Characterization of the effects of cannabinoid receptor deletion on energy metabolism in female C57BL mice.

Background: Despite the evidence that energy balance is regulated differently in females and that the endocannabinoid system is sexually dimorphic, previous studies on the endocannabinoid system and energy balance predominantly used male models. Here, we characterize the effects of cannabinoid receptor deletion on body weight gain and glucose metabolism in female C57BL mice. Methods: Female mice lacking the cannabinoid-1 receptor (CB1R-/-), cannabinoid-2 receptor (CB2R-/-), or both receptors (CB1R-/-/CB2R-/-) and wild-type (WT) mice were fed with a low (LFD; 10% of calories from fat) or high-fat diet (HFD; 45% of calories from fat) for six weeks. Results: Female WT mice fed with HFD gained significantly more weight than WT mice fed with LFD (p < 0.001). Similar pattern was observed for CB2/- mice fed with HFD compared to CB2R-/- mice fed with LFD (p < 0.001), but not for CB1R-/- fed with HFD vs. LFD (p = 0.22) or CB1R-/-/CB2R-/- fed with HFD vs. LFD (p = 0.96). Comparing the 4 groups on LFD, weight gain of CB1R-/- mice was greater than all other genotypes (p < 0.05). When fed with HFD, the deletion of CB1R alone in females did not attenuate weight gain compared to WT mice (p = 0.72). Female CB1R-/-/CB2R-/- mice gained less weight than WT mice when fed with HFD (p = 0.007) despite similar food intake and locomotor activity, potentially owing to enhanced thermogenesis in the white adipose tissue. No significant difference in weight gain was observed for female CB2R-/- and WT mice on LFD or HFD. Fasting glucose, however, was higher in CB2R-/- mice fed with LFD than all other groups (p < 0.05). Conclusion: The effects of cannabinoid receptor deletion on glucose metabolism in female mice were similar to previously published findings on male mice, yet the effects on body weight gain and thermogenesis were attenuated in CB1R-/- mice.

Dynamic changes of gut microbiota in mouse models of metabolic dysfunction-associated steatohepatitis and its transition to hepatocellular carcinoma.

Dysbiosis of gut microbiota may account for pathobiology in simple fatty liver (SFL), metabolic dysfunction-associated steatohepatitis (MASH), fibrotic progression, and transformation to MASH-associated hepatocellular carcinoma (MASH-HCC). The aim of the present study is to investigate gut dysbiosis in this progression. Fecal microbial rRNA-16S sequencing, absolute quantification, histopathologic, and biochemical tests were performed in mice fed high fat/calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) or control diet (CD) for 2, 16 weeks, or 14 months. Histopathologic examination verified an early stage of SFL, MASH, fibrotic, or MASH-HCC progression with disturbance of lipid metabolism, liver injury, and impaired gut mucosal barrier as indicated by loss of occludin in ileum mucosa. Gut dysbiosis occurred as early as 2 weeks with reduced α diversity, expansion of Kineothrix, Lactococcus, Akkermansia; and shrinkage in Bifidobacterium, Lactobacillus, etc., at a genus level. Dysbiosis was found as early as MAHS initiation, and was much more profound through the MASH-fibrotic and oncogenic progression. Moreover, the expansion of specific species, such as Lactobacillus johnsonii and Kineothrix alysoides, was confirmed by an optimized method for absolute quantification. Dynamic alterations of gut microbiota were characterized in three stages of early SFL, MASH, and its HCC transformation. The findings suggest that the extent of dysbiosis was accompanied with MASH progression and its transformation to HCC, and the shrinking or emerging of specific microbial species may account at least in part for pathologic, metabolic, and immunologic alterations in fibrogenic progression and malignant transition in the liver.

The Possible Neuroprotective Effect of Caffeic Acid on Cognitive Changes and Anxiety-Like Behavior Occurring in Young Rats Fed on High-Fat Diet and Exposed to Chronic Stress: Role of ß-Catenin/GSK-3B Pathway.

Lifestyle influences physical and cognitive development during the period of adolescence greatly. The most important of these lifestyle factors are diet and stress. Therefore, the aim of this study was to investigate the impact of high fat diet (HFD) and chronic mild stress on cognitive function and anxiety-like behaviors in young rats and to study the role of caffeic acid as a potential treatment for anxiety and cognitive dysfunction. Forty rats were assigned into 4 groups: control, HFD, HFD + stress, and caffeic acid-treated group. Rats were sacrificed after neurobehavioral testing. We detected memory impairment and anxiety-like behavior in rats which were more exaggerated in stressed rats. Alongside the behavioral changes, there were biochemical and histological changes. HFD and/or stress decreased hippocampal brain-derived neurotrophic factor (BDNF) levels and induced oxidative and inflammatory changes in the hippocampus. In addition, they suppressed Wnt/ß-catenin pathway which was associated with activation of glycogen synthase kinase 3ß (GSK3ß). HFD and stress increased arginase 1 and inducible nitric oxide synthase (iNOS) levels as well. These disturbances were found to be aggravated in stressed rats than HFD group. However, caffeic acid was able to reverse these deteriorations leading to memory improvement and ameliorating anxiety-like behavior. So, the current study highlights an important neuroprotective role for caffeic acid that may guard against induction of cognitive dysfunction and anxiety disorders in adolescents who are exposed to HFD and/or stress.

Metagenomic and metabolomic analysis showing the adverse risk-benefit trade-off of the ketogenic diet.

BACKGROUND: Ketogenic diets are increasingly popular for addressing obesity, but their impacts on the gut microbiota and metabolome remain unclear. This paper aimed to investigate how a ketogenic diet affects intestinal microorganisms and metabolites in obesity. METHODS: Male mice were provided with one of the following dietary regimens: normal chow, high-fat diet, ketogenic diet, or high-fat diet converted to ketogenic diet. Body weight and fat mass were measured weekly using high-precision electronic balances and minispec body composition analyzers. Metagenomics and non-targeted metabolomics data were used to analyze differences in intestinal contents. RESULTS: Obese mice on the ketogenic diet exhibited notable improvements in weight and body fat. However, these were accompanied by a significant decrease in intestinal microbial diversity, as well as an increase in Firmicutes abundance and a 247% increase in the Firmicutes/Bacteroidetes ratio. The ketogenic diet also altered multiple metabolic pathways in the gut, including glucose, lipid, energy, carbohydrate, amino acid, ketone body, butanoate, and methane pathways, as well as bacterial secretion and colonization pathways. These changes were associated with increased intestinal inflammation and dysbiosis in obese mice. Furthermore, the ketogenic diet enhanced the secretion of bile and the synthesis of aminoglycoside antibiotics in obese mice, which may impair the gut microbiota and be associated with intestinal inflammation and immunity. CONCLUSIONS: The study suggest that the ketogenic diet had an unfavorable risk-benefit trade-off and may compromise metabolic homeostasis in obese mice.

Obesity is associated with lower levels of negative emotions in polycystic ovary syndrome in clinical and animal studies.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in women of reproductive age. It is frequently comorbid with obesity and negative emotions. Currently, there are few reports on the relationship between obesity and negative emotions in patients with PCOS. Here we performed both basic and clinical studies to study the relationship between obesity and negative emotions in PCOS. METHODS: We performed a cross-sectional study including 608 patients with PCOS and 184 healthy participants to assess the mental health status of people with different body mass indices (BMI). Self-rated anxiety, depression, and perceived stress scales were used for subjective mood evaluations. Rat PCOS models fed 45 and 60% high-fat diets were used to confirm the results of the clinical study. Elevated plus maze and open field tests were used to assess anxiety- and depression-like behaviors in rats. RESULTS: We observed overweight/obesity, increased depression, anxiety, and perceived stress in women with PCOS, and found that anxiety and depression were negatively correlated with BMI in patients with severe obesity and PCOS. Similar results were confirmed in the animal study; the elevated plus maze test and open field test demonstrated that only 60% of high fat diet-induced obesity partly reversed anxiety- and depression-like behaviors in PCOS rats. A high-fat diet also modulated rat hypothalamic and hippocampal luteinizing hormone and testosterone levels. CONCLUSION: These results reveal a potential relationship between obesity and negative emotions in PCOS and prompt further investigation. The interactions between various symptoms of PCOS may be targeted to improve the overall well-being of patients.

Obesity was negatively correlated with negative emotions in patients with PCOS.Obesity may affect the downregulation of LH and testosterone and participate in the regulation of emotions.Increased BMI may be beneficial for patients with PCOS in terms of the psychological aspects.

IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease.

Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2-/-) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2-/- mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.

Intermittent hypoxia exacerbates anxiety in high-fat diet-induced diabetic mice by inhibiting TREM2-regulated IFNAR1 signaling.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and obstructive sleep apnea (OSA) are mutual risk factors, with both conditions inducing cognitive impairment and anxiety. However, whether OSA exacerbates cognitive impairment and anxiety in patients with T2DM remains unclear. Moreover, TREM2 upregulation has been suggested to play a protective role in attenuating microglia activation and improving synaptic function in T2DM mice. The aim of this study was to explore the regulatory mechanisms of TREM2 and the cognitive and anxiety-like behavioral changes in mice with OSA combined with T2DM. METHODS: A T2DM with OSA model was developed by treating mice with a 60% kcal high-fat diet (HFD) combined with intermittent hypoxia (IH). Spatial learning memory capacity and anxiety in mice were investigated. Neuronal damage in the brain was determined by the quantity of synapses density, the number and morphology of brain microglia, and pro-inflammatory factors. For mechanism exploration, an in vitro model of T2DM combined with OSA was generated by co-treating microglia with high glucose (HG) and IH. Regulation of TREM2 on IFNAR1-STAT1 pathway was determined by RNA sequencing and qRT-PCR. RESULTS: Our results showed that HFD mice exhibited significant cognitive dysfunction and anxiety-like behavior, accompanied by significant synaptic loss. Furthermore, significant activation of brain microglia and enhanced microglial phagocytosis of synapses were observed. Moreover, IH was found to significantly aggravate anxiety in the HFD mice. The mechanism of HG treatment may potentially involve the promotion of TREM2 upregulation, which in turn attenuates the proinflammatory microglia by inhibiting the IFNAR1-STAT1 pathway. Conversely, a significant reduction in TREM2 in IH-co-treated HFD mice and HG-treated microglia resulted in the further activation of the IFNAR1-STAT1 pathway and consequently increased proinflammatory microglial activation. CONCLUSIONS: HFD upregulated the IFNAR1-STAT1 pathway and induced proinflammatory microglia, leading to synaptic damage and causing anxiety and cognitive deficits. The upregulated TREM2 inT2DM mice brain exerted a negative regulation of the IFNAR1-STAT1 pathway. Mice with T2DM combined with OSA exacerbated anxiety via the downregulation of TREM2, causing heightened IFNAR1-STAT1 pathway activation and consequently increasing proinflammatory microglia.

Single-cell transcriptomic profiling unveils insights into ovarian fibrosis in obese mice.

BACKGROUND: Adiposity profoundly impacts reproductive health in both humans and animals. However, the precise subpopulations contributing to infertility under obese conditions remain elusive. RESULTS: In this study, we established an obese mouse model through an eighteen-week high-fat diet regimen in adult female mice. Employing single-cell RNA sequencing (scRNA-seq), we constructed a comprehensive single-cell atlas of ovarian tissues from these mice to scrutinize the impact of obesity on the ovarian microenvironment. ScRNA-seq revealed notable alterations in the microenvironment of ovarian tissues in obese mice. Granulosa cells, stromal cells, T cells, and macrophages exhibited functional imbalances compared to the control group. We observed heightened interaction strength in the SPP1-CD44 pairing within lgfbp7+ granulosa cell subtypes and Il1bhigh monocyte subtypes in the ovarian tissues of obese mice. Moreover, the interaction strength between Il1bhigh monocyte subtypes and Pdgfrb+ stromal cell subtypes in the form of TNF - TNFrsf1α interaction was also enhanced subsequently to obesity, potentially contributing to ovarian fibrosis pathogenesis. CONCLUSIONS: We propose a model wherein granulosa cells secrete SPP1 to activate monocytes, subsequently triggering TNF-α secretion by monocytes, thereby activating stromal cells and ultimately leading to the development of ovarian fibrosis. Intervening in this process may represent a promising avenue for improving clinical outcomes in fertility treatments for obese women.

Distinct gut flora profile induced by postnatal trans-fat diet in gestationally bisphenol A-exposed rats.

There has been much evidence showing the repercussions of prenatal bisphenol A (BPA) exposure with a postnatal high fat-diet (HFD) on offspring's health. However, the information on how the interaction between these two variables affects the gut microbiome is rather limited. Hence, we investigated the impact of a postnatal trans fat diet (TFD) on the gut microbiome of offspring exposed to BPA during the prenatal period in an animal model. Pregnant rats were divided into 5 mg/kg/day BPA, vehicle Tween80 (P80) or control (CTL) drinking water until delivery (N = 6 per group). Then, weaned male pups were further subdivided into three normal diet (ND) groups (CTLND, P80ND, and BPAND) and three TFD groups (CTLTFD, P80TFD, and BPATFD) (n = 6 per group). 180-250 g of faecal samples were collected on days 50 and 100 to assess the composition of the offspring's intestinal flora using next-generation sequencing. The alpha diversity indices of TFD offspring with and without BPA were markedly lower than their ND counterparts (p<0.001-p<0.05). The beta diversity, hierarchical cluster and network analyses of the offspring's microbiome demonstrated that the microbiome species of the TFD group with and without BPA were distinctly different compared to the ND group. Consistently, TFD and ND offspring pairings exhibited a higher number of significantly different species (p<0.0001-p<0.05) compared to those exposed to prenatal BPA exposure and different life stages comparisons, as shown by the multivariate parametric analysis DESeq2. Predictive functional profiling of the offspring's intestinal flora demonstrated altered expressions of genes involved in metabolic pathways. In summary, the gut flora composition of the rat offspring may be influenced by postnatal diet instead of prenatal exposure to BPA. Our data indicate the possibility of perturbed metabolic functions and epigenetic modifications, in offspring that consumed TFD, which may theoretically lead to metabolic diseases in middle or late adulthood. Further investigation is necessary to fully understand these implications.

LncRNA SNHG12 suppresses adipocyte inflammation and insulin resistance by regulating the HDAC9/Nrf2 axis.

Obesity is often associated with low-grade inflammation. The incidence of obesity has increased annually worldwide, which seriously affects human health. A previous study indicated that long noncoding RNA SNHG12 was downregulated in obesity. Nevertheless, the role of SNHG12 in obesity remains to be elucidated. In this study, qRT-PCR, western blot, and ELISA were utilized to examine the gene and protein expression. Flow cytometry was employed to investigate the M2 macrophage markers. RNA pull-down assay and RIP were utilized to confirm the interactions of SNHG12, hnRNPA1, and HDAC9. Eventually, a high-fat diet-fed mouse model was established for in vivo studies. SNHG12 overexpression suppressed adipocyte inflammation and insulin resistance and promoted M2 polarization of macrophages that was caused by TNF-α treatment. SNHG12 interacted with hnRNPA1 to downregulate HDAC9 expression, which activated the Nrf2 signaling pathway. HDAC9 overexpression reversed the effect of SNHG12 overexpression on inflammatory response, insulin resistance, and M2 phenotype polarization. Overexpression of SNHG12 improved high-fat diet-fed mouse tissue inflammation. This study revealed the protective effect of SNHG12 against adipocyte inflammation and insulin resistance. This result further provides a new therapeutic target for preventing inflammation and insulin resistance in obesity.

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.

Moderate beta-cell ablation triggers synergic compensatory mechanisms even in the absence of overt metabolic disruption.

Regeneration, the ability to replace injured tissues and organs, is a phenomenon commonly associated with lower vertebrates but is also observed in mammals, in specific tissues. In this study, we investigated the regenerative potential of pancreatic islets following moderate beta-cell loss in mice. Using a rapid model of moderate ablation, we observed a compensatory response characterized by transient inflammation and proliferation signatures, ultimately leading to the recovery of beta-cell identity and function. Interestingly, this proliferative response occurred independently of inflammation, as demonstrated in ablated immunodeficient mice. Furthermore, exposure to high-fat diet stimulated beta-cell proliferation but negatively impacted beta-cell function. In contrast, an equivalent slower ablation model revealed a delayed but similar proliferative response, suggesting proliferation as a common regenerative response. However, high-fat diet failed to promote proliferation in this model, indicating a differential response to metabolic stressors. Overall, our findings shed light on the complex interplay between beta-cell loss, inflammation, and stress in modulating pancreatic islet regeneration. Understanding these mechanisms could pave the way for novel therapeutic strategies based on beta-cell proliferation.

Comprehensive analysis of key host gene-microbe networks in the cecum tissues of the obese rabbits induced by a high-fat diet.

The Cecum is a key site for cellulose digestion in nutrient metabolism of intestine, but its mechanisms of microbial and gene interactions has not been fully elucidated during pathogenesis of obesity. Therefore, the cecum tissues of the New Zealand rabbits and their contents between the high-fat diet-induced group (Ob) and control group (Co) were collected and analyzed using multi-omics. The metagenomic analysis indicated that the relative abundances of Corallococcus_sp._CAG:1435 and Flavobacteriales bacterium species were significantly lower, while those of Akkermansia glycaniphila, Clostridium_sp._CAG:793, Mycoplasma_sp._CAG:776, Mycoplasma_sp._CAG:472, Clostridium_sp._CAG:609, Akkermansia_sp._KLE1605, Clostridium_sp._CAG:508, and Firmicutes_bacterium_CAG:460 species were significantly higher in the Ob as compared to those in Co. Transcriptomic sequencing results showed that the differentially upregulated genes were mainly enriched in pathways, including calcium signaling pathway, PI3K-Akt signaling pathway, and Wnt signaling pathway, while the differentially downregulated genes were mainly enriched in pathways of NF-kappaB signaling pathway and T cell receptor signaling pathway. The comparative analysis of metabolites showed that the glycine, serine, and threonine metabolism and cysteine and methionine metabolism were the important metabolic pathways between the two groups. The combined analysis showed that CAMK1, IGFBP6, and IGFBP4 genes were highly correlated with Clostridium_sp._CAG:793, and Akkermansia_glycaniphila species. Thus, the preliminary study elucidated the microbial and gene interactions in cecum of obese rabbit and provided a basis for further studies in intestinal intervention for human obesity.

Dulaglutide reduces oxidative DNA damage and hypermethylation in the somatic cells of mice fed a high-energy diet by restoring redox balance, inflammatory responses, and DNA repair gene expressions.

Obesity is an established risk factor for numerous malignancies, although it remains uncertain whether the disease itself or weight-loss drugs are responsible for a greater predisposition to cancer. The objective of the current study was to determine the impact of dulaglutide on genetic and epigenetic DNA damage caused by obesity, which is a crucial factor in the development of cancer. Mice were administered a low-fat or high-fat diet for 12 weeks, followed by a 5-week treatment with dulaglutide. Following that, modifications of the DNA bases were examined using the comet assay. To clarify the underlying molecular mechanisms, oxidized and methylated DNA bases, changes in the redox status, levels of inflammatory cytokines, and the expression levels of some DNA repair genes were evaluated. Animals fed a high-fat diet exhibited increased body weights, elevated DNA damage, oxidation of DNA bases, and DNA hypermethylation. In addition, obese mice showed altered inflammatory responses, redox imbalances, and repair gene expressions. The findings demonstrated that dulaglutide does not exhibit genotoxicity in the investigated conditions. Following dulaglutide administration, animals fed a high-fat diet demonstrated low DNA damage, less oxidation and methylation of DNA bases, restored redox balance, and improved inflammatory responses. In addition, dulaglutide treatment restored the upregulated DNMT1, Ogg1, and p53 gene expression. Overall, dulaglutide effectively maintains DNA integrity in obese animals. It reduces oxidative DNA damage and hypermethylation by restoring redox balance, modulating inflammatory responses, and recovering altered gene expressions. These findings demonstrate dulaglutide's expediency in treating obesity and its associated complications.

EGR3 reduces podocyte inflammatory damage in obesity related glomerulopathy by inhibiting the PRMT1/p-STAT3 pathway. / EGR3通过抑制PRMT1/p-STAT3é€šè·¯å‡è½»è‚¥èƒ–ç›¸å ³æ€§è‚¾ç— è¶³ç»†èƒžç‚Žç—‡æŸä¼¤.

OBJECTIVES: Obesity related glomerulopathy (ORG) is induced by obesity, but the pathogenesis remains unclear. This study aims to investigate the expression of early growth response protein 3 (EGR3) in the renal cortex tissues of ORG patients and high-fat diet-induced obese mice, and to further explore the molecular mechanism of EGR3 in inhibiting palmitic acid (PA) induced human podocyte inflammatory damage. METHODS: Renal cortex tissues were collected from ORG patients (n=6) who have been excluded from kidney damage caused by other diseases and confirmed by histopathology, and from obese mice induced by high-fat diet (n=10). Human and mouse podocytes were intervened with 150 µmol/L PA for 48 hours. EGR3 was overexpressed or silenced in human podocytes. Enzyme linked immunosorbent assay (ELISA) was used to detcet the levels of interleukin-6 (IL-6) and interleukin-1ß (IL-1ß). Real-time RT-PCR was used to detect the mRNA expressions of EGR3, podocytes molecular markers nephrosis 1 (NPHS1), nephrosis 2 (NPHS2), podocalyxin (PODXL), and podoplanin (PDPN). RNA-seq was performed to detect differentially expressed genes (DEGs) after human podocytes overexpressing EGR3 and treated with 150 µmol/L PA compared with the control group. Co-immunoprecipitation (Co-IP) combined with liquid chromatography tandem mass spectrometry (LC-MS) was used to detect potential interacting proteins of EGR3 and the intersected with the RNA-seq results. Co-IP confirmed the interaction between EGR3 and protein arginine methyltransferases 1 (PRMT1), after silencing EGR3 and PRMT1 inhibitor intervention, the secretion of IL-6 and IL-1ß in PA-induced podocytes was detected. Western blotting was used to detect the expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) after overexpression or silencing of EGR3. RESULTS: EGR3 was significantly upregulated in renal cortex tissues of ORG patients and high-fat diet-induced obese mice (both P<0.01). In addition, after treating with 150 µmol/L PA for 48 hours, the expression of EGR3 in human and mouse podocytes was significantly upregulated (both P<0.05). Overexpression or silencing of EGR3 in human podocytes inhibited or promoted the secretion of IL-6 and IL-1ß in the cell culture supernatant after PA intervention, respectively, and upregulated or downregulated the expression of NPHS1, PODXL, NPHS2,and PDPN (all P<0.05). RNA-seq showed a total of 988 DEGs, and Co-IP+LC-MS identified a total of 238 proteins that may interact with EGR3. Co-IP confirmed that PRMT1 was an interacting protein with EGR3. Furthermore, PRMT1 inhibitors could partially reduce PA-induced IL-6 and IL-1ß secretion after EGR3 silencing in human podocytes (both P<0.05). Overexpression or silencing of EGR3 negatively regulated the expression of PRMT1 and p-STAT3. CONCLUSIONS: EGR3 may reduce ORG podocyte inflammatory damage by inhibiting the PRMT1/p-STAT3 pathway.

Gut-specific Neprilysin Deletion Protects Against Fat-induced Insulin Secretory Dysfunction in Male Mice.

Neprilysin is a ubiquitous peptidase that can modulate glucose homeostasis by cleaving insulinotropic peptides. While global deletion of neprilysin protects mice against high-fat diet (HFD)-induced insulin secretory dysfunction, strategies to ablate neprilysin in a tissue-specific manner are favored to limit off-target effects. Since insulinotropic peptides are produced in the gut, we sought to determine whether gut-specific neprilysin deletion confers beneficial effects on insulin secretion similar to that of global neprilysin deletion in mice fed a HFD. Mice with conditional deletion of neprilysin in enterocytes (NEPGut-/-) were generated by crossing Vil-Cre and floxed neprilysin mice. Neprilysin activity was almost abolished throughout the gut in NEPGut-/- mice, and was similar in plasma, pancreas, and kidney in NEPGut-/- vs control mice. An oral glucose tolerance test was performed at baseline and following 14 weeks of HFD feeding, during which glucose tolerance and glucose-stimulated insulin secretion (GSIS) were assessed. Despite similar body weight gain at 14 weeks, NEPGut-/- displayed lower fasting plasma glucose levels, improved glucose tolerance, and increased GSIS compared to control mice. In conclusion, gut-specific neprilysin deletion recapitulates the enhanced GSIS seen with global neprilysin deletion in HFD-fed mice. Thus, strategies to inhibit neprilysin specifically in the gut may protect against fat-induced glucose intolerance and beta-cell dysfunction.

Beneficial metabolic effects of PAHSAs depend on the gut microbiota in diet-induced obese mice but not in chow-fed mice.

Dietary lipids play an essential role in regulating the function of the gut microbiota and gastrointestinal tract, and these luminal interactions contribute to mediating host metabolism. Palmitic Acid Hydroxy Stearic Acids (PAHSAs) are a family of lipids with antidiabetic and anti-inflammatory properties, but whether the gut microbiota contributes to their beneficial effects on host metabolism is unknown. Here, we report that treating chow-fed female and male germ-free (GF) mice with PAHSAs improves glucose tolerance, but these effects are lost upon high fat diet (HFD) feeding. However, transfer of feces from PAHSA-treated, but not vehicle-treated, chow-fed conventional mice increases insulin sensitivity in HFD-fed GF mice. Thus, the gut microbiota is necessary for, and can transmit, the insulin-sensitizing effects of PAHSAs in HFD-fed GF male mice. Analyses of the cecal metagenome and lipidome of PAHSA-treated mice identified multiple lipid species that associate with the gut commensal Bacteroides thetaiotaomicron (Bt) and with insulin sensitivity resulting from PAHSA treatment. Supplementing live, and to some degree, heat-killed Bt to HFD-fed female mice prevented weight gain, reduced adiposity, improved glucose tolerance, fortified the colonic mucus barrier and reduced systemic inflammation compared to HFD-fed controls. These effects were not observed in HFD-fed male mice. Furthermore, ovariectomy partially reversed the beneficial Bt effects on host metabolism, indicating a role for sex hormones in mediating the Bt probiotic effects. Altogether, these studies highlight the fact that PAHSAs can modulate the gut microbiota and that the microbiota is necessary for the beneficial metabolic effects of PAHSAs in HFD-fed mice.

Quinic acid alleviates high-fat diet-induced neuroinflammation by inhibiting DR3/IKK/NF-κB signaling via gut microbial tryptophan metabolites.

With the increasing of aging population and the consumption of high-fat diets (HFD), the incidence of Alzheimer's disease (AD) has skyrocketed. Natural antioxidants show promising potential in the prevention of AD, as oxidative stress and neuroinflammation are two hallmarks of AD pathogenesis. Here, we showed that quinic acid (QA), a polyphenol derived from millet, significantly decreased HFD-induced brain oxidative stress and neuroinflammation and the levels of Aß and p-Tau. Examination of gut microbiota suggested the improvement of the composition of gut microbiota in HFD mice after QA treatment. Metabolomic analysis showed significant increase of gut microbial tryptophan metabolites indole-3-acetic acid (IAA) and kynurenic acid (KYNA) by QA. In addition, IAA and KYNA showed negative correlation with pro-inflammatory factors and AD indicators. Further experiments on HFD mice proved that IAA and KYNA could reproduce the effects of QA that suppress brain oxidative stress and inflammation and decrease the levels of of Aß and p-Tau. Transcriptomics analysis of brain after IAA administration revealed the inhibition of DR3/IKK/NF-κB signaling pathway by IAA. In conclusion, this study demonstrated that QA could counteract HFD-induced brain oxidative stress and neuroinflammation by regulating inflammatory DR3/IKK/NF-κB signaling pathway via gut microbial tryptophan metabolites.

The Lipid-Metabolism-Associated Anti-Obesity Properties of Rapeseed Diacylglycerol Oil.

To investigate the effects of rapeseed diacylglycerol oil (RDG) intake on lipid accumulation and metabolism in C57BL/6J mice, obese mice were fed a high-fat diet in which 45% of the total energy content came from RDG (RDGM group) or rapeseed triacylglycerol oil (RTGM group). This diet intervention was conducted for 12 weeks following the establishment of the obese mouse model. By the end of the experiment, the serum glucose levels of the mice in the RTGM and RDGM groups were 13.0 ± 1.3 mmol/L and 9.7 ± 1.5 mmol/L, respectively. Meanwhile, the serum triglyceride level in the RDGM group was 26.3% lower than that in the RTGM group. The weight-loss effect in the RDGM group was accompanied by a significant decrease in the white adipose tissue (WAT) index. The RDG intervention did not significantly change the antioxidant and anti-inflammatory properties of the rapeseed oil in vivo. The RDG diet improved the liver lipid metabolism abnormalities induced by a high-fat diet, leading to decreased liver damage index values (AST and ALT). Additionally, compared to that in the RTGM group, the expression of the adipogenic genes PPAR-γ and DGAT decreased in both the liver and intestine by 21.7% and 16.7% and by 38.7% and 47.2%, respectively, in the RDGM group. Further, most lipolytic genes in BAT showed no significant change after the RDG intervention. This implies that RDG regulates lipid metabolism by altering the expression of adipogenic genes in the liver, intestine, and adipose tissue, thereby reducing the accumulation of WAT. Furthermore, the RDG diet enhanced gut flora diversity, increasing the relative levels of unclassified Muribaculaceae and decreasing the levels of Dubosiella and Faecalibaculum in the mouse gut, potentially accelerating lipid metabolism. Thus, a three-month RDG diet intervention in obese mice exhibited benefits in regulating the somatotype, serum obesity-related indices, gut flora structure, and lipid metabolism in the adipose tissue, liver, and intestine.

High-Fat Diet Augments Myocardial Inflammation and Cardiac Dysfunction in Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease characterized by cardiac dysfunction, arrhythmias, and myocardial inflammation. Exercise and stress can influence the disease's progression. Thus, an investigation of whether a high-fat diet (HFD) contributes to ACM pathogenesis is warranted. In a robust ACM mouse model, 8-week-old Desmoglein-2 mutant (Dsg2mut/mut) mice were fed either an HFD or rodent chow for 8 weeks. Chow-fed wildtype (WT) mice served as controls. Echo- and electrocardiography images pre- and post-dietary intervention were obtained, and the lipid burden, inflammatory markers, and myocardial fibrosis were assessed at the study endpoint. HFD-fed Dsg2mut/mut mice showed numerous P-wave perturbations, reduced R-amplitude, left ventricle (LV) remodeling, and reduced ejection fraction (%LVEF). Notable elevations in plasma high-density lipoprotein (HDL) were observed, which correlated with the %LVEF. The myocardial inflammatory adipokines, adiponectin (AdipoQ) and fibroblast growth factor-1, were substantially elevated in HFD-fed Dsg2mut/mut mice, albeit no compounding effect was observed in cardiac fibrosis. The HFD not only potentiated cardiac dysfunction but additionally promoted adverse cardiac remodeling. Further investigation is warranted, particularly given elevated AdipoQ levels and the positive correlation of HDL with the %LVEF, which may suggest a protective effect. Altogether, the HFD worsened some, but not all, disease phenotypes in Dsg2mut/mut mice. Notwithstanding, diet may be a modifiable environmental factor in ACM disease progression.