High-intensity interval training improves hypothalamic inflammation by suppressing HIF-1α signaling in microglia of male C57BL/6J mice.

Repeated bouts of high-intensity interval training (HIIT) induce an improvement in metabolism via plasticity of melanocortin circuits and attenuated hypothalamic inflammation. HIF-1α, which plays a vital role in hypothalamus-mediated regulation of peripheral metabolism, is enhanced in the hypothalamus by HIIT. This study aimed to investigate the effects of HIIT on hypothalamic HIF-1α expression and peripheral metabolism in obese mice and the underlying molecular mechanisms. By using a high-fat diet (HFD)-induced obesity mouse model, we determined the effect of HIIT on energy balance and the expression of the hypothalamic appetite-regulating neuropeptides, POMC and NPY. Moreover, hypothalamic HIF-1α signaling and its downstream glycolytic enzymes were explored after HIIT intervention. The state of microglia and microglial NF-κB signaling in the hypothalamus were also examined in vivo. In vitro by using an adenovirus carrying shRNA-HIF1ß, we explored the impact of HIF-1 signaling on glycolysis and NF-κB inflammatory signaling in BV2 cells. Food intake was suppressed and whole-body metabolism was improved in exercised DIO mice, accompanied by changes in the expression of POMC and NPY. Moreover, total and microglial HIF-1α signaling were obviously attenuated in the hypothalamus, consistent with the decreased levels of glycolytic enzymes. Both HFD-induced microglial activation and hypothalamic NF-κB signaling were significantly suppressed following HIIT in vivo. In BV2 cells, after HIF-1 complex knockdown, glycolysis and NF-κB inflammatory signaling were significantly attenuated. The data indicate that HIIT improves peripheral metabolism probably via attenuated HFD-induced microglial activation and microglial NF-κB signaling in the hypothalamus, which could be mediated by suppressed microglial HIF-1α signaling.

Effects of a Ketogenic Diet on Body Composition in Healthy, Young, Normal-Weight Women: A Randomized Controlled Feeding Trial.

This study investigates the effects of a ketogenic low-carbohydrate high-fat (LCHF) diet on body composition in healthy, young, normal-weight women. With the increasing interest in ketogenic diets for their various health benefits, this research aims to understand their impact on body composition, focusing on women who are often underrepresented in such studies. Conducting a randomized controlled feeding trial with a crossover design, this study compares a ketogenic LCHF diet to a Swedish National Food Agency (NFA)-recommended control diet over four weeks. Seventeen healthy, young, normal-weight women adhered strictly to the provided diets, with ketosis confirmed through blood ß-hydroxybutyrate concentrations. Dual-energy X-ray absorptiometry (DXA) was utilized for precise body composition measurements. To avoid bias, all statistical analyses were performed blind. The findings reveal that the ketogenic LCHF diet led to a significant reduction in both lean mass (-1.45 kg 95% CI: [-1.90;-1.00]; p < 0.001) and fat mass (-0.66 kg 95% CI: [-1.00;-0.32]; p < 0.001) compared to the control diet, despite similar energy intake and physical activity levels. This study concludes that while the ketogenic LCHF diet is effective for weight loss, it disproportionately reduces lean mass over fat mass, suggesting the need for concurrent strength training to mitigate muscle loss in women following this diet.

Dyslipidemia and hyperglycemia induce overexpression of Syndecan-3 in erythrocytes and modulate erythrocyte adhesion.

Erythrocytes are important vascular components that play vital roles in maintaining vascular homeostasis, in addition to carrying oxygen. Previously, we reported that the changes in the internal milieu (e.g., hyperglycemia or hypercholesterolemia) increase erythrocyte adhesion to various ECM components, potentially through altering glycosaminoglycans (GAGs). In this study, we have investigated the expression of syndecan (Sdc) family members that could be involved in mediating cytoadherence under conditions of dyslipidemia and hyperglycemia. Among the Sdc family members analyzed, we found significant overexpression of Sdc-3 in erythrocyte membranes harvested from high-fat-fed control and diabetic animals. Animal studies revealed a positive correlation between Sdc-3 expression, blood sugar levels, and erythrocyte adhesion. In the human study, diabetic cohorts with BMI >24.9 showed significantly increased expression of Sdc-3. Interestingly, blocking the Sdc-3 moiety with an anti-Sdc-3 antibody revealed that the core protein might not be directly involved in erythrocyte adhesion to fibronectin despite the GAGs bringing about adhesion. Lastly, Nano LC-MS/MS verified the presence of Sdc-3 in erythrocyte membranes. In conclusion, the high-fat diet and diabetes modulated Sdc-3 expression in the erythrocyte membrane, which may alter its adhesive properties and promote vascular complications.

Sex-Specific Effects of THRß Signaling on Metabolic Responses to High Fat Diet in Mice.

Thyroid hormone (TH) plays a crucial role in regulating the functions of both bone and adipose tissue. Given that TH exerts its cholesterol-lowering effects in hepatic tissue through the TH receptor-ß (TRß), we hypothesized that TRß agonist therapy using MGL3196 (MGL) would be effective in treating increased adiposity and bone loss in response to a 12-week high-fat diet (HFD) in adult C57BL/6J mice. Transcriptional and serum profiling revealed that HFD-induced leptin promoted weight gain in both males and females, but MGL only suppressed leptin induction and weight gain in males. In vitro studies suggest that estrogen suppresses MGL activity in adipocytes, indicating that estrogen might interfere with MGL-TRß function. Compared to systemic adiposity, HFD reduced bone mass in male but not female mice. Paradoxically, MGL treatment reversed macroscopic bone mineral density loss in appendicular bones, but micro-CT revealed that MGL exacerbated HFD-induced trabecular bone loss, and reduced bone strength. In studies on the mechanisms for HFD effects on bone, we found that HFD induced Rankl expression in male femurs that was blocked by MGL. By ex vivo assays, we found that RANKL indirectly represses osteoblast lineage allocation of osteoprogenitors by induction of inflammatory cytokines TNFα, IL-1ß, and CCL2. Finally, we found that MGL functions in both systemic adiposity and bone by nongenomic TRß signaling, as HFD-mediated phenotypes were not rescued in TRß147F knockout mice with normal genomic but defective nongenomic TRß signaling. Our findings demonstrate that the negative effects of HFD on body fat and bone phenotypes are impacted by MGL in a gender-specific manner.

Systems genetics of metabolic health in the BXD mouse genetic reference population.

Susceptibility to metabolic syndrome (MetS) is dependent on genetics, environment, and gene-by-environment interactions, rendering the study of underlying mechanisms challenging. The majority of experiments in model organisms do not incorporate genetic variation and lack specific evaluation criteria for MetS. Here, we derived a continuous metric, the metabolic health score (MHS), based on standard clinical parameters and defined its molecular signatures in the liver and circulation. In human UK Biobank, the MHS associated with MetS status and was predictive of future disease incidence, even in individuals without MetS. Using quantitative trait locus analyses in mice, we found two MHS-associated genetic loci and replicated them in unrelated mouse populations. Through a prioritization scheme in mice and human genetic data, we identified TNKS and MCPH1 as candidates mediating differences in the MHS. Our findings provide insights into the molecular mechanisms sustaining metabolic health across species and uncover likely regulators. A record of this paper's transparent peer review process is included in the supplemental information.

Distinct roles of SOX9 in self-renewal of progenitors and mesenchymal transition of the endothelium.

Regenerative capabilities of the endothelium rely on vessel-resident progenitors termed endothelial colony forming cells (ECFCs). This study aimed to investigate if these progenitors are impacted by conditions (i.e., obesity or atherosclerosis) characterized by increased serum levels of oxidized low-density lipoprotein (oxLDL), a known inducer of Endothelial-to-Mesenchymal Transition (EndMT). Our investigation focused on understanding the effects of EndMT on the self-renewal capabilities of progenitors and the associated molecular alterations. In the presence of oxLDL, ECFCs displayed classical features of EndMT, through reduced endothelial gene and protein expression, function as well as increased mesenchymal genes, contractility, and motility. Additionally, ECFCs displayed a dramatic loss in self-renewal capacity in the presence of oxLDL. RNA-sequencing analysis of ECFCs exposed to oxLDL validated gene expression changes suggesting EndMT and identified SOX9 as one of the highly differentially expressed genes. ATAC sequencing analysis identified SOX9 binding sites associated with regions of dynamic chromosome accessibility resulting from oxLDL exposure, further pointing to its importance. EndMT phenotype and gene expression changes induced by oxLDL in vitro or high fat diet (HFD) in vivo were reversed by the silencing of SOX9 in ECFCs or the endothelial-specific conditional knockout of Sox9 in murine models. Overall, our findings support that EndMT affects vessel-resident endothelial progenitor's self-renewal. SOX9 activation is an early transcriptional event that drives the mesenchymal transition of endothelial progenitor cells. The identification of the molecular network driving EndMT in vessel-resident endothelial progenitors presents a new avenue in understanding and preventing a range of condition where this process is involved.

Alleviation of hepatic insulin resistance and steatosis with NMN via improving endoplasmic reticulum-Mitochondria miscommunication in the liver of HFD mice.

The interaction between endoplasmic reticulum (ER) and mitochondria has been shown to play a key role in hepatic steatosis during chronic obesity. ß-nicotinamide mononucleotide (NMN) has been reported to regulate obesity, however, its molecular mechanism at the subcellular level remains unclear. Here, NMN improved liver steatosis and insulin resistance in chronic high-fat diet (HFD) mice. RNA-seq showed that compared with the liver of HFD mice, NMN intervention enhanced fat digestion and absorption and stimulated the cholesterol metabolism signaling pathways, while impaired insulin resistance and the fatty acid biosynthesis signaling pathways. Mechanistically, NMN ameliorated mitochondrial dysfunction and ER oxidative stress in the liver of HFD mice by increasing hepatic nicotinamide adenine dinucleotide (NAD+) (P < 0.01) levels. This effect increased the contact sites (mitochondria-associated membranes [MAMs]) between ER and mitochondria, thereby promoting intracellular ATP (P < 0.05) production and mitigating lipid metabolic disturbances in the liver of HFD mice. Taken together, this study provided a theoretical basis for restoring metabolic dynamic equilibrium in the liver of HFD mice by increasing MAMs via the nutritional strategy of NMN supplementation.

Comparative Screening of the Liver Gene Expression Profiles from Type 1 and Type 2 Diabetes Rat Models.

Experimental animal models of diabetes can be useful for identifying novel targets related to disease, for understanding its physiopathology, and for evaluating emerging antidiabetic treatments. This study aimed to characterize two rat diabetes models: HFD + STZ, a high-fat diet (60% fat) combined with streptozotocin administration (STZ, 35 mg/kg BW), and a model with a single STZ dose (65 mg/kg BW) in comparison with healthy rats. HFD + STZ- induced animals demonstrated a stable hyperglycemia range (350-450 mg/dL), whereas in the STZ-induced rats, we found glucose concentration values with a greater dispersion, ranging from 270 to 510 mg/dL. Moreover, in the HFD + STZ group, the AUC value of the insulin tolerance test (ITT) was found to be remarkably augmented by 6.2-fold higher than in healthy animals (33,687.0 ± 1705.7 mg/dL/min vs. 5469.0 ± 267.6, respectively), indicating insulin resistance (IR). In contrast, a more moderate AUC value was observed in the STZ group (19,059.0 ± 3037.4 mg/dL/min) resulting in a value 2.5-fold higher than the average exhibited by the control group. After microarray experiments on liver tissue from all animals, we analyzed genes exhibiting a fold change value in gene expression <-2 or >2 (p-value <0.05). We found 27,686 differentially expressed genes (DEG), identified the top 10 DEGs and detected 849 coding genes that exhibited opposite expression patterns between both diabetes models (491 upregulated genes in the STZ model and 358 upregulated genes in HFD + STZ animals). Finally, we performed an enrichment analysis of the 849 selected genes. Whereas in the STZ model we found cellular pathways related to lipid biosynthesis and metabolism, in the HFD + STZ model we identified pathways related to immunometabolism. Some phenotypic differences observed in the models could be explained by transcriptomic results; however, further studies are needed to corroborate these findings. Our data confirm that the STZ and the HFD + STZ models are reliable experimental models for human T1D and T2D, respectively. These results also provide insight into alterations in the expression of specific liver genes and could be utilized in future studies focusing on diabetes complications associated with impaired liver function.

Narirutin-Rich Celluclast Extract from Mandarin (Citrus unshiu) Peel Alleviates High-Fat Diet-Induced Obesity and Promotes Energy Metabolism in C57BL/6 Mice.

Mandarin peel, a main by-product from the processing of citrus juice, has been highlighted for its various bioactivities and functional ingredients. Our previous study proved the inhibitory effects of Celluclast extract from mandarin peel (MPCE) on lipid accumulation and differentiation in 3T3-L1 adipocytes. Therefore, the current study aimed to evaluate the anti-obesity effect of MPCE in high-fat diet (HFD)-induced obese mice. The high-performance liquid chromatography (HPLC) analysis exhibited that narirutin and hesperidin are the main active components of MPCE. Our current results showed that MPCE supplementation decreased adiposity by reducing body and organ weights in HFD-induced obese mice. MPCE also reduced triglyceride (TG), alanine transaminase (ALT), aspartate transaminase (AST), and leptin contents in the serum of HFD-fed mice. Moreover, MPCE significantly inhibited hepatic lipid accumulation by regulating the expression levels of proteins associated with lipid metabolism, including sterol regulatory element-binding protein (SREBP1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). Furthermore, MPCE administration significantly inhibited both adipogenesis and lipogenesis, with modulation of energy metabolism by activating 5' adenosine monophosphate-activated protein kinase (AMPK) and lipolytic enzymes such as hormone-sensitive lipase (HSL) in the white adipose tissue (WAT). Altogether, our findings indicate that MPCE improves HFD-induced obesity and can be used as a curative agent in pharmaceuticals and nutraceuticals to alleviate obesity and related disorders.

Resveratrol relieves HFD-induced insulin resistance in skeletal muscle tissue through antioxidant capacity enhancement and the Nrf2-Keap1 signaling pathway.

BACKGROUND: Resveratrol has received much attention due to its beneficial effects including antioxidant activity. The purpose of this study was to investigate the therapeutic effects of resveratrol treatment on oxidative stress and insulin resistance in the skeletal muscle of high-fat diet (HFD)-fed animals. METHODS AND RESULTS: A total of 30 six-week-old C57BL/6J mice were randomly allocated to three groups (10 animals in each group): The control group in which mice were fed a normal chow diet (NCD); the HFD group in which mice were fed an HFD for 26 weeks; and the HFD-resveratrol group in which HFD was replaced by a resveratrol supplemented-HFD (400 mg/kg diet) after 10 weeks of HFD feeding. At the end of this period, gastrocnemius muscle samples were examined to determine insulin resistance and the oxidative status in the presence of HFD and resveratrol. Resveratrol supplementation in HFD-fed mice reduced body and adipose tissue weight, improved insulin sensitivity, and decreased oxidative stress as indicated by lower malonaldehyde (MDA) levels and higher total antioxidant capacity. The supplement also increased the expression and activity of antioxidative enzymes in gastrocnemius muscle and modulated Nrf2 and Keap1 expression levels. CONCLUSIONS: These results suggest that resveratrol is effective in improving the antioxidant defense system of the skeletal muscle in HFD-fed mice, indicating its therapeutic potential to combat diseases associated with insulin resistance and oxidative stress.

Targeting liver and adipose tissue in obese mice: Effects of a N-acylethanolamine mixture on insulin resistance and adipocyte reprogramming.

N-acylethanolamines (NAEs) are endogenous lipid-signalling molecules involved in inflammation and energy metabolism. The potential pharmacological effect of NAE association in managing inflammation-based metabolic disorders is unexplored. To date, targeting liver-adipose axis can be considered a therapeutic approach for the treatment of obesity and related dysfunctions. Here, we investigated the metabolic effect of OLALIAMID® (OLA), an olive oil-derived NAE mixture, in limiting liver and adipose tissue (AT) dysfunction of high-fat diet (HFD)-fed mice. OLA reduced body weight and fat mass in obese mice, decreasing insulin resistance (IR), as shown by homeostasis model assessment index, and leptin/adiponectin ratio, a marker of adipocyte dysfunction. OLA improved serum lipid and hepatic profile and the immune/inflammatory pattern of metainflammation. In liver of HFD mice, OLA treatment counteracted glucose and lipid dysmetabolism, restoring insulin signalling (phosphorylation of AKT and AMPK), and reducing mRNAs of key markers of fatty acid accumulation. Furthermore, OLA positively affected AT function deeply altered by HFD by reprogramming of genes involved in thermogenesis of interscapular brown AT (iBAT) and subcutaneous white AT (scWAT), and inducing the beigeing of scWAT. Notably, the NAE mixture reduced inflammation in iBAT and promoted M1-to-M2 macrophage shift in scWAT of obese mice. The tissue and systemic anti-inflammatory effects of OLA and the increased expression of glucose transporter 4 in scWAT contributed to the improvement of gluco-lipid toxicity and insulin sensitivity. In conclusion, we demonstrated that this olive oil-derived NAE mixture is a valid nutritional strategy to counteract IR and obesity acting on liver-AT crosstalk, restoring both hepatic and AT function and metabolism.

Better than Goodenough? Evaluating new computational techniques for finding diagnostic structure in children's drawings.

In her 1926 book Measurement of Intelligence by Drawings, Florence Goodenough pioneered the quantitative analysis of children's human-figure drawings as a tool for evaluating their cognitive development. This influential work launched a broad enterprise in cognitive evaluation that continues to the present day, with most clinicians and researchers deploying variants of the checklist-based scoring methods that Goodenough invented. Yet recent work leveraging computational innovations in cognitive science suggests that human-figure drawings possess much richer structure than checklist-based approaches can capture. The current study uses these contemporary tools to characterize structure in the images from Goodenough's original work, then assesses whether this structure carries information about demographic and cognitive characteristics of the participants in that early study. The results show that contemporary methods can reliably extract information about participant age, gender, and mental faculties from images produced over 100 years ago, with no expert training and with minimal human effort. Moreover, the new analyses suggest a different relationship between drawing and mental ability than that captured by Goodenough's highly influential approach, with important implications for the use of drawings in cognitive evaluation in the present day.

FTO Stabilizes MIS12 to Inhibit Vascular Smooth Muscle Cell Senescence in Atherosclerotic Plaque.

Purpose: Atherosclerosis is the main cause of atherosclerotic cardiovascular disease (CVD). Here, we aimed to uncover the role and mechanisms of fat mass and obesity-associated genes (FTO) in the regulation of vascular smooth muscle cell (VSMC) senescence in atherosclerotic plaques. Methods: ApoE-/- mice fed a high-fat diet (HFD) were used to establish an atherosclerotic animal model. Immunohistochemistry, and the staining of hematoxylin-eosin, Oil Red O, Sirius red, and Masson were performed to confirm the role of FTO in atherosclerosis in vivo. Subsequently, FTO expression in primary VSMCs is either upregulated or downregulated. Oxidized low-density lipoprotein (ox-LDL) was used to treat VSMCs, followed by EdU staining, flow cytometry, senescence-associated ß-galactosidase (SA-ß-gal) staining, immunofluorescence, telomere detection, RT-qPCR, and Western blotting to determine the molecular mechanisms by which FTO inhibits VSMC senescence. Results: Decreased FTO expression was observed in progressive atherosclerotic plaques of ApoE-/- mice fed with HFD. FTO upregulation inhibits atherosclerotic lesions in mice. FTO inhibits VSMC aging in atherosclerotic plaques by helping VSMC withstand ox-LDL-induced cell cycle arrest and senescence. This process is achieved by stabilizing the MIS12 protein in VSMC through a proteasome-mediated pathway. Conclusion: FTO inhibits VSMC senescence and subsequently slows the progression of atherosclerotic plaques by stabilizing the MIS12 protein.

Prebiotics modulate the microbiota-gut-brain axis and ameliorate anxiety and depression-like behavior in HFD-fed mice.

Previous research has demonstrated that Prebiotics can influence the composition of the gut microbiota, consequently impacting mood regulation. This study aimed to assess the effects of Prebiotics, specifically Fructooligosaccharides (FOS) and Galactooligosaccharides (GOS) on neuroinflammation, depression, and anxiety-like behavior in a mouse model fed a high-fat diet (HFD). Initially, mice were divided into two groups: a control group on a standard diet (n = 15) and a group on an HFD for 18 weeks (n = 45). By the 13th week, the HFD group was further divided into experimental groups: Control (n = 15), HFD (n = 15), HFD receiving Prebiotics (n = 15), and HFD receiving Fluoxetine (n = 15). From the 13th week onward, the HFD + Prebiotics group received both the high-fat diet and a combination of FOS and GOS, while the HFD + Fluoxetine group received Fluoxetine in their drinking water. In the 18th week, all mice underwent tests to evaluate behavior, including the Tail Suspension Test (TST), Forced Swimming Test (FST), Sucrose Preference Test (SPT), and the Plus Maze Test (PMT), after which they were euthanized. Mice on the HFD exhibited increased body weight, abdominal size, blood glucose, triglyceride levels, cholesterol, insulin, HOMA index, and higher serum IL-1ß. These obese mice also displayed an increased number of microglia and astrocytes, activation of the TLR4 pathway, and elevated levels of neuroinflammatory markers like TNF-α, IL-1ß, and COX-2. Moreover, obese mice showed increased activation of the IDO pathway and decreased levels of NMDA receptors. Additionally, markers of neurogenesis and synaptic plasticity, such as PSD, SAP 102, CREB-p, and BDNF, were lower. Treatment with FOS and GOS reversed symptoms of depression and anxiety in mice subjected to HD. This improvement in behavior resulted from a reduction in dysbiosis with an increase in acetate-producing bacteria (B. acidifaciens and B. dorei) and intestinal permeability, leading to a decrease in chronic peripheral and central inflammation. Furthermore, the modulation of the gut-brain axis by FOS and GOS promoted elevated acetate and GPR43 levels in the brain and a reduction in the levels of pro-inflammatory cytokines, positively impacting signaling pathways of neuronal proliferation and survival in the hippocampus and prefrontal cortex.

Amelioration of endothelial integrity by 3,5,4'-trihydroxy-trans-stilbene against high-fat-diet-induced obesity and -associated vasculopathy and myocardial infarction in rats, targeting TLR4/MyD88/NF-κB/iNOS signaling cascade.

Exacerbated expression of TLR4 protein (foremost pattern recognition receptor) during obesity could trigger NF-κB/iNOS signaling through linker protein (MyD88), predisposed to an indispensable inflammatory response. The induction of this detrimental cascade leads to myocardial and vascular abnormalities. Molecular docking was studied for protein-ligand interaction between these potential targets and resveratrol. The pre-treatment of resveratrol (20 mg/kg/p.o/per day for ten weeks) was given to investigate the therapeutic effect against HFD-induced obesity and associated vascular endothelial dysfunction (VED) and myocardial infarction (MI) in Wistar rats. In addition to accessing the levels of serum biomarkers for VED and MI, oxidative stress, inflammatory cytokines, and histopathology of these tissues were investigated. Lipopolysaccharide (for receptor activation) and protein expression analysis were introduced to explore the mechanistic involvement of TLR4/MyD88/NF-κB/iNOS signaling. Assessment of in-silico analysis showed significant interaction between protein and ligand. The involvement of this proposed signaling (TLR4/MyD88/NF-κB/iNOS) was further endorsed by the impact of lipopolysaccharide and protein expression analysis in obese and treated rats. Moreover, resveratrol pre-treated rats showed significantly lowered cardio and vascular damage measured by the distinct down expression of the TLR4/MyD88/NF-κB/iNOS pathway by resveratrol treatment endorses its ameliorative effect against VED and MI.

Qingzhuan dark tea Theabrownin alleviates hippocampal injury in HFD-induced obese mice through the MARK4/NLRP3 pathway.

Background: Feeding on a high-fat diet (HFD) results in obesity and chronic inflammation, which may have long-term effects on neuroinflammation and hippocampal injury. Theabrownin, a biologically active compound derived from the microbial fermentation of Qingzhuan dark tea, exhibits anti-inflammatory properties and lipid-lowering effects. Nevertheless, its potential in neuroprotection has yet to be investigated. Consequently, this study aims to investigate the neuroprotective effects of Theabrownin extracted from Qingzhuan dark tea, as well as its potential therapeutic mechanisms. Methods: Male C57 mice were subjected to an 8-week HFD to induce obesity, followed by oral administration of Theabrownin from Qingzhuan dark tea. Lipid levels were detected by Elisa kit, hippocampal morphological damage was evaluated by HE and Nissl staining, and the expression levels of GFAP, IBA1, NLRP3, MARK4, and BAX in the hippocampus were detected by immunofluorescence (IF), and protein expression levels of NLRP3, MARK4, PSD95, SYN1, SYP, and Bcl-2 were detected by Western Blot (WB). Results: Theabrownin treatment from Qingzhuan dark tea prevents alterations in body weight and lipid levels in HFD-fed mice. Furthermore, Theabrownin decreased hippocampal morphological damage and reduced the activation of astrocytes and microglia in HFD-fed mice. Moreover, Theabrownin decreased the expression of MARK4 and NLRP3 in HFD-fed mice. Besides, Theabrownin elevated the expression of PSD95, SYN1, and SYP in HFD-fed obese mice. Finally, Theabrownin prevented neuronal apoptosis, reduced the expression of BAX, and increased the expression of Bcl-2 in HFD-fed obese mice. Conclusions: In summary, our current study presents the first demonstration of the effective protective effect of Theabrownin from Qingzhuan dark tea against HFD-induced hippocampal damage in obese mice. This protection may result from the regulation of the MARK4/NLRP3 signaling pathway, subsequently inhibiting neuroinflammation, synaptic plasticity, and neuronal apoptosis.

Transcriptome analysis provides insights into high fat diet-induced kidney injury and moderate intensity continuous training-mediated protective effects.

Although physics exercise has been utilized to prevent and treat a variety of metabolic diseases, its role in obesity-related kidney diseases remains poorly understood. In this study, we assessed the protective potential of moderate intensity continuous training (MICT) against high fat diet (HFD)-induced kidney injury and found that MICT could significantly reduce obesity indexes (body weight, serum glucose, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol) and kidney injury indexes (serum creatinine and the expression of Kim-1 mRNA) in HFD-fed mice. PAS staining and Masson staining displayed that MICT maintained the morphological structure of kidney subunits and reduced kidney fibrosis in HFD-fed mice. By kidney RNA-seq, we identified several genes and pathways (Cd9, Foxq1, Mier3, TGF-ß signaling pathway etc.) that might underlie HFD-induced kidney injury and MICT-mediated protective effects. In conclusion, this study revealed the protective role of MICT in HFD-induced kidney injury and suggested potential targets for the prevention and treatment of obesity-related kidney diseases.

Long-Term High-Fat Diet Consumption Aggravates ß-Amyloid Deposition and Tau Pathology Accompanied by Microglial Activation in an Alzheimer's Disease Model.

Alzheimer's disease (AD) is the most prevailing form of dementia, with long-term high-fat diet (HFD) consumption being a pivotal contributor to AD pathogenesis. As microglial dysfunction is a crucial factor in the AD onset, it becomes imperative to explore the effects of HFD on microglial function and AD pathogenesis. In the present study, 3xTg-AD model mice at the age of 9-month are subjected to random allocation, with one group receiving a standard diet (ND) and the other an HFD for 3 months. Subsequently, transcriptomic profiling of microglia unveils that HFD alters fatty acid metabolism and mediates T cell infiltration. Within the hippocampus, microglia exhibit aberrant morphology and lipid accretion in response to the HFD, evidenced by conspicuously enlarged microglial cell bodies and accumulation of lipid droplets. These lipid-droplet-accumulating microglia exhibit diminished migratory capacity and compromise plaque consolidation, thereby exacerbating the accumulation of ß-amyloid. Noteworthy, the HFD induces T cell infiltration, thereby aggravating neuroinflammation and Tau phosphorylation. Morris water maze test reveals that HFD-consuming mice display marked impairment in memory performance. In summary, this study demonstrates that prolonged HFD consumption exacerbates amyloid deposition, tau pathology, and cognitive deficits, which is associated with the accumulation of lipid droplets within microglia.

FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia in aged rats fed a high-fat diet.

FoxO6, an identified factor, induces hyperlipidemia and hepatic steatosis during aging by activating hepatic lipoprotein secretion and lipogenesis leading to increased ApoC3 concentrations in the bloodstream. However, the intricate mechanisms underlying hepatic steatosis induced by elevated FoxO6 under hyperglycemic conditions remain intricate and require further elucidation. In order to delineate the regulatory pathway involving ApoC3 controlled by FoxO6 and its resultant functional impacts, we employed a spectrum of models including liver cell cultures, aged rats subjected to HFD, transgenic mice overexpressing FoxO6 (FoxO6-Tg), and FoxO6 knockout mice (FoxO6-KO). Our findings indicate that FoxO6 triggered ApoC3-driven lipid accumulation in the livers of aged rats on an HFD and in FoxO6-Tg, consequently leading to hepatic steatosis and hyperglycemia. Conversely, the absence of FoxO6 attenuated the expression of genes involved in lipogenesis, resulting in diminished hepatic lipid accumulation and mitigated hyperlipidemia in murine models. Additionally, the upregulation of FoxO6 due to elevated glucose levels led to increased ApoC3 expression, consequently instigating cellular triglyceride mediated lipid accumulation. The transcriptional activation of FoxO6 induced by both the HFD and high glucose levels resulted in hepatic steatosis by upregulating ApoC3 and genes associated with gluconeogenesis in aged rats and liver cell cultures. Our conclusions indicate that the upregulation of ApoC3 by FoxO6 promotes the development of hyperlipidemia, hyperglycemia, and hepatic steatosis in vivo, and in vitro. Taken together, our findings underscore the significance of FoxO6 in driving hyperlipidemia and hepatic steatosis specifically under hyperglycemic states by enhancing the expression of ApoC3 in aged rats.

Peripheral administration of lipidized NPAF and NPFF analogs does not influence central food intake regulation but induces anxiety-like behavior.

RF-amide peptides influence multiple physiological processes, including the regulation of appetite, stress responses, behavior, and reproductive and endocrine functions. In this study, we examined the roles of neuropeptide FF receptors (NPFFR1 and NPFFR2) by generating several lipidized analogs of neuropeptide AF (NPAF) and 1DMe, a stable analog of neuropeptide FF (NPFF). These analogs were administered peripherally for the first time to investigate their effects on food intake and other potential physiological outcomes. Lipidized NPAF and 1DMe analogs exhibited enhanced stability and increased pharmacokinetics. These analogs demonstrated preserved high affinity for NPFFR2 in the nanomolar range, while the binding affinity for NPFFR1 was tens of nanomoles. They activated the ERK and Akt signaling pathways in cells overexpressing the NPFFR1 and NPFFR2 receptors. Acute food intake in fasted mice decreased after the peripheral administration of oct-NPAF or oct-1DMe. However, this effect was not as pronounced as that observed after the injection of palm11-PrRP31, a potent anorexigenic compound used as a comparator that binds to GPR10 and the NPFFR2 receptor with high affinity. Neither oct-1DMe nor oct-NPAF decreased food intake or body weight in mice with diet-induced obesity during long-term treatment. In mice treated with oct-1DMe, we observed decreased activity in the central zone during the open field test and decreased activity in the open arms of the elevated plus maze. Furthermore, we observed a decrease in plasma noradrenaline levels and an increase in plasma corticosterone levels, as well as an increase in Crh expression in the hypothalamus. Moreover, neuronal activity in the hypothalamus was increased after treatment with oct-1DMe. In this study, we report that oct-1DMe did not have any long-term effects on the central regulation of food intake; however, it caused anxiety-like behavior.