EphA3 deficiency in the hypothalamus promotes high-fat diet-induced obesity in mice

Erythropoietin-producing hepatocellular carcinoma A3(EphA3)is a member of the largest subfamily of tyrosine kinase receptors-Eph receptors.Previous studies have shown that EphA3 is associated with tissue development.Recently,we have found that the expression of EphA3 is elevated in the hypothalamus of mice with diet-induced obesity(DIO).However,the role of EphA3 in hypothalamic-controlled energy metabolism remains unclear.In the current study,we demonstrated that the deletion of EphA3 in the hypothalamus by CRISPR/Cas9-mediated gene editing promotes obesity in male mice with high-fat diet feeding rather than those with normal chow diet feeding.Moreover,the deletion of hypothalamic EphA3 promotes high-fat DIO by increasing food intake and reducing energy expenditure.Knockdown of EphA3 leads to smaller intracellular vesicles in GT1-7 cells.The current study reveals that hypothalamic EphA3 plays important roles in promoting DIO.

Bitter Melon Powder Protects against Obesity-associated Fatty Liver Disease by Improving Colonic Microenvironment in Rats with High-fat Diet-induced Obesity

This study explored how bitter melon powder （BMP） alters the colonic microenvironment during the development of obesity-associated fatty liver in rats. We observed that BMP effectively inhibited the body weight gain and lipid accumulation in the liver, ameliorated glucose intolerance, and increased the colon weight after an 8-week treatment compared to that in the high-fat diet （HFD） group. BMP significantly decreased fecal water toxicity towards HT-29 cells, as revealed by the cell counting kit （CCK）-8 assay results, and the mRNA expression of Toll-like receptor 4 （TLR4） in colon mucosa. Additionally, gut permeability in the BMP group was restored to normal levels. Finally, BMP alleviated the inflammatory state of the rat colon mucosa and liver tissues as well as the systemic inflammation.

Docosahexaenoic acid-rich fish oil prevented insulin resistance by modulating gut microbiome and promoting colonic peptide YY expression in diet-induced obesity mice

It is unclear how docosahexaenoic acid(DHA)improves insulin resistance via modulating gut microbiome in obese individuals.We used diet-induced obesity(DIO)mice as a model to study the effects of DHA-rich fish oil(DHA-FO)on host metabolic disorders and colonic microbiome.DHA-FO reduced fat deposition,regulated lipid profiles and alleviated insulin resistance in DIO mice.Probably because DHA-FO prevented the permeation of lipopolysaccharide across intestinal epithelial barrier,and promoted peptide YY(PYY)secretion via the mediation of short chain fatty acids receptor(FFAR2)in colon.Furthermore,DHA-FO might regulate PYY expression by reversing microbial dysbiosis,including increasing the abundance ofAkkermansia muciniphila and Lactobacillus,and suppressing the growth of Helicobacter.DHA-FO also altered gut microbial function(e.g."linoleic acid metabolism")associated with PYY expression(r>0.80,P<0.05).Herein,DHA-FO enhanced insulin action on glucose metabolism by altering gut microbiome and facilitating colonic PYY expression in DIO mice.

Lingguizhugan decoction attenuates diet-induced obesity and hepatosteatosis via gut microbiota

BACKGROUND Obesity is a major risk factor for a variety of diseases such as diabetes,nonalcoholic fatty liver disease, and cardiovascular diseases. Restricting energy intake, or caloric restriction(CR), can reduce body weight and improve metabolic parameters in overweight or obese patients. We previously found that Lingguizhugan decoction(LZD) in combination with CR can effectively lower plasma lipid levels in patients with metabolic syndrome. However, the mechanism underlying CR and LZD treatment is still unclear.AIM To investigate whether CR and LZD improve metabolic parameters by modulating gut microbiota.METHODS We extracted the water-soluble components out of raw materials and dried as LZD extracts. Eight-week old male C57 BL/6 mice were treated with a 3-d treatment regime that included 24 h-fasting followed by gavage of LZD extracts for 2 consecutive days, followed by a normal diet(ND) ad libitum for 16 wk. To test the effects of gut microbiota on diet-induced obesity, 8-wk old male C57 BL/6 mice received fecal microbiota transplantation(FMT) from CR and LZD-treated mice every 3 d and were fed with high-fat diet(HFD) ad libitum for 16 wk.Control mice received either saline gavage or FMT from ND-fed mice receiving saline gavage as mentioned above. Body weight was monitored bi-weekly. Food consumption of each cage hosting five mice was recorded weekly. To monitor blood glucose, total cholesterol, and total triglycerides, blood samples were collected via submandibular bleeding after 6 h fasting. Oxygen consumption rate was monitored with metabolic cages. Feces were collected, and fecal DNA was extracted. Profiles of gut microbiota were mapped by metagenomic sequencing.RESULTS We found that CR and LZD treatment significantly reduced the body weight of mice fed with ND(28.71 ± 0.29 vs 28.05 ± 0.15, P < 0.05), but did not affect plasma total cholesterol or total triglyceride levels. We then transplanted the fecal microbiota collected from CR and LZD-treated mice under ND feeding to HFDfed mice. Intriguingly, transplanting the mice with fecal microbiota from CR and LZD-treated mice potently reduced body weight(44.95 ± 1.02 vs 40.53 ± 0.97, P <0.001). FMT also reduced HFD-induced hepatosteatosis, in addition to improved glycemic control. Mechanistic studies found that FMT increased OCR of the mice and suppressed the expression and protein abundance of lipogenic genes in the liver. Metagenomic analysis revealed that HFD drastically altered the profile of gut microbiota, and FMT modified the profile of the gut microbiota.CONCLUSION Our study suggests that CR and LZD improve metabolic parameters by modulating gut microbiota.

Interaction of Dietary Composition and PYY Gene Expression in Diet-induced Obesity in Rats

The interaction of high-fat diet and the peptide YY (PYY) gene expression in diet-induced obesity and the mechanisms which predisposed some individuals to become obese on high-fat diet were explored. Thirty-six male SD rats were randomly divided into high-fat diet group (n=27) and chow fed control group (n=9). After 15 weeks of either a high-fat diet or chew fed diet, the high-fat diet group was subdivided into dietary induced obesity (DIO) and dietary induced obesity resistant (DIR) group according to the final body weight. Then the DIO rats were subdivided into two groups for a 8-week secondary dietary intervention. One of the group was switched to chew fed diet, whereas the other DIO and DIR rats continued on the initial high-fat diet. Weight gain and food intake were measured, food efficiency was calculated, and the concentrations of plasma neuropeptide Y (NPY) and PYY were assayed. Hypothalamic NPY mRNA expression and PYY mRNA expression in ileum and colon was detected by RT-PCR. The results showed that at the end of 15th week, the levels of body weight and caloric intake were significantly higher in DIO group than in DIR or control group (P<0.01), while no significant difference was found between DIR and control group (P>0.05). The concentration of plasma PYY was significantly higher in DIR group than in DIO and CF group, while no significant difference was found between DIO and CF group (P<0.01). After switching the DIO rats to chow fed diet, their body weight gains were significantly lower than that of the DIO-HF group. The expression of PYY mRNA was increased in DIO-HF/CF rats than in DIO-HF rats, and the expression of hypothalamic NPY mRNA was decreased in DIO-HF/CF rats than in DIO-HF group. It was concluded that both dietary composition and PYY gene expression could potently alter the hypothalamic NPY expression and result in different susceptibility to obese and overeating. The decreased PYY was associated with the increased NPY expression and their predisposal to obese and overeating in rats.

Fucoidan antagonizes diet-induced obesity and inflammation in mice

Obesity is an escalating global pandemic posing a serious threat to human health.The intervention therapy using weight-reducing drugs,accompanied by lifestyle modification,is a strategy for the treatment of obesity.In the present study,we explored the role of fucoidan,a seaweed compound,on high-fat diet(HFD)-induced obesity in mice.We found that fucoidan treatment significantly reduced the body fat and caused redistribution of visceral and subcutaneous fat in HFD-fed mice.Meanwhile,fucoidan treatment inhibited adipocyte hypertrophy and inflammation in adipose tissue.Collectively,these results suggest that fucoidan may be a promising treatment for obesity and obesity-induced complications.

Diacylglycerol-enriched Oil from Hydrolysis of Soybean Oil with Rhizopus Oryzae Lipase Against High-fat Diet-induced Obesity in Mice

The present work aimed to investigate the impact of intake of diacylglycerol(DAG) from soybean oil on the reduction of fat accumulation and the long-term effects of dietary intake of DAG and triacylglycerol(TAG) with similar fatty acid compositions on the development of obesity. Kuming mice were used to compare the effects of low-dose TAG(2.5 g/kg BW), low-dose DAG(2.5 g/kg BW), high-dose TAG(10 g/kg BW), and high-dose DAG(10 g/kg BW) on the induced obesity. The results showed that the body weight and serum triglyceride concentration decreased significantly in both DAG-treated groups compared with the TAG-treated groups(P < 0.01, P < 0.05, respectively). However, the plasma glucose concentration was significantly lower in the DAG-treated groups than the TAG-treated groups(P < 0.05); the weight and morphology of the liver and kidney in DAG-treated groups were similar to those in the control group, there were no significant differences within each group. The present results indicated the anti-obesity and lipid-lowering effects of dietary DAG oil in mice and its potential use as a functional food for humans.

Role of pentoxifylline in non-alcoholic fatty liver disease in high-fat diet-induced obesity in mice

AIM:To study pentoxifylline effects in liver and adipose tissue inflammation in obese mice induced by high-fat diet(HFD).METHODS: Male swiss mice(6-wk old) were fed a highfat diet(HFD; 60% kcal from fat) or AIN-93(control diet; 15% kcal from fat) for 12 wk and received pentoxifylline intraperitoneally(100 mg/kg per day) for the last 14 d. Glucose homeostasis was evaluated by measurements of basal glucose blood levels and insulin tolerance test two days before the end of the protocol. Final body weight was assessed. Epididymal adipose tissue was collected and weighted for adiposity evaluation. Liver and adipose tissue biopsies were homogenized in solubilization buffer and cytokines were measured in supernatant by enzyme immunoassay or multiplex kit, respectively. Hepatic histopathologic analyses were performed in sections of paraformaldehyde-fixed, paraffin-embedded liver specimens stained with hematoxylin-eosin by an independent pathologist. Steatosis(macrovesicular and microvesicular), ballooning degeneration and inflammation were histopathologically determined. Triglycerides measurements were performed after lipid extraction in liver tissue. RESULTS: Pentoxifylline treatment reduced microsteatosis and tumor necrosis factor(TNF)-α in liver(156.3 ± 17.2 and 62.6 ± 7.6 pg/mL of TNF-α for non-treated and treated obese mice, respectively; P < 0.05). Serum aspartate aminotransferase levels were also reduced(23.2 ± 6.9 and 12.1 ± 1.6 U/L for nontreated and treated obese mice, respectively; P < 0.05) but had no effect on glucose homeostasis. In obese adipose tissue, pentoxifylline reduced TNF-α(106.1 ± 17.6 and 51.1 ± 9.6 pg/mL for non-treated and treated obese mice, respectively; P < 0.05) and interleukin-6(340.8 ± 51.3 and 166.6 ± 22.5 pg/mL for non-treated and treated obese mice, respectively; P < 0.05) levels; however, leptin(8.1 ± 0.7 and 23.1 ± 2.9 ng/mL for non-treated and treated lean mice, respectively; P < 0.05) and plasminogen activator inhibitor-1(600.2 ± 32.3 and 1508.6 ± 210.4 pg/mL for non-treated and treated lean mice, respectively; P < 0.05) levels increased in lean adipose tissue. TNF-α level in the liver of lean mice also increased(29.6 ± 6.6 and 75.4 ± 12.6 pg/mL for non-treated and treated lean mice, respectively; P < 0.05) while triglycerides presented a tendency to reduction.CONCLUSION: Pentoxifylline was beneficial in obese mice improving liver and adipose tissue inflammation. Unexpectedly, pentoxifylline increased pro-inflammatory markers in the liver and adipose tissue of lean mice.

The Effects of Xylitol on Body Weight Loss Management and Lipid Profile on Diet-Induced Obesity Mice

Xylitol is an alternative sweetener which has been previously reported to have many beneficial effects such as prevention from dental caries, reduction of visceral fat and increased synthesis of collagen. However, its role in body weight loss management has not been uncovered before. This study sought to investigate the effects of xylitol on body weight loss management, blood glucose and lipid profile on diet-induced obesity (DOI) mice. Fifteen male mice were subjected to high fat diet (60 kcal%) and normal drinking water for 28 days and then randomly divided into three (control, glucose and xylitol) groups. Each group of mice was then fed with normal diet for another 28 days with supplied normal drinking water (control);glucose solution 10% and xylitol solution 10%. Body weight loss was found to be significantly high in xylitol mice (2.56 ± 0.21, p = 0.003) compared to the other two groups. Lowest blood glucose level was found in the control group mice with the mean 7.65 ± 0.10 (p = 0.001). Xylitol mice had also showed the lowest total cholesterol level (4.20 ± 0.90, p = 0.000) than the other groups, but highest in HDL level (2.72 ± 0.14, p = 0.000). In conclusion, these findings proved that xylitol has the potential to reduce body weight, lowering the blood glucose but yet increase the HDL level.

Raspberry ketone attenuates high-fat diet-induced obesity by improving metabolic homeostasis in rats

Objective:To investigate the molecular mechanisms of the antiobese effect of raspberry ketone against high-fat diet fed rats.Methods:Fifty adult male rats were randomly assigned to receive a standard diet,a high fat diet,and the high-fat diet and 0.5%,1%or 2%raspberry ketone.Body weight,biochemical parameters and gene expression of CCAAT enhancer-binding protein(C/EBP)-δ,fatty acid synthase(FAS),acetyl Co A carboxylase(ACC),peroxisome proliferator-activated receptor alpha(PPAR-α),hormone-sensitive lipase(HSL)and hepatic carnitine palmitoyltransferase 1A(CPT1A)were investigated.Results:Body weight,blood glucose,insulin,total lipids,triacylglycerols,total cholesterol and low-density lipoprotein cholesterol were increased in high-fat diet fed rats.These high fat diet-induced changes were attenuated by treatment with raspberry ketone.High-density lipoprotein cholesterol was decreased in highfat diet fed rats but increased in rats treated with raspberry ketone.Molecular investigations showed induction of gene expression of C/EBP-δ,FAS,ACC,CPT1A and inhibition of gene expression of PPAR-αand HSL in high-fat diet fed rats as compared with control.Raspberry ketone treament reversed these changes except CPT1A.Conclusions:Raspberry ketone can prevent obesity induced by a high-fat diet in rats by induction of the expression of enzymes,controlling lipolysis and fatty acidsβoxidation as well as inhibition of gene expressions of adipogenic factors.

Impact of age on host responses to diet-induced obesity:Development of joint damage and metabolic set points

Background:Osteoarthritis is one of the leading causes of pain and disability worldwide,and a large percentage of patients with osteoarthritis are individuals who are also obese.In recent years,a series of animal models have demonstrated that obesity-inducing diets can result in synovial joint damage(both with and without the superimposition of trauma),which may be related to changes in percentage of body fat and a series of low-level systemic inflammatory mediators.Of note,there is a disparity between whether the dietary challenges commence at weaning,representing a weanling onset,or at skeletal maturity,representing an adult onset of obesity.We wished to evaluate the effect ofthe dietary exposure time and the age at which animals are exposed to a high-fat and high-sucrose(HFS) diet to determine whether these factors may result in disparate outcomes,as there is evidence suggesting that these factors result in differential metabolic disturbances.Based on dietary exposure time,we hypothesized that rats fed an HFS diet for 14 weeks from weaning(HFS Weanling) would demonstrate an increase in knee joint damage scores,whereas rats exposed to the HFS diet for 4 weeks,starting at 12 weeks of age(HFS Adult) and rats exposed to a standard chow diet(Chow)would not display an increase in knee joint damage scores.Methods:Male Sprague-Dawley rats were fed either an HFS diet for 14 weeks from weaning(HFS Weanling) or an HFS diet for 4 weeks,starting at 12 weeks of age(HFS Adult).At sacrifice,joints were scored using the modified Mankin Criteria,and serum was analyzed for a defined subset of inflammatory markers(Interleukin-6,leptin,monocyte chemoattractant protein-1,and tumor necrosis factorα).Results:When the HFS Weanling and HFS Adult groups were compared,both groups had a similar percent of body fat,although the HFS Weanling group had a significantly greater body mass than the HFS Adult group.The HFS Weanling and HFS Adult animals had a significant increase in body mass and percentage of body fat when compared to the Chow group.Although knee joint damage scores were low in all 3 groups,we found,contrary to our hypothesis,that the HFS Adult group had statistically significant greater knee joint damage scores than the Chow and HFS Weanling groups.Furthermore,we observed that the HFS Weanling group did not have significant differences in knee joint damage scores relative to the Chow group.Conclusion:These findings indicate that the HFS Weanling animals were better able to cope with the dietary challenge of an HFS diet than the HFS Adult group.Interestingly,when assessing various serum proinflammatory markers,no significant differences were detected between the HTS Adult and HFS Weanling groups.Although details regarding the mechanisms underlying an increase in knee joint damage scores in the HFS Adult group remain to be elucidated,these findings indicate that dietary exposure time maybe less important than the age at which an HFS diet is introduced.Moreover,increases in serum proinflammatory mediators do not appear to be directly linked to knee joint damage scores in the HFS Weanling group animals but may be partially responsible for the observed knee joint damage in the adults over the very short time of exposure to the HFS diet.

Salvianolic acid B improves glucolipid metabolism by regulating adipogenic transcription factors in mice with diet-induced obesity

Objective:To determine the effect of Salvianolic acid B (Sal B) on glucose and lipid metabolism in mice with high-fat diet (HFD)-induced obesity,and to investigate the underlying mechanisms by measuring the expression levels of key adipogenic transcription factors.Methods:Six-week-old C57BL/6J male mice were fed for 12 weeks with a HFD to induce obesity or a standard diet to serve as normal controls.A mean body weight increase of more than 20% after these 12 weeks was used as the criteria for obesity.HFD-fed obese mice then received a supplement of Sal B (100 mg/kg body weight/day),metformin (75 mg/kg body weight/day) or water (an equivalent volume;served as model controls) by oral gavage for an additional 8 weeks,and the normal controls received water (an equivalent volume) by oral gavage for the same period.Results:Sal B significantly reduced body weight gain (P <.05) without influencing food intake in HFD-fed obese mice relative to model controls.Sal B also reduced the body fat mass of the obese mice relative to model controls in a time-dependent manner (P <.05).Sal B significantly decreased the serum concentrations of low-density lipoprotein cholesterol,total cholesterol,triglyceride and free fatty acids by 25.5%,20.2%,20.6% and 13.4%,respectively,and increased the concentration of high-density lipoprotein cholesterol by 50.1% relative to model controls.In addition,Sal B significantly lowered fasting glucose concentrations and improved insulin sensitivity relative to model controls (P <.05).Sal B acted by ameliorating the histopathological changes in both brown and white adipose tissues of obese mice.Moreover,in brown adipose tissue,Sal B up-regulated the mRNA and protein expression of PPARγ and c/EBPα,and the protein expression of PPARα and SREBP-1 (P <.05).In white adipose tissue,Sal B down-regulated the mRNA expression of PPARγ and c/EBPα,and decreased the protein expression of PPARγ and SREBP-1(P <.05).Conclusjons:The results suggest that Sal B can reduce body weight gain and regulate glucose and lipid metabolism in mice with diet-induced obesity by regulating adipogenic transcription factors in their adipose tissues.

Comparative Study on Effect of Chrysophyllum albidum and Irvingia gabonensis Leaves Extracts on High-Fat Diet-Induced Obesity in Wistar Rats

Leaves of Chrysophyllum albidum and Irvingia gabonensis have been reported to possess saponins, flavonoids, alkaloids, steroids and tannins which have several health benefits. This study investigated the anti-obesity effect of methanol extract of leaves of Chrysophyllum albidum and Irvingia gabonensis in high fat diet (HFD) fed rats. Male Wistar rats were fed with HFD for eight weeks to induce obesity. Rats in different groups were thereafter treated with extracts of Chrysophyllum albidum (250 and 500 mg/kg;p.o), Irvingia gabonensis (250 and 500 mg/kg;p.o) or the reference anti-obesity drug (orlistat&reg;20 mg/kg, p.o) for four weeks. Body weight, body mass index (BMI) and Lee’s index were recorded. Following sacrifice of the rats, weight of adipose tissues (retroperitoneal and epididymal fat), serum lipid profile, kidney function markers, liver and cardiac function enzymes were measured. Histopathological examination of the liver and kidney tissues were carried out. Obese rats treated with Chrysophyllum albidum, Irvingia gabonensis or orlistat showed normal body weights. Weights of adipose tissues, BMI and Lee’s index were comparable with those of normal control [normal fat diet (NFD) fed rats]. Also, serum analysis showed that orlistat and extracts treated rats had restored lipid profile, liver, kidney and cardiac function parameters in contrast with the untreated HFD fed obese group. Furthermore, liver and kidney of orlistat and extracts treated groups showed normal architecture while those of the untreated HFD group showed inflammation and hepatic steatosis. Findings from the study suggest that methanol extracts of Chrysophyllum albidum and Irvingia gabonensis leaves have anti-obesity and anti-hyperlipidaemic properties. Comparatively, extract of Irvingia gabonensis appeared to be a better suppressor of adiposity than extract of Chrysophyllum albidum.

Apolipoprotein E in diet-induced obesity:a paradigm shift from conventional perception

Apolipoprotein E（APOE） is a major protein component of peripheral and brain lipoprotein transport systems.APOE in peripheral circulation does not cross the blood brain barrier or blood cerebrospinal fluid barrier. As a result,peripheral APOE expression does not affect brain APOE levels and vice versa. Numerous epidemiological studies suggest a key role of peripherally expressed APOE in the development and progression of coronary heart disease while brain APOE has been associated with dementia and Alzheimer＇s disease. More recent studies, mainly in experimental mice, suggested a link between Apoe and morbid obesity. According to the latest findings, expression of human apolipoprotein E3（APOE3） isoform in the brain of mice is associated with a potent inhibition of visceral white adipose tissue（WAT） mitochondrial oxidative phosphorylation leading to significantly reduced substrate oxidation,increased fat accumulation and obesity. In contrast, hepatically expressed APOE3 is associated with a notable shift of substrate oxidation towards non-shivering thermogenesis in visceral WAT mitochondria, leading to resistance to obesity. These novel findings constitute a major paradigm shift from the widely accepted perception that APOE promotes obesity via receptor-mediated postprandial lipid delivery to WAT. Here, we provide a critical review of the latest facts on the role of APOE in morbid obesity.

Effects of ginseng dietary supplementation on a high-Fat diet-induced obesity in C57BL/6 Mice

Excess caloric intake increases the amount of adipose tissue and contributes to metabolic disorders in disrupted metabolic homeostasis.This study aimed to investigate the anti-obesity effects of ginseng and the alternation of gut microbiota composition in high-fat diet(HFD)-induced obesity.The results showed that HFD treatment influenced body weight gain,adipose tissue accumulation and biochemical parameter changes.Compared to the HFD group,ginseng supplementation of HFD-fed mice decreased body weight,adipose tissue mass,total cholesterol(T-CHO)and high-density lipoprotein(HDL)/low-density lipoprotein(LDL)ratio.To analysis the alterations of gut microbiota,ginseng in dietary supplements decreased Firmicutes abundance and increased Bacteroidetes abundance.Taken together,these findings suggest ginseng may modulate the energy storage and alter gut microbiota composition.

Deletion of liver kinase B1 in POMC neurons predisposes to diet-induced obesity

Liver kinase BI(LKB1)is a serine/threonine kinase.LKB1 has been used as a tumor suppressor and metabolic regulator because of its anti-cancer effect and regulation of peripheral glucose metabolism.Although many biological functions of LKB1 have been identified,the role of hypothalamic LKB1 in the regulation of central energy metabolism and susceptibility to obesity is unknown.We previously found that LKBl overexpression in the hypothalamus decreased energy intake,inhibited the development of obesity.To further elucidate the role of hypothalamic LKB1 in energy metabolism and obesity susceptibility,we generated POMC neuron-specific LKB1 knockout mice(PomcLkb1 KO)and studied it at the physiological,morphological,and molecular biology levels.PomcLkb1 KO mice did not exhibit impairments under normal physiological conditions.After HFD intervention,the metabolic phenotype of the PomcLkbl KO mice changed,manifesting as increased food intake and an enhanced obesity phenotype.More seriously,PomcLkbl KO mice showed increased leptin resistance,worsened hypothala mic inflammation and reduced POMC neuronal expression.

Salvia miltiorrhiza extract may exert an anti-obesity effect in rats with high-fat diet-induced obesity by modulating gut microbiome and lipid metabolism

BACKGROUND Studies have shown that a high-fat diet(HFD) can alter gut microbiota(GM)homeostasis and participate in lipid metabolism disorders associated with obesity.Therefore, regulating the construction of GM with the balance of lipid metabolism has become essential for treating obesity. Salvia miltiorrhiza extract(Sal), a common traditional Chinese medicine, has been proven effective against atherosclerosis, hyperlipidemia, obesity, and other dyslipidemia-related diseases.AIM To investigate the anti-obesity effects of Sal in rats with HFD-induced obesity, and explore the underlying mechanism by focusing on GM and lipid metabolism.METHODS Obesity was induced in rats with an HFD for 7 wk, and Sal(0.675 g/1.35 g/2.70g/kg/d) was administered to treat obese rats for 8 wk. The therapeutic effect was evaluated by body weight, body fat index, waistline, and serum lipid level. Lipid factors(cAMP, PKA, and HSL) in liver and fat homogenates were analyzed by ELISA. The effect of Sal on GM and lipid metabolism was assessed by 16S rRNAbased microbiota analysis and untargeted lipidomic analysis(LC-MS/MS),respectively.RESULTS Sal treatment markedly reduced weight, body fat index, serum triglycerides(TG), total cholesterol(TC), low-density lipoprotein, glucose, free fatty acid, hepatic lipid accumulation, and adipocyte vacuolation, and increased serum high-density lipoprotein(HDL-C) in rats with HFD-induced obesity. These effects were associated with increased concentrations of lipid factors such as c AMP, PKA, and HSL in the liver and adipose tissues, enhanced gut integrity, and improved lipid metabolism. GM analysis revealed that Sal could reverse HFD-induced dysbacteriosis by promoting the abundance of Actinobacteriota and Proteobacteria, and decreasing the growth of Firmicutes and Desulfobacterita. Furthermore, LC-MS/MS analysis indicated that Sal decreased TGs(TG18:2/18:2/20:4, TG16:0/18:2/22:6), DGs(DG14:0/22:6, DG22:6/22:6), CL(18:2/18:1/18:1/20:0), and increased ceramides(Cers;Cer d16:0/21:0, Cer d16:1/24:1),(O-acyl)-ω-hydroxy fatty acids(OAHFAs;OAHFA18:0/14:0) in the feces of rats. Spearman’s correlation analysis further indicated that TGs, DGs, and CL were negatively related to the abundance of Facklamia and Dubosiella, and positively correlated with Blautia and Quinella, while OAHFAs and Cers were the opposite.CONCLUSION Sal has an anti-obesity effect by regulating the GM and lipid metabolism.

Alisol B 23-acetate promotes white adipose tissue browning to mitigate high-fat diet-induced obesity by regulating mTOR-SREBP1 signaling

Objective Obesity is a global health concern with management strategies encompassing bariatric surgery and anti-obesity drugs;however,concerns regarding complexities and side effects persist,driving research for more effective,low-risk strategies.The promotion of white adipose tissue(WAT)browning has emerged as a promising approach.Moreover,alisol B 23-acetate(AB23A)has demonstrated efficacy in addressing metabolic disorders,suggesting its potential as a therapeutic agent in obesity management.Therefore,in this study,we aimed to investigate the therapeutic potential of AB23A for mitigating obesity by regulating metabolic phenotypes and lipid distribution in mice fed a high-fat diet(HFD).Methods An obesity mouse model was established by administration of an HFD.Glucose and insulin metabolism were assessed via glucose and insulin tolerance tests.Adipocyte size was determined using hematoxylin and eosin staining.The expression of browning markers in WAT was evaluated using Western blotting and quantitative real-time polymerase chain reaction.Metabolic cage monitoring involved the assessment of various parameters,including food and water intake,energy metabolism,respiratory exchange rates,and physical activity.Moreover,oil red O staining was used to evaluate intracellular lipid accumulation.A bioinformatic analysis tool for identifying the molecular mechanisms of traditional Chinese medicine was used to examine AB23A targets and associated signaling pathways.Results AB23A administration significantly reduced the weight of obese mice,decreased the mass of inguinal WAT,epididymal WAT,and perirenal adipose tissue,improved glucose and insulin metabolism,and reduced adipocyte size.Moreover,treatment with AB23A promoted the expression of browning markers in WAT,enhanced overall energy metabolism in mice,and had no discernible effect on food intake,water consumption,or physical activity.In 3T3-L1 cells,AB23A inhibited lipid accumulation,and both AB23A and rapamycin inhibited the mammalian target of rapamycin-sterol regulatory element-binding protein-1(mTOR-SREBP1)signaling pathway.Furthermore,3-isobutyl-1-methylxanthine,dexamethasone and insulin,at concentrations of 0.25 mmol/L,0.25μmol/L and 1μg/mL,respectively,induced activation of the mTOR-SREBP1 signaling pathway,which was further strengthened by an mTOR activator MHY1485.Notably,MHY1485 reversed the beneficial effects of AB23A in 3T3-L1 cells.Conclusion AB23A promoted WAT browning by inhibiting the mTOR-SREBP1 signaling pathway,offering a potential strategy to prevent obesity.

Piperine regulates the circadian rhythms of hepatic clock gene expressions and gut microbiota in high-fat diet-induced obese rats

The interplay between the host circadian clock and microbiota has significant influences on host metabolism processes,and circadian desynchrony triggered by high-fat diet(HFD)is closely related to metabolic disorders.In this study,the modulatory effects of piperine(PIP)on lipid metabolism homeostasis,gut microbiota community and circadian rhythm of hepatic clock gene expressions in obese rats were investigated.The Sprague-Dawley(SD)rats were fed with normal diet(ND),HFD and HFD supplemented with PIP,respectively.After 9 weeks,rats were sacrificed with tissue and fecal samples collected for circadian analysis.Results showed that chronic PIP administration ameliorated the obesity-induced alterations in lipid metabolism and dysregulation of hepatic clock gene expressions in obese rats.The gut microbial communities studied through 16S rRNA sequencing showed that PIP ameliorated the imbalanced nicrobiota and recovered the circadian rhythm of Lactobacillaceae,Desulfovibrionaceae,Paraprevotellaceae,and Lachnospiraceae.The fecal metabolic profiles indicated that 3-dehydroshikimate,cytidine and lithocholyltaurine were altered,which were involved in the amino acid and fatty acid metabolism process.These findings could provide theoretical basis for PIP to work as functional food to alleviate the lipid metabolism disorder,circadian rhythm misalignment,and gut microbiota dysbiosis with wide applications in the food and pharmaceutic industries.

Maternal helminth infection protects offspring from high-fat-diet-induced obesity through altered microbiota and SCFAs

Helminth-induced Th2 immunity and gut microbiota have been recently shown to be highly effective in modulating metabolic syndromes in animal models.This study aimed to determine whether maternal immunity and microbial factors affect the induction and development of obesity in offspring.Here,Heligomosomoides polygyrus(Hp)-infected or control female C57BL/6J mice mated with normal males and their offspring were fed a high-fat diet(HFD)for 9 weeks after weaning.Our results showed that Hp-induced maternal outcomes during gestation and lactation significantly impacted offspring metabolic phenotypes.This was evidenced by results showing that offspring from helminth-infected mothers on an HFD(Hp-offspring+HFD)gained significantly less body weight than those from uninfected mothers(Cont-offspring+HFD).Hp-offspring+HFD exhibited no Th2 phenotype but displayed a pattern of gut microbiota composition similar to that of Hp-infected mothers.Cross-fostering experiments confirmed that the helminth-induced maternal attenuation of offspring obesity was mediated through both prenatal and postnatal effects.Our results further showed that helminth-infected dams and their offspring had a markedly altered gut microbiome composition,with increased production of short-chain fatty acids(SCFAs).Intriguingly,Hp-infected mothers and Hp-offspring+HFD showed increased SCFA receptor(GPR)expression in adipose and colonic tissues compared to noninfected mothers and Cont-offspring+HFD,respectively.Moreover,SCFA supplementation to the pups of uninfected control mothers during lactation protected against HFD-induced weight gain,which corresponded with changes in gut bacterial colonization.Collectively,our findings provide new insights into the complex interaction of maternal immune status and gut microbiome,Hp infection,and the immunity and gut microbiome in obese-prone offspring in infant life.