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.

Association between thyroid hormone resistance and obesity: a cross-sectional study and mouse stimulation test.

OBJECTIVE: Thyroid hormone influences key metabolic pathways, and reduced sensitivity to thyroid hormone is considered a new risk factor for adverse metabolic outcomes. However, the association between thyroid hormone resistance and obesity in euthyroid individuals is still unknown. METHODS: We enrolled 8021 euthyroid individuals, calculated thyroid hormone resistance indices, and analyzed the association between thyroid hormone resistance and obesity by regression analysis. Furthermore, we conducted the thyrotropin-releasing hormone stimulation test in both control and obese mice (n = 5) to demonstrate the association. RESULTS: The euthyroid adults with overweight and obesity had increased thyroid hormone resistance indices (all p < 0.05). BMI and prevalence of overweight and obesity increased (odds ratio of thyroid feedback quantile-based index [ORTFQI] = 1.164, p = 0.036; OR of free triiodothyronine/free thyroxine [ORFT3/FT4] = 1.508, p < 0.001) following the elevation of thyroid hormone resistance indices. Mediation analysis indicated a complete mediation effect (beta coefficient of indirect effect [ßInd]= 6.838, p < 0.001) of metabolic disorders in the relationship. Furthermore, in the mice with obesity, the thyrotropin response to thyrotropin-releasing hormone stimulation (68.33-90.89 pg/mL) was comparatively blunted (p = 0.029). CONCLUSIONS: Euthyroid individuals with obesity exhibit both central and peripheral thyroid hormone resistance, a phenomenon that is more pronounced in individuals with metabolic abnormalities. Thyroid hormone resistance is associated with an increased prevalence of overweight and obesity mediated by metabolic disorders.

Combined UPLC-QqQ-MS/MS and AP-MALDI Mass Spectrometry Imaging Method for Phospholipidomics in Obese Mouse Kidneys: Alleviation by Feeding Sea Cucumber Phospholipids.

Sea cucumber phospholipids have ameliorative effects on various diseases related to lipid metabolism. However, it is unclear whether it can ameliorate obesity-associated glomerulopathy (ORG) induced by a high-fat diet (HFD). The present study applied UPLC-QqQ-MS/MS and atmospheric pressure matrix-assisted laser desorption ionization mass spectrometry imaging (AP-MALDI MSI) to investigate the effects of sea cucumber phospholipids, including plasmalogen PlsEtn and plasmanylcholine PakCho, on phospholipid profiles in the HFD-induced ORG mouse kidney. Quantitative analysis of 135 phospholipids revealed that PlsEtn and PakCho significantly modulated phospholipid levels. Notably, PlsEtn modulated kidney overall phospholipids better than PakCho. Imaging the "space-content" of 9 phospholipids indicated that HFD significantly increased phospholipid content within the renal cortex. Furthermore, PlsEtn and PakCho significantly decreased the expression of transport-related proteins CD36, while elevating the expression of fatty acid ß-oxidation-related protein PPAR-α in the renal cortex. In conclusion, sea cucumber phospholipids reduced renal lipid accumulation, ameliorated renal damage, effectively regulated the content and distribution of renal phospholipids, and improved phospholipid homeostasis, exerting an anti-OGR effect.

[Intervention mechanism of ginsenoside Rb_1 on liver steatosis in db/db obese mice based on TLR4/MyD88/NF-κB signaling pathway].

Based on the Toll-like receptor 4(TLR4)/myeloid differentiation factor 88(MyD88)/nuclear factor kappaB(NF-κB) signaling pathway, this study observed the regulatory effect of ginsenoside Rb_1(Rb_1) on liver lipid metabolism in db/db obese mice and explored its potential mechanism. Thirty 6-week-old male db/db mice were randomly divided into a model group, a metformin group, and Rb_1 groups with low, medium, and high doses, with six mice in each group. Additionally, six age-matched male db/m mice were assigned to the normal group. The intervention lasted for five weeks. Body weight, fasting blood glucose, and food intake were mea-sured weekly. At the end of the experiment, serum lipid levels and liver function were detected. Hematoxylin-eosin(HE) staining and oil red O staining were performed to observe pathological changes in liver tissue. Real-time quantitative PCR and immunohistochemistry on paraffin sections were used to detect the mRNA and protein expression of TLR4, MyD88, and NF-κB p65. RESULTS:: showed that compared with the normal group, the model group exhibited significant increases in body weight, liver weight, liver index, epididymal fat mass, epididymal fat index, total cholesterol, low-density lipoprotein cholesterol, liver function parameters, and fasting blood glucose levels. Liver lipid accumulation significantly increased, along with elevated mRNA and protein expression of TLR4, MyD88, and NF-κB p65 in the liver. After Rb_1 treatment, the above-mentioned parameters in the intervention groups showed significant reversals. In conclusion, Rb_1 can improve obesity and obesity-related hepatic steatosis in mice while regulating abnormal lipid and glucose meta-bolism. Mechanistically, Rb_1 may improve liver steatosis in db/db obese mice by modulating the TLR4/MyD88/NF-κB signaling pathway.

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.

Intermittent Fasting Attenuates Obesity-Induced Triple-Negative Breast Cancer Progression by Disrupting Cell Cycle, Epithelial-Mesenchymal Transition, Immune Contexture, and Proinflammatory Signature.

Obesity is associated with one-fifth of cancer deaths, and breast cancer is one of the obesity-related cancers. Triple-negative breast cancer (TNBC) lacks estrogen and progesterone receptors and human epidermal growth factor receptor 2, leading to the absence of these therapeutic targets, followed by poor overall survival. We investigated if obesity could hasten TNBC progression and intermittent fasting (IF) could attenuate the progression of obesity-related TNBC. Our meta-analysis of the TNBC outcomes literature showed that obesity led to poorer overall survival in TNBC patients. Fasting-mimicking media reduced cell proliferation disrupted the cell cycle, and decreased cell migration and invasion. IF decreased body weight in obese mice but no change in normal mice. Obese mice exhibited elevated plasma glucose and cholesterol levels, increased tumor volume and weight, and enhanced macrophage accumulation in tumors. The obesity-exacerbated TNBC progression was attenuated after IF, which decreased cyclin B1 and vimentin levels and reduced the proinflammatory signature in the obesity-associated tumor microenvironment. IF attenuated obesity-induced TNBC progression through reduced obesity and tumor burdens in cell and animal experiments, supporting the potential of a cost-effective adjuvant IF therapy for TNBC through lifestyle change. Further evidence is needed of these IF benefits in TNBC, including from human clinical trials.

Environmental Enrichment Prevents Gut Dysbiosis Progression and Enhances Glucose Metabolism in High-Fat Diet-Induced Obese Mice.

Obesity is a global health concern implicated in numerous chronic degenerative diseases, including type 2 diabetes, dyslipidemia, and neurodegenerative disorders. It is characterized by chronic low-grade inflammation, gut microbiota dysbiosis, insulin resistance, glucose intolerance, and lipid metabolism disturbances. Here, we investigated the therapeutic potential of environmental enrichment (EE) to prevent the progression of gut dysbiosis in mice with high-fat diet (HFD)-induced metabolic syndrome. C57BL/6 male mice with obesity and metabolic syndrome, continuously fed with an HFD, were exposed to EE. We analyzed the gut microbiota of the mice by sequencing the 16s rRNA gene at different intervals, including on day 0 and 12 and 24 weeks after EE exposure. Fasting glucose levels, glucose tolerance, insulin resistance, food intake, weight gain, lipid profile, hepatic steatosis, and inflammatory mediators were evaluated in serum, adipose tissue, and the colon. We demonstrate that EE intervention prevents the progression of HFD-induced dysbiosis, reducing taxa associated with metabolic syndrome (Tepidimicrobium, Acidaminobacteraceae, and Fusibacter) while promoting those linked to healthy physiology (Syntrophococcus sucrumutans, Dehalobacterium, Prevotella, and Butyricimonas). Furthermore, EE enhances intestinal barrier integrity, increases mucin-producing goblet cell population, and upregulates Muc2 expression in the colon. These alterations correlate with reduced systemic lipopolysaccharide levels and attenuated colon inflammation, resulting in normalized glucose metabolism, diminished adipose tissue inflammation, reduced liver steatosis, improved lipid profiles, and a significant reduction in body weight gain despite mice's continued HFD consumption. Our findings highlight EE as a promising anti-inflammatory strategy for managing obesity-related metabolic dysregulation and suggest its potential in developing probiotics targeting EE-modulated microbial taxa.

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.

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.

Citrus depressa peel extract acts as a prebiotic to reduce lipid accumulation and modulate gut microbiota in obese mice.

Citrus peels contain abundant polyphenols, particularly flavonoids, and have been shown to exert lipid accumulation decreasing ability. In this study, Citrus depressa peel applied to oven drying and extracted with ethanol extract as CDEE to analyze its flavonoids compositions and investigated its effects on a high-fat diet (HFD)-induced obese mice model. CDEE contained several flavonoids such as hesperidin, sinesentin, nobiletin, tangeretin, 5-demethylnobiletin, and 5-demethyltangeretin. The mice fed an HFD, and administration of 2% CDEE to could decrease weight gain, abdominal fat weight, inguinal fat weight, and the adipocyte size, and CDEE also reduced serum total cholesterol (TCHO), triacylglycerol (TG) compared with mice fed only on HFD. CDEE hindered lipid accumulation through a decreased fatty acid synthase (FAS) protein expression via upregulation of the protein expression of AMP-activated protein kinase α (AMPKα). Moreover, CDEE modulated gut microbiota that altered by HFD through an increased abundance of Lactobacillus reuteri compared with the HFD group. The results demonstrated that CDEE helps decrease lipid accumulation through the AMPK pathway, which also indicates a prebiotic-like effect on gut microbiota.

Dapagliflozin attenuates fat accumulation and insulin resistance in obese mice with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), a common endocrine disorder affecting premenopausal women, is associated with various metabolic consequences such as insulin resistance, hyperlipidemia, obesity, and type 2 diabetes mellitus (T2DM). Insulin sensitizers, such as metformin and pioglitazone, though effective, often leads to significant gastrointestinal adverse effects or weight gain, limiting its suitability for women with PCOS. There is an urgent need for safe, effective and affordable agents. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, enhances glucose elimination through urine, thereby reducing body weight and improving glucose and lipid metabolism. Nevertheless, it is not currently recommended as a therapeutic option for PCOS in clinical guidelines. In this study, we systematically examined the impact of dapagliflozin on an obese PCOS mouse model, focusing on alterations in glucose metabolism, adipose tissue morphology, and plasma lipid profile. Obese PCOS was induced in mice by continuous dihydrotestosterone (DHEA) injections over 21 days and high-fat diet (HFD) feeding. PCOS mice were then orally gavaged with dapagliflozin (1 mg/kg), metformin (50 mg/kg), or vehicle daily for 8 weeks, respectively. Our results demonstrated that dapagliflozin significantly prevented body weight gain and reduced fat mass in obese PCOS mice. Meanwhile, dapagliflozin treatment improved glucose tolerance and increased insulin sensitivity compared to the control PCOS mice. Furthermore, dapagliflozin significantly improved adipocyte accumulation and morphology in white adipose tissue, resulting in a normalized plasma lipid profile in PCOS mice. In conclusion, our results suggest that dapagliflozin is an effective agent in managing glucose and lipid metabolism disorders in obese PCOS mice.

Effects of Statin and Annatto-extracted Tocotrienol Supplementation on Glucose Homeostasis, Bone Microstructure, and Gut Microbiota Composition in Obese Mice.

BACKGROUND/AIM: This study examined the effects of tocotrienols (TT) in conjunction with statin on glucose homeostasis, bone microstructure, gut microbiome, and systemic and liver inflammatory markers in obese C57BL/6J mice. MATERIALS AND METHODS: Forty male C57BL/6J mice were fed a high-fat diet (HFD) and assigned into four groups in a 2 (no statin vs. 120 mg statin/kg diet)×2 (no TT vs. 400 mg TT/kg diet) factorial design for 14 weeks. RESULTS: Statin and TT improved glucose tolerance only when each was given alone, and only statin supplementation decreased insulin resistance. Consistently, only statin supplementation decreased serum insulin levels and HOMA-IR. Pancreatic insulin was also increased with statin treatment. Statin and TT, alone or in combination, reduced the levels of serum IL-6, but only TT attenuated the increased serum leptin levels induced by a HFD. Statin supplementation increased bone area/total area and connectivity density at LV-4, while TT supplementation increased bone area/total area and trabecular number, but decreased trabecular separation at the distal femur. Statin supplementation, but not TT, reduced hepatic inflammatory cytokine gene expression. Neither TT supplementation nor statin supplementation statistically altered microbiome species evenness or richness. However, they altered the relative abundance of certain microbiome species. Most notably, both TT and statin supplementation increased the relative abundance of Lachnospiraceae UCG-006. CONCLUSION: TT and statin collectively benefit bone microstructure, glucose homeostasis, and microbial ecology in obese mice. Such changes may be, in part, associated with suppression of inflammation in the host.

Inhibition of ER stress using tauroursodeoxycholic acid rescues obesity-evoked cardiac remodeling and contractile anomalies through regulation of ferroptosis.

Interrupted ER homeostasis contributes to the etiology of obesity cardiomyopathy although it remains elusive how ER stress evokes cardiac anomalies in obesity. Our study evaluated the impact of ER stress inhibition on cardiac anomalies in obesity. Lean and ob/ob obese mice received chemical ER chaperone tauroursodeoxycholic acid (TUDCA, 50 mg/kg/d, p.o.) for 35 days prior to evaluation of glucose sensitivity, echocardiographic, myocardial geometric, cardiomyocyte mechanical and subcellular Ca2+ property, mitochondrial integrity, oxidative stress, apoptosis, and ferroptosis. Intracellular Ca2+ governing domains including sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) were monitored by45Ca2+uptake and immunoblotting. Our results noted that TUDCA alleviated myocardial remodeling (fibrosis, hypertrophy, enlarged LVESD), echocardiographic anomalies (compromised fractional shortening and ejection fraction), cardiomyocyte contractile dysfunction (amplitude and velocity of cell shortening, relengthening time) and intracellular Ca2+ anomalies (compromised subcellular Ca2+ release, clearance and SERCA function), mitochondrial damage (collapsed membrane potential, downregulated mitochondrial elements and ultrastructural alteration), ER stress (GRP78, eIF2α and ATF4), oxidative stress, apoptosis and ferroptosis [downregulated SLC7A11, GPx4 and upregulated transferrin receptor (TFRC)] without affecting global glucose sensitivity and serum Fe2+ in obese mice. Obesity-evoked change in HSP90, phospholamban and Na+-Ca2+ exchanger was spared by the chemical ER chaperone. Moreover, in vitro results noted that TUDCA, PERK inhibitor GSK2606414, TFRC neutralizing antibody and ferroptosis inhibitor LIP1 mitigated palmitic acid-elicited changes in lipid peroxidation and mechanical function. Our findings favored a role for ferroptosis in obesity cardiomyopathy downstream of ER stress.

Lactoferrin alleviates chronic low­grade inflammation response in obese mice by regulating intestinal flora.

Chronic low­grade inflammation defines obesity as a metabolic disorder. Alterations in the structure of gut flora are strongly associated with obesity. Lactoferrin (LF) has a biological function in regulating intestinal flora. The present study aimed to investigate the therapeutic and anti­-inflammatory effects of LF in obese mice based on intestinal flora. A total of 30 C57BL/6 mice were divided into three groups consisting of 10 mice each. Subsequently, one group was fed a normal diet (Group K), another group was fed a high­fat diet (Group M) and the remaining group switched from regular drinking to drinking 2% LF water (Group Z2) after 2 weeks of high­fat diet; all mice were fed for 12 weeks. After the experiment, the mouse blood lipid and lipopolysaccharide levels, levels of inflammatory factors and intestinal tight junction proteins were assessed. Mouse stool samples were analyzed using 16S ribosomal RNA sequencing. The results showed that LF reduced serum total cholesterol, triglycerides and low­density lipoprotein levels, elevated high­density lipoprotein levels, suppressed metabolic endotoxemia and attenuated chronic low­grade inflammatory responses in obese mice. In addition, LF upregulated zonula occludens­1 and occludin protein expression levels in the intestine, thereby improving intestinal barrier integrity. LF altered the intestinal microbial structure of obese mice, reduced the ratio of Firmicutes and an elevated ratio of Bacteroidota, modifying the bacterial population to the increased relative abundance of Alistipes, Acidobacteriota, Psychrobacter and Bryobacter.

Edible bird's nest regulates glucose and lipid metabolic disorders via the gut-liver axis in obese mice.

Edible bird's nest (EBN) is a traditional food known for its nourishing and functional properties and is found to be involved in anti-oxidation, anti-aging, and anti-influenza mechanisms, immune regulation, and improving cardiovascular diseases, among others. However, the potential of EBN to improve glycolipid metabolism disorders in high-fat-diet induced obesity and the underlying mechanisms remain unexplored. We examined the effects of EBN on glycolipid metabolism in obese mice fed a high-fat diet. Male C57BL/6J mice were fed a high-fat diet for 8 weeks to establish an obesity model. The obese mice were selected and divided into six groups: two model control groups (normal and high-fat diets) and four intervention groups [Neu5Ac and low-, medium-, and high-dose EBN], with 12 mice in each group. After 10 weeks of continuous gavage intervention, only mice in the high-dose EBN intervention group had lower body weight and total fat content, especially visceral fat. Meanwhile, intervention with three doses of EBN reduced serum FBG, TC, LDL, Ox-LDL, IL-1ß, IL-6, and TNF-α levels and increased serum HDL levels and energy expenditure. Using the high dosage as a paradigm, EBN intervention increased the sialic acid content in LDL, decreased TMAO in the liver, and increased GLP-1 levels in sera. EBN increased the colonic abundances of Akkermansia, Lactobacillus, and Desulfovibrio and reduced those of Lysinibacillus and Bacillus. The changes in the microbial community contribute to increasing colonic bile acids, reducing lipopolysaccharide synthesis to protect the intestinal barrier, and lowering inflammation levels. Changes were also observed in colonic transcripts and metabolites and liver gene transcripts and metabolites, which were mainly enriched in pathways of glycolipid metabolism, immune function amelioration, inflammatory signal mitigation, circadian rhythm, bile acid metabolism and insulin resistance. Therefore, EBN may enhance the gut microbiota and intestinal immunity, relieve chronic inflammation levels in serum, improve antioxidant capacity and circadian rhythm in the liver, promote bile acid metabolism, and decrease lipid absorption and lipid synthesis via the gut-liver axis. Consequently, this may reduce blood lipid and fat accumulation as well as improve islet function and reduce blood glucose levels.

Establishment of a novel obesity mouse model: the induction of intestinal microbiota dysbiosis.

To establish and evaluate an intestinal microbiota dysbiosis-induced obesity mouse model. 50 C57BL/6 J male healthy mice were randomly divided into an obesity model group and the control group. The body weight, body length, and Lee's index of the two groups of mice at week 1 and week 10 were compared. Serum glucose (GLU), total cholesterol (TC) and triglyceride (TG) were measured by enzyme-labeled colorimetric methods. Illumina HiSeq 16S rDNA high-throughput sequencing technology was used to characterize intestinal microbiota in feces. The success rate of model establishment in obese mice was 52%. The body weight, body length, Lee's index, and abdominal fat (wet weight) in the obese model group were all higher than those in the control group, and the differences were statistically significant (P < 0.01). Serum GLU and TC levels in the obesity model group were higher than those in the control group (P < 0.05), and there was no difference in TG levels between the two groups (P > 0.05). The control group contained more abundant intestinal microbiota phyla and genera than did the obesity model group; the differences between the two groups were significant (FDR ≤ 0.05, P ≤ 0.05). Intestinal microbiota dysbiosis can be used to generate an obesity model in mice.

7-MEGA™ inhibits adipogenesis in 3T3-L1 adipocytes and suppresses obesity in high-fat-diet-induced obese C57BL/6 mice.

BACKGROUND: Overweight, often known as obesity, is the abnormal and excessive accumulation of fat that exposes the health of a person at risk by increasing the likelihood that they may experience many chronic conditions. Consequently, obesity has become a global health threat, presenting serious health issues, and attracting a lot of attention in the healthcare profession and the scientific community. METHOD: This study aims to explore the anti-adipogenic properties of 7-MEGA™ in an attempt to address obesity, using both in vitro and in vivo research. The effects of 7MEGA™ at three distinct concentrations were investigated in obese mice who were given a high-fat diet (HFD) and 3T3-L1 adipocytes. RESULTS: 7MEGA™ decreased the total fat mass, overall body weight, and the perirenal and subcutaneous white adipose tissue (PWAT and SWAT) contents in HFD mice. Additionally, 7MEGA™ showed promise in improving the metabolic health of individuals with obesity and regulate the levels of insulin hormone, pro-inflammatory cytokines and adipokines. Furthermore, Peroxisome proliferator-activated receptors (PPAR) α and γ, Uncoupling Protein 1 (UCP-1), Sterol Regulatory Element-Binding Protein 1 (SREBP-1), Fatty Acid-Binding Protein 4 (FABP4), Fatty Acid Synthase (FAS), Acetyl-CoA Carboxylase (ACC), Stearoyl-CoA Desaturase-1 (SCD-1) and CCAAT/Enhancer-Binding Protein (C/EBPα) were among the adipogenic regulators that 7MEGA™ could regulate. CONCLUSION: In summary, this study uncovered that 7MEGA™ demonstrates anti-adipogenic and anti-obesity effects, suggesting its potential in combating obesity.

Alleviation of lipid metabolic dysfunction through regulation of intestinal bacteriophages and bacteria by green tea polyphenols in Ob/Ob mice.

Green tea polyphenols (GTP) have been shown to ameliorate lipid metabolic disorders by regulating intestinal bacteria. Given the significant role of intestinal bacteriophages in shaping the gut microbiota, this study investigates GTP's influence on gut bacteriophage-bacteria interactions and lipid metabolism using metagenomics and metabonomics. The research results indicated that GTP significantly reduced body weight, serum triglycerides, leptin, insulin resistance, interleukin-6, and TNF-α levels while increasing adiponectin in ob/ob mice fed high-fat diet, aiding intestinal repair. GTP improved gut health by decreasing Enterobacter, Siphoviridae and Enterobacteria_phage_sfv, increasing Bifidobacterium and intestinal metabolites SCFA and hippuric acid. Correlation analysis showed negative correlations between Enterobacter sp. 50,588,862 and Enterobacteria_phages, Shigella_phages with 4-hydroxyphenylpyruvate and hippuric acid. Bifidobacterium choerinum and Bifidobacterium sp. AGR2158 were positively correlated with fatty acids and bile acids. In conclusion, GTP reduced fat accumulation and inflammation, enhanced gut barrier function in obese mice, closely associated with changes in the gut bacteriophage community.

Limiting extracellular matrix expansion in diet-induced obese mice reduces cardiac insulin resistance and prevents myocardial remodelling.

OBJECTIVE: Obesity increases deposition of extracellular matrix (ECM) components of cardiac tissue. Since obesity aggregates with insulin resistance and heart disease, it is imperative to determine whether the increased ECM deposition contributes to this disease cluster. The hypotheses tested in this study were that in cardiac tissue of obese mice i) increased deposition of ECM components (collagens and hyaluronan) contributes to cardiac insulin resistance and that a reduction in these components improves cardiac insulin action and ii) reducing excess collagens and hyaluronan mitigates obesity-associated cardiac dysfunction. METHODS: Genetic and pharmacological approaches that manipulated collagen and hyaluronan contents were employed in obese C57BL/6 mice fed a high fat (HF) diet. Cardiac insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and cardiac function was measured by pressure-volume loop analysis in vivo. RESULTS: We demonstrated a tight association between increased ECM deposition with cardiac insulin resistance. Increased collagen deposition by genetic deletion of matrix metalloproteinase 9 (MMP9) exacerbated cardiac insulin resistance and pirfenidone, a clinically available anti-fibrotic medication which inhibits collagen expression, improved cardiac insulin resistance in obese mice. Furthermore, decreased hyaluronan deposition by treatment with PEGylated human recombinant hyaluronidase PH20 (PEGPH20) improved cardiac insulin resistance in obese mice. These relationships corresponded to functional changes in the heart. Both PEGPH20 and pirfenidone treatment in obese mice ameliorated HF diet-induced abnormal myocardial remodelling. CONCLUSION: Our results provide important new insights into the role of ECM deposition in the pathogenesis of cardiac insulin resistance and associated dysfunction in obesity of distinct mouse models. These findings support the novel therapeutic potential of targeting early cardiac ECM abnormalities in the prevention and treatment of obesity-related cardiovascular complications.

Inhibition of somatostatin enhances the long-term metabolic outcomes of sleeve gastrectomy in mice.

OBJECTIVE: Bariatric surgery is an effective treatment to obesity, leading to weight loss and improvement in glycemia, that is characterized by hypersecretion of gastrointestinal hormones. However, weight regain and relapse of hyperglycemia are not uncommon. We set to identify mechanisms that can enhance gastrointestinal hormonal secretion following surgery to sustain weight loss. METHODS: We investigated the effect of somatostatin (Sst) inhibition on the outcomes of bariatric surgery using a mouse model of sleeve gastrectomy (SG). RESULTS: Sst knockout (sst-ko) mice fed with a calorie-rich diet gained weight normally and had a mild favorable metabolic phenotype compared to heterozygous sibling controls, including elevated plasma levels of GLP-1. Mathematical modeling of the feedback inhibition between Sst and GLP-1 showed that Sst exerts its maximal effect on GLP-1 under conditions of high hormonal stimulation, such as following SG. Obese sst-ko mice that underwent SG had higher levels of GLP-1 compared with heterozygous SG-operated controls. The SG-sst-ko mice regained less weight than controls and maintained lower glycemia months after surgery. Obese wild-type mice that underwent SG and were treated daily with a Sst receptor inhibitor for two months had higher GLP-1 levels, regained less weight, and improved metabolic profile compared to saline-treated SG-operated controls, and compared to inhibitor or saline-treated sham-operated obese mice. CONCLUSIONS: Our results suggest that inhibition of Sst signaling enhances the long-term favorable metabolic outcomes of bariatric surgery.