation of NF-κB p65.