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Intermittent fasting (IF), an alternating pattern of dietary restriction, reduces obesity-induced insulin resistance and inflammation. However, the crosstalk between adipose tissue and the hippocampus in diabetic encephalopathy is not fully understood. Here, we investigated the protective effects of IF against neuroinflammation and cognitive impairment in high-fat diet(HFD)-fed mice. Histological analysis revealed that IF reduced crown-like structures and adipocyte apoptosis in the adipose tissue of HFD mice. In addition to circulating lipocalin-2 (LCN2) and galectin-3 (GAL3) levels, IF reduced HFD-induced increases in LCN2- and GAL3-positive macrophages in adipose tissue. IF also improved HFD-induced memory deficits by inhibiting blood–brain barrier breakdown and neuroinflammation. Furthermore, immunofluorescence showed that IF reduced HFD-induced astrocytic LCN2 and microglial GAL3 protein expression in the hippocampus of HFD mice. These findings indicate that HFD-induced adipocyte apoptosis and macrophage infiltration may play a critical role in glial activation and that IF reduces neuroinflammation and cognitive impairment by protecting against blood–brain barrier leakage.

Age-related microglial activation is associated with cognitive impairment. Tonicity-responsive enhancer-binding protein (TonEBP) is a critical mediator of microglial activation in response to neuroinflammation. However, the precise role of TonEBP in the middle-aged brain is not yet known. We used TonEBP haploinsufficient mice to investigate the role of TonEBP in middle-aged or amyloid β oligomer (AβO)–injected brains and examined the effect of TonEBP knockdown on AβO-treated BV2 microglial cells. Consistent with an increase in microglial activation with aging, hippocampal TonEBP expression levels were increased in middle-aged (12-month-old) and old (24-month-old) mice compared with young (6-month-old) mice. Middle-aged TonEBP haploinsufficient mice showed reduced microglial activation and fewer memory deficits than wild-type mice. Electron microscopy revealed that synaptic pruning by microglial processes was reduced by TonEBP haploinsufficiency. TonEBP haploinsufficiency also reduced dendritic spine loss and improved memory deficits in AβO-treated mice. Furthermore, TonEBP knockdown attenuated migration and phagocytosis in AβO-treated BV2 cells. These findings suggest that TonEBP plays important roles in age-related microglial activation and memory deficits.

An intermittent fasting (IF) regimen has been shown to protect against metabolic dysfunction-associated steatohepatitis (MASH). However, the precise mechanism remains unclear. Here, we explored how IF reduced hepatic lipid accumulation, inflammation, and fibrosis in mice with MASH. The mice were fed a high-fat diet (HFD) for 30 weeks and either continued on the HFD or were subjected to IF for the final 22 weeks. IF reduced body weight, insulin resistance, and hepatic lipid accumulation in HFD-fed mice. Lipidome analysis revealed that IF modified HFD-induced hepatic lipid composition. In particular, HFD-induced impaired autophagic flux was reversed by IF. The decreased hepatic lysosome-associated membrane protein 1 level in HFD-fed mice was upregulated in HFD+IF-fed mice. However, increased hepatic lysosomal acid lipase protein levels in HFD-fed mice were reduced by IF. IF attenuated HFD-induced hepatic inflammation and galectin-3-positive Kupffer cells. In addition to the increases in hepatic hydroxyproline and lumican levels, lipocalin-2-mediated signaling was reversed in HFD-fed mice by IF. Taken together, our findings indicate that the enhancement of the autophagy–lysosomal pathway may be a critical mechanism of MASH reduction by IF.

This study aimed to investigate the clinical implications and prognostic value of artificial intelligence (AI)-based results for chest radiographs (CXR) in coronavirus disease 2019 (COVID-19) patients. Patients who were admitted due to COVID-19 from September 2021 to March 2022 were retrospectively included. A commercial AI-based software was used to assess CXR data for consolidation and pleural effusion scores. Clinical data, including laboratory results, were analyzed for possible prognostic factors. Total O2 supply period, the last SpO2 result, and deterioration were evaluated as prognostic indicators of treatment outcome. Generalized linear mixed model and regression tests were used to examine the prognostic value of CXR results. Among a total of 228 patients (mean 59.9 ± 18.8 years old), consolidation scores had a significant association with erythrocyte sedimentation rate and C-reactive protein changes, and initial consolidation scores were associated with the last SpO2 result (estimate −0.018, p = 0.024). All consolidation scores during admission showed significant association with the total O2 supply period and the last SpO2 result. Early changing degree of consolidation score showed an association with deterioration (odds ratio 1.017, 95% confidence interval 1.005–1.03). In conclusion, AI-based CXR results for consolidation have potential prognostic value for predicting treatment outcomes in COVID-19 patients.

Adzuki bean is well known as a potential functional food that improves metabolic complications from obesity and diabetes. Lipocalin-2 (LCN2) has been implicated to have an important role in obesity and diabetes. However, the protective roles of adzuki bean MY59 extract (ABE) on insulin resistance and hepatic steatosis are not fully understood. In the present study, we investigated the effects of ABE on LCN2 expression in high-fat diet (HFD)-fed mice. ABE reduced HFD-induced fat mass and improved insulin resistance. In addition to hepatic steatosis, HFD-fed mice showed many apoptotic cells and neutrophils in the epididymal fat pads. However, these findings were significantly reduced by ABE supplementation. In particular, we found that increased LCN2 proteins from serum, epididymal fat pads, and liver in HFD-fed mice are significantly reduced by ABE. Furthermore, ABE reduced increased heme oxygenase-1 and superoxide dismutase-1 expressions in adipose tissue and liver in HFD-fed mice. We found that hepatic nuclear factor-kappa B (NF-κB) p65 expression in HFD-fed mice was also reduced by ABE. Thus, these findings indicate that ABE feeding could improve insulin resistance and hepatic steatosis by decreasing LCN2-mediated inflammation and oxidative stress in HFD-fed mice.

We investigated the feasibility of ultrasound attenuation imaging (ATI) for assessing pediatric hepatic steatosis. A total of 111 children and adolescents who underwent liver ultrasonography with ATI for suspected hepatic steatosis were included. Participants were classified into the normal, mild, or moderate–severe fatty liver group according to grayscale US findings. Associations between clinical factors, magnetic resonance imaging proton density fat fraction, steatosis stage and ATI values were evaluated. To determine the cutoff values of ATI for staging hepatic steatosis, areas under the curve (AUCs) were analyzed. Factors that could cause measurement failure with ATI were assessed. Of 111 participants, 88 had successful measurement results. Median ATI values were significantly increased according to steatosis stage (p < 0.001). Body mass index (BMI) was a significant factor for increased ATI values (p = 0.047). To differentiate fatty liver from normal liver, a cutoff value of 0.59 dB/cm/MHz could be used with an AUC value of 0.853. To differentiate moderate to severe fatty liver from mild fatty liver, a cutoff value of 0.69 dB/cm/MHz could be used with an AUC value up to 0.91. ATI can be used in children as an effective ultrasonography technique for quantifying and staging pediatric hepatic steatosis.

Background: Lipocalin-2 (LCN2) is an acute-phase protein that has been linked to insulin resistance, diabetes, and neuroinflammatory diseases. Triggering receptor expressed on myeloid cells-2 (TREM2) has been also implicated in microglia-mediated neuroinflammation. However, the potential role of LCN2 on TREM2 in diabetic mouse models is not fully understood. Methods: We investigated hepatic and hippocampal TREM2 expressions in high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic LCN2 knockout (KO) mice. Results: In addition to increased serum LCN2 level, diabetic wild-type (WT) mice had insulin resistance and hepatic steatosis. However, LCN2 deletion attenuated these metabolic parameters in diabetic mice. We also found that LCN2 deletion reduced hepatic inflammation and microglial activation in diabetic mice. In particular, diabetic LCN2 KO mice had a reduction in hepatic and hippocampal TREM2 expressions compared with diabetic WT mice. Furthermore, we found that many TREM2-positive Kupffer cells and microglia in diabetic WT mice were reduced through LCN2 deletion. Conclusions: These findings indicate that LCN2 may promote hepatic inflammation and microglial activation via upregulation of TREM2 in diabetic mice.

Lipocalin-2 (LCN2) is an inflammatory protein with diverse functions in the brain. Although many studies have investigated the mechanism of LCN2 in brain injuries, the effect of LCN2 on amyloid-toxicity-related memory deficits in a mouse model of Alzheimer’s disease (AD) has been less studied. We investigated the role of LCN2 in human AD patients using a mouse model of AD. We created an AD mouse model by injecting amyloid-beta oligomer (AβO) into the hippocampus. In this model, animals exhibited impaired learning and memory. We found LCN2 upregulation in the human brain frontal lobe, as well as a positive correlation between white matter ischemic changes and serum LCN2. We also found increased astrocytic LCN2, microglia activation, iron accumulation, and blood–brain barrier disruption in AβO-treated hippocampi. These findings suggest that LCN2 is involved in a variety of amyloid toxicity mechanisms, especially neuroinflammation and oxidative stress.

Obesity and insulin resistance accelerate aging-related sarcopenia, which is associated with iron load and oxidative stress. Lipocalin-2 (LCN2) is an iron-binding protein that has been associated with skeletal muscle regeneration, but details regarding its role in obese sarcopenia remain unclear. Here, we report that elevated LCN2 levels in skeletal muscle are linked to muscle atrophy-related inflammation and oxidative stress in leptin-deficient ob/ob mice. RNA sequencing analyses indicated the LCN2 gene expression is enhanced in skeletal muscle of ob/ob mice with sarcopenia. In addition to muscular iron accumulation in ob/ob mice, expressions of iron homeostasis-related divalent metal transporter 1, ferritin, and hepcidin proteins were increased in ob/ob mice compared to lean littermates, whereas expressions of transferrin receptor and ferroportin were reduced. Collectively, these findings demonstrate that LCN2 functions as a potent proinflammatory factor in skeletal muscle in response to obesity-related sarcopenia and is thus a therapeutic candidate target for sarcopenia treatment.

The hippocampal cell death that follows kainic acid (KA)-induced seizures is associated with blood–brain barrier (BBB) leakage and oxidative stress. Lipocalin-2 (LCN2) is an iron-trafficking protein which contributes to both oxidative stress and inflammation. However, LCN2′s role in KA-induced hippocampal cell death is not clear. Here, we examine the effect of blocking LCN2 genetically on neuroinflammation and oxidative stress in KA-induced neuronal death. LCN2 deficiency reduced neuronal cell death and BBB leakage in the KA-treated hippocampus. In addition to LCN2 upregulation in the KA-treated hippocampus, circulating LCN2 levels were significantly increased in KA-treated wild-type (WT) mice. In LCN2 knockout mice, we found that the expressions of neutrophil markers myeloperoxidase and neutrophil elastase were decreased compared to their expressions in WT mice following KA treatment. Furthermore, LCN2 deficiency also attenuated KA-induced iron overload and oxidative stress in the hippocampus. These findings indicate that LCN2 may play an important role in iron-related oxidative stress and neuroinflammation in KA-induced hippocampal cell death.

Obesity-induced adipocyte apoptosis promotes inflammation and insulin resistance. Src homology domain-containing inositol 5′-phosphatase 1 (SHIP1) is a key factor of apoptosis and inflammation. However, the role of SHIP1 in obesity-induced adipocyte apoptosis and autophagy is unclear. We found that diet-induced obesity (DIO) mice have significantly greater crown-like structures and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL)-positive cells than ob/ob or control mice. Using RNA sequencing (RNA-seq) analysis, we identified that the apoptosis- and inflammation-related gene Ship1 is upregulated in DIO and ob/ob mice compared with control mice. In particular, DIO mice had more SHIP1-positive macrophages and lysosomal-associated membrane protein 1 (LAMP1) as well as a higher B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 ratio compared with ob/ob or control mice. Furthermore, caloric restriction attenuated adipose tissue inflammation, apoptosis, and autophagy by reversing increases in SHIP1-associated macrophages, Bax/Bcl2-ratio, and autophagy in DIO and ob/ob mice. These results demonstrate that DIO, not ob/ob, aggravates adipocyte inflammation, apoptosis, and autophagy due to differential SHIP1 expression. The evidence of decreased SHIP1-mediated inflammation, apoptosis, and autophagy indicates new therapeutic approaches for obesity-induced chronic inflammatory diseases.

Glucagon-like peptide 1 (GLP-1) mimetics have been approved as an adjunct therapy for glycemic control in type 2 diabetic patients for the increased insulin secretion under hyperglycemic conditions. Recently, it is reported that such agents elicit neuroprotective effects against diabetes-associated cognitive decline. However, there is an issue of poor compliance by multiple daily subcutaneous injections for sufficient glycemic control due to their short duration, and neuroprotective actions were not fully studied, yet. In this study, using the prepared exendin-4 fusion protein agent, we investigated the pharmacokinetic profile and the role of this GLP-1 mimetics on memory deficits in a high-fat diet (HFD)/streptozotocin (STZ) mouse model of type 2 diabetic mellitus. After induction of diabetes, mice were administered weekly by intraperitoneal injection of GLP-1 mimetics for 6 weeks. This treatment reversed HFD/STZ-induced metabolic symptoms of increased body weight, hyperglycemia, and hepatic steatosis. Furthermore, the impaired cognitive performance of diabetic mice was significantly reversed by GLP-1 mimetics. GLP-1 mimetic treatment also reversed decreases in GLP-1/GLP-1 receptor expression levels in both the pancreas and hippocampus of diabetic mice; increases in hippocampal inflammation, mitochondrial fission, and calcium-binding protein levels were also reversed. These findings suggest that GLP-1 mimetics are promising agents for both diabetes and neurodegenerative diseases that are associated with increased GLP-1 expression in the brain.

Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist that protects against brain injury. However, little is known about the effect of Ex-4 on kainic acid (KA)-induced seizures and hippocampal cell death. Therefore, this study evaluated the neuroprotective effects of Ex-4 pretreatment in a mouse model of KA-induced seizures. Three days before KA treatment, mice were intraperitoneally injected with Ex-4. We found that Ex-4 pretreatment reversed KA-induced reduction of GLP-1R expression in the hippocampus and attenuated KA-induced seizure score, hippocampal neuronal death, and neuroinflammation. Ex-4 pretreatment also dramatically reduced hippocampal lipocalin-2 protein in KA-treated mice. Furthermore, immunohistochemical studies showed that Ex-4 pretreatment significantly alleviated blood–brain barrier leakage. Finally, Ex-4 pretreatment stimulated hippocampal expression of phosphorylated cyclic adenosine monophosphate (cAMP) response element-binding protein (p-CREB), a known target of GLP-1/GLP-1R signaling. These findings indicate that Ex-4 pretreatment may protect against KA-induced neuronal damage by regulating GLP-1R/CREB-mediated signaling pathways.