Diet-induced Metabolic Syndrome Research Articles

Baicalin attenuate diet-induced metabolic syndrome by improving abnormal metabolism and gut microbiota

In this work, we examined whether baicalin (BC), a bioactive flavonoid in Scutellaria baicalensis Georgi, can reduce high-fat diet (HFD)-induced metabolic syndrome (MetS) in mice. The UPLC-QTOF/MS was used for metabolome profiles analysis, and an analysis of bacterial 16S rDNA in feces was used to examine the effects of BC on gut microbiota composition. Our results showed that BC (400 mg/kg) could reduce the body weight gain, decrease hepatic fat accumulation and abnormal blood lipids, and increase insulin sensitivity after 8 weeks of treatment. BC could reverse the alteration of 7 metabolites induced by HFD and the metabolic pathways responsive to BC intervention including citrate cycle, alanine, aspartate and glutamate metabolism, glycerophospholipid metabolism, and aminoacyl-tRNA biosynthesis. 16S rDNA analysis demonstrated that BC altered the composition and function of gut microbiota in MetS mice. Notably, we found that the change in succinic acid was negatively associated with the changes in Bacteroides and Sutterella, and positively associated with the change in Mucispirillum. Moreover, we confirmed that succinic acid displayed a metabolic protective effect on MetS mice. The antibiotic treatment verified that BC exerts metabolic protection through gut microbiota. Our findings suggested BC may be a potential therapeutic drug to ameliorate diet induced MetS and gut microbiome may be a novel mechanistic target of BC for treatment of MetS.

Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure

Hepatokines, secretory proteins from the liver, mediate inter-organ communication to maintain a metabolic balance between food intake and energy expenditure. However, molecular mechanisms by which hepatokine levels are rapidly adjusted following stimuli are largely unknown. Here, we unravel how CNOT6L deadenylase switches off hepatokine expression after responding to stimuli (e.g., exercise and food) to orchestrate energy intake and expenditure. Mechanistically, CNOT6L inhibition stabilizes hepatic Gdf15 and Fgf21 mRNAs, increasing corresponding serum protein levels. The resulting upregulation of GDF15 stimulates the hindbrain to suppress appetite, while increased FGF21 affects the liver and adipose tissues to induce energy expenditure and lipid consumption. Despite the potential of hepatokines to treat metabolic disorders, their administration therapies have been challenging. Using small-molecule screening, we identified a CNOT6L inhibitor enhancing GDF15 and FGF21 hepatokine levels, which dramatically improves diet-induced metabolic syndrome. Our discovery, therefore, lays the foundation for an unprecedented strategy to treat metabolic syndrome.

Harmonic Distortion of Blood Pressure Waveform as a Measure of Arterial Stiffness.

Aging and disease alter the composition and elastic properties of the aortic wall resulting in shape changes in blood pressure waveform (BPW). Here, we propose a new index, harmonic distortion (HD), to characterize BPW and its relationship with other in vitro and in vivo measures. Using a Fourier transform of the BPW, HD is calculated as the ratio of energy above the fundamental frequency to that at the fundamental frequency. Male mice fed either a normal diet (ND) or a high fat, high sucrose (HFHS) diet for 2–10 months were used to study BPWs in diet-induced metabolic syndrome. BPWs were recorded for 20 s hourly for 24 h, using radiotelemetry. Pulse wave velocity (PWV), an in vivo measure of arterial stiffness, was measured in the abdominal aorta via ultrasound sonography. Common carotid arteries were excised from a subset of mice to determine the tangent modulus using biaxial tension-inflation test. Over a 24-h period, both HD and systolic blood pressure (SBP) show a large variability, however HD linearly decreases with increasing SBP. HD is also linearly related to tangent modulus and PWV with slopes significantly different between the two diet groups. Overall, our study suggests that HD is sensitive to changes in blood pressure and arterial stiffness and has a potential to be used as a noninvasive measure of arterial stiffness in aging and disease.

Biomechanical Properties of Mouse Carotid Arteries With Diet-Induced Metabolic Syndrome and Aging.

Metabolic syndrome increases the risk of cardiovascular diseases. Arteries gradually stiffen with aging; however, it can be worsened by the presence of conditions associated with metabolic syndrome. In this study, we investigated the combined effects of diet-induced metabolic syndrome and aging on the biomechanical properties of mouse common carotid arteries (CCA). Male mice at 2 months of age were fed a normal or a high fat and high sucrose (HFHS) diet for 2 (young group), 8 (adult group) and 18–20 (old group) months. CCAs were excised and subjected to in vitro biaxial inflation-extension tests and the Cauchy stress-stretch relationships were determined in both the circumferential and longitudinal directions. The elastic energy storage of CCAs was obtained using a four-fiber family constitutive model, while the material stiffness in the circumferential and longitudinal directions was computed. Our study showed that aging is a dominant factor affecting arterial remodeling in the adult and old mice, to a similar extent, with stiffening manifested with a significantly reduced capability of energy storage by ∼50% (p < 0.05) and decreases in material stiffness and stress (p < 0.05), regardless of diet. On the other hand, high fat high sucrose diet resulted in an accelerated arterial remodeling in the young group at pre-diabetic stage by affecting the circumferential material stiffness and stress (p < 0.05), which was eventually overshadowed by aging progression. These findings have important implications on the effects of metabolic syndrome on elastic arteries in the younger populations.

The efficiency of remote ischemic postconditioning of the myocardium in rats with induced metabolic syndrome depends on the leptin level

Remote postconditioning (RPost) has a great therapeutic potential for protecting the myocardium during ischemiareperfusion in clinical practice. At the same time, an important problem limiting the use of conditioning effects in the clinic is the presence of metabolic disorders in the patient. The aim of this work was to assess the effect of induced metabolic syndrome (iMetS) on the efficacy of the infarct-limiting effect of remote ischemic postconditioning (RPost) in rats and to study the mechanisms of this effect.The study was carried out on Wistar rats. MetS was induced by high-carbohydrate high-fat diet. Criteria of metabolic syndrome were an increase in the weight of animals, abdominal fat volume, the development of arterial hypertension, hypercholesterolemia, an increase in triglycerides in serum, hyperleptinemia, hyperglycemia, the development of a state of insulin resistance by a significant increase in the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index and glucose tolerance. All animals were subjected to 45 min coronary occlusion and 120 min reperfusion.RPost led to a twofold reduction of infarct size in rats with intact metabolism (р &lt; 0.0001), while in rats with iMetS a decrease in infarct size during RPost was 25 % (p = 0.00003), which was significantly lower than in animals without iMetC (р &lt; 0.0001). A direct correlation was found between of infarct size during RPost and the serum leptin level of rats with iMetC.The presented data suggested that a decrease in the efficiency of remote postconditioning in rats with diet-induced metabolic syndrome depends on leptin content in blood.

Multi-Omic Analysis in a Metabolic Syndrome Porcine Model Implicates Arachidonic Acid Metabolism Disorder as a Risk Factor for Atherosclerosis.

BackgroundThe diet-induced gut microbiota dysbiosis has been suggested as a major risk factor for atherothrombosis, however, the detailed mechanism linking these conditions is yet to be fully understood.MethodsWe established a long-term excessive-energy diet-induced metabolic syndrome (MetS) inbred Wuzhishan minipig model, which is characterized by its genetic stability, small size, and human-like physiology. The metabolic parameters, atherosclerotic lesions, gut microbiome, and host transcriptome were analyzed. Metabolomics profiling revealed a linkage between gut microbiota and atherothrombosis.ResultsWe showed that white atheromatous plaque was clearly visible on abdominal aorta in the MetS model. Furthermore, using metagenome and metatranscriptome sequencing, we discovered that the long-term excessive energy intake altered the local intestinal microbiota composition and transcriptional profile, which was most dramatically illustrated by the reduced abundance of SCFAs-producing bacteria including Bacteroides, Lachnospiraceae, and Ruminococcaceae in the MetS model. Liver and abdominal aorta transcriptomes in the MetS model indicate that the diet-induced gut microbiota dysbiosis activated host chronic inflammatory responses and significantly upregulated the expression of genes related to arachidonic acid-dependent signaling pathways. Notably, metabolomics profiling further revealed an intimate linkage between arachidonic acid metabolism and atherothrombosis in the host-gut microbial metabolism axis.ConclusionsThese findings provide new insights into the relationship between atherothrombosis and regulation of gut microbiota via host metabolomes and will be of potential value for the treatment of cardiovascular diseases in MetS.

Pathological involvement of apoptotic and inflammatory molecules in cardiovascular remodeling in rats on high fructose diet-induced metabolic syndrome.

Fructose consumption has been linked to manifestation of metabolic syndrome (MS); an emerging epidemic. The current study attempts to demonstrate fructose overconsumption-mediated cardiovascular disease (CVD) remodeling in Wistar rats. Rats were randomly segregated into control (CON) and high fructose diet (FFR) groups and received customized diets for 20weeks. Levels of diabetic, lipid, antioxidant, markers, mRNA levels of inflammatory, apoptotic markers, and histopathological changes were assessed in excised hearts of both groups. Significant increase in uric acid, pro-oxidants diabetic, lipid, inflammatory markers, cytosolic cytochrome C, nuclear NF-кB-p65, and decrease in antioxidants was observed in FFR group. Abnormal myocardial architecture was observed in the FFR group along with elevated mRNA levels of inflammatory, apoptotic markers, and MMP-9, -2. The outcomes of the study are suggestive of role of aforementioned molecules in high fructose intake-mediated pathological deterioration of heart and development of MS-associated CVD progression. PRACTICAL APPLICATIONS: Excessive fructose consumption in the form of high fructose corn syrup, sugary drinks, and commonly available fast foods has been shown to be linked with many diseases such as liver malfunction, metabolic syndrome diabetes, and cardiovascular diseases. However, delineated pathways and clear mechanisms and their role in cardiovascular remodeling due to excessive fructose consumption are yet to be established. The present study establishes the deleterious effects of foods with high sugar content on progression toward metabolic syndrome and cardiovascular remodeling. It further investigates the role of different pathways involved in the development of high fructose-induced diet-induced metabolic syndrome, and thereby leading to harmful effects on the hearts of rats consuming high fructose diet leading to cardiovascular in Wistar rats. The study suggests the role of immunomodulation and oxidative stress in the remodeling of cardiac muscles and in turn progression toward metabolic syndrome and cardiovascular remodeling. The study, therefore, throws light on the deleterious effects of consumption of foods and easily available fast foods on progression toward numerous non-communicable diseases.

Protective effect of high-oleic acid peanut oil and extra-virgin olive oil in rats with diet-induced metabolic syndrome by regulating branched-chain amino acids metabolism

High-oleic acid peanut oil (HOPO) and extra-virgin olive oil (EVOO) have been reported previously to have an attenuating effect on metabolic syndrome (MS). This study aimed to evaluate the metabolic effect of HOPO and EVOO supplementation in attenuating MS and the role of gut microbiota in regulating the metabolic profile. Sprague-Dawley rats were continuously fed with a normal diet, high-fructose and high-fat (HFHF) diet, HFHF diet containing HOPO, or a HFHF diet containing EVOO for 12 weeks. The metabolomics profiles of feces and serum samples were compared using untargeted metabolomics based on UPLC-Q/TOF-MS. Partial Least Squares Discriminant Analysis (PLS-DA) was used to identify the potential fecal and serum biomarkers from different groups. Correlation between gut microbiota and biomarkers was assessed, and pathway analysis of serum biomarkers was conducted. Differences in metabolic patterns in feces and serum were observed among different groups. There were 8 and 12 potential biomarkers in feces and 15 and 6 potential biomarkers in serum of HOPO group and EVOO group, respectively, suggesting that HOPO and EVOO supplementation mainly altered amino acids, peptides, and their analogs in feces and serum. The branched-chain amino acids (BCAAs) biosynthesis pathway was identified as a major pathway regulated by HOPO or EVOO. This study suggests that HOPO and EVOO supplementation ameliorate diet-induced MS, mainly via modulation of the BCAAs biosynthesis pathway.

Impact of a Novel Anti-Inflammatory Ketoprofen-Lysine Prodrug on Cerebral Pathology and Cognition in a Comorbid APP21 Transgenic Rat with Diet-Induced Metabolic Syndrome

Impact of a Novel Anti-Inflammatory Ketoprofen-Lysine Prodrug on Cerebral Pathology and Cognition in a Comorbid APP21 Transgenic Rat with Diet-Induced Metabolic Syndrome

7,8-Dihydroxyflavone Alleviates Endoplasmic Reticulum Stress in Cafeteria Diet-Induced Metabolic Syndrome

7,8-Dihydroxyflavone Alleviates Endoplasmic Reticulum Stress in Cafeteria Diet-Induced Metabolic Syndrome

Effect of Aronia melanocarpa fruit juice on the antioxidant defense system in rats with diet-induced metabolic syndrome

INTRODUCTION: The role of oxidative stress in the development of metabolic syndrome (MS) has been well established. Aronia melanocarpa fruits are very rich in polyphenols, which possess an antioxidant effect. AIM: The current study aimed to evaluate the effect of Aronia melanocarpa fruit juice (AMFJ) on the antioxidant defense system in rats with diet-induced MS. MATERIALS AND METHODS: Fifty male Wistar rats were allocated into 5 groups: control, MS, MS + AMFJ 2.5 , MS + AMFJ 5 and MS + AMFJ 10. For 10 weeks,the control group received regular diet and the other groups—high-fat high-fructose diet (HFHF). During this period, the control group and MS group were treated daily orally with 10 mL/kg distilled water and the other groups—with increasing volume (2.5 mL/kg, 5 mL/kg, and 10 mL/kg) of AMFJ. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured in the serum using commercial colorimetric kits. RESULTS: A significantly higher SOD level was observed in MS group (0.0069 ± 0.0007 U/mL) compared to the control group (0.0051 ± 0.0003 U/mL) (p&lt;0.01). AMFJ treatment returned the level of SOD to the control values, with the effect being significant in MS + AMFJ 2.5 (0.0053 ± 0.0003 U/mL)and MS + AMFJ 5 (0.0053±0.0003 U/mL) groups (p&lt;0.05 vs. MS). No significant difference was detected in the activity of GPx in all groups. CONCLUSION: HFHF diet-induced MS might be associated with superoxide production and compensatory activation of SOD. Due to its antioxidant properties, AMFJ counteracted these processes in the treated groups. Neither the HFHF diet, nor the AMFJ treatment affected the activity of GPx.

Mulinum spinosum root extract, rich in antioxidant compounds, mitigates harmful effects in mice with diet-induced metabolic syndrome

Background: Metabolic syndrome (MetS) is a health issue with a high incidence in adult population. Using herbal medicines for the management of serious complications of MetS, such as dyslipidemia and hyperglycemia, is highly promising. An aqueous extract from Mulinum spinosum (M. spinosum), traditionally used as hyperglycemic and anti-inflammatory, could have beneficial effects on the treatment of MetS.Purpose: The present study was aimed to characterize the composition of M. spinosum roots decoction, and to evaluate antidiabetic, antilipemic and antioxidant effects in an animal model of MetS.Study design and methods: M. spinosum roots extract was characterized using high-performance liquid chromatography coupled with diode array detection (HPLC-DAD) method. Total Phenolic Content (TPC) was spectrophotometrically measured and the antioxidant capacity was determined by the oxygen radical absorbance capacity (ORAC) assay. To generate the MetS model, adult male C57BL/6 mice were fed with a 20% w/v fructose (Fru) in drinking water combined with 30% w/w high fat diet (HFD) over a period of 12 weeks. M. spinosum aqueous extracts (3 or 6 g/kg/day) were administered in drinking water together with Fru-HFD. At the end of the exposure period, mice were weighed and glucose tolerance test was determined. After sacrifice, adipose tissues were isolated and blood samples were collected to evaluate lipid profile, lipid peroxidation level (LPO) and ferric reducing antioxidant power (FRAP).Results: The characterization of M. spinosum revealed the presence of caffeic acid, trans-resveratrol, kaempferol-3-glucoside, (-)-epicatechin, (-)-gallocatechin gallate, (-)-epigallocatechin and (+)-catechin. A high antioxidant capacity of the extract was revealed by ORAC test. Mice fed a Fru-HF diet and treated with M. spinosum, reduced diet-induced weight gain and significantly decreased mesenteric fat compared with Fru-HFD group (p<0.01). Post prandial glycaemia significantly diminished when mice were treated with M. spinosum, and also total cholesterol, LDL-cholesterol and triglycerides (TG) were reduced. Regarding the antioxidant effect of the consumption of M. spinosum, we found a decrease in plasmatic LPO, and a significant increase in plasmatic FRAP.Conclusion: To our knowledge, the phenolic composition and the antioxidant capacity of M. spinosum roots decoction is reported for the first time. In addition, we provide evidence that M. spinosum root extract is a promising source of antioxidants able to alleviates Fru-HFD-induced metabolic alterations and slow the progression of MetS.

Nannochloropsis oceanica as a Microalgal Food Intervention in Diet-Induced Metabolic Syndrome in Rats.

The microalgal genus Nannochloropsis has broad applicability to produce biofuels, animal feed supplements and other value-added products including proteins, carotenoids and lipids. This study investigated a potential role of N. oceanica in the reversal of metabolic syndrome. Male Wistar rats (n = 48) were divided into four groups in a 16-week protocol. Two groups were fed either corn starch or high-carbohydrate, high-fat diets (C and H, respectively) for the full 16 weeks. The other two groups received C and H diets for eight weeks and then received 5% freeze-dried N. oceanica in these diets for the final eight weeks (CN and HN, respectively) of the protocol. The H diet was high in fructose and sucrose, together with increased saturated and trans fats. H rats developed obesity, hypertension, dyslipidaemia, fatty liver disease and left ventricular fibrosis. N. oceanica increased lean mass in CN and HN rats, possibly due to the increased protein intake, and decreased fat mass in HN rats. Intervention with N. oceanica did not change cardiovascular, liver and metabolic parameters or gut structure. The relative abundance of Oxyphotobacteria in the gut microbiota was increased. N. oceanica may be an effective functional food against metabolic syndrome as a sustainable protein source.

Tea polyphenols act as a natural antihyperglycemic feed additive candidate in grass carp ( Ctenopharyngodon idella )

Dietary supplementation with tea polyphenols (TPs) is associated with reduced diet-induced obesity and/or metabolic syndrome in mammal studies. However, TPs have rarely been related to fish metabolic syndrome caused by intensive aquaculture. In this study, TPs were supplemented to three diets with different protein to carbohydrate ratios (P38C30, P32C26, P26C42) to grass carp for 8 weeks. After the feeding trial, contrast to the anti-obesity effect in mammals, TPs improved the growth performance and spared protein of grass carp in the case of high protein and low carbohydrate diet intake. Dietary TPs supplementation reduced hepatic g6pc and pck expressions to suppress gluconeogenesis without altered glycolysis (unchanged glk and pk expression), resulted in lower plasma glucose levels compared with no supplemented diets. The hepatic glycogen was induced by dietary TPs supplementation through increasing gys expression or decreasing pyg expression. In addition, dietary TPs supplementation provided health benefits in our fish through enhancing the activities of plasma superoxide dismutase and glutathione peroxidase, and glutathione content, meanwhile, reducing the content of malondialdehyde. Therefore, TPs could be used as a natural antihyperglycemic feed additive candidate for sparing dietary protein and improving feed efficiency in aquaculture.

Hypothalamic administration of sargahydroquinoic acid elevates peripheral thermogenic signaling and ameliorates high fat diet-induced obesity through the sympathetic nervous system

Sargassum serratifolium (C. Agardh) C.Agardh, a marine brown alga, has been consumed as a food and traditional medicine in Asia. A previous study showed that the meroterpenoid-rich fraction of an ethanolic extract of S. serratifolium (MES) induced adipose tissue browning and suppressed diet-induced obesity and metabolic syndrome when orally supplemented. Sargahydroquinoic acid (SHQA) is a major component of MES. However, it is unclear whether SHQA regulates energy homeostasis through the central nervous system. To examine this, SHQA was administrated through the third ventricle in the hypothalamus in high-fat diet-fed C57BL/6 mice and investigated its effects on energy homeostasis. Chronic administration of SHQA into the brain reduced body weight without a change in food intake and improved metabolic syndrome-related phenotypes. Cold experiments and biochemical analyses indicated that SHQA elevated thermogenic signaling pathways, as evidenced by an increase in body temperature and UCP1 signaling in white and brown adipose tissues. Peripheral denervation experiments using 6-OHDA indicated that the SHQA-induced anti-obesity effect is mediated by the activation of the sympathetic nervous system, possibly by regulating genes associated with sympathetic outflow and GABA signaling pathways. In conclusion, hypothalamic injection of SHQA elevates peripheral thermogenic signaling and ameliorates diet-induced obesity.

Time and frequency domain analysis of long-term heart rate variability in an experimental model of diet-induced metabolic syndrome

Abstract Background Metabolic syndrome (MetS) is defined as the set of at least three of the following conditions: central obesity, elevation of triglycerides, decreased in high-density lipoproteins, systemic hypertension and glucose intolerance. MetS is linked with a high prevalence of cardiovascular disease, including sudden cardiac death and atrial arrhythmias, which may be a consequence of changes related to the structure, function and autonomic control of the heart. One of the underlying mechanisms responsible could be the alteration of sinus node automaticity. Heart rate variability (HRV) analysis is a useful non-invasive tool for evaluating alterations in neural control of cardiac automaticity. Purpose To examine the changes in long-term HRV using time- and frequency- domain analyses in an experimental model of diet-induced MetS which develops all its components. Methods Male NZW rabbits were randomly assigned to control (n=10) or MetS group (n=10), fed with high-fat (10% coconut oil and 5% lard) and high sucrose (15% dissolved in water) diet during 28 weeks. At week 28, 24 hour ECG recording was performed (eMotion Faros 180, Mega Electronics®, 1 kHz). We analyzed 60 minutes of RR time series, comparing day (from 8:00 to 19:59 h) and night (from 20:00 to 7:59 h), and quantified the standard parameters of time and frequency domains: 1) Time domain: RR, SDNN, triangular index (Ti), RMSSD and TINN; 2) Frequency domain: very low (VLF), low (LF), high frequency (HF), and LF/HF index. Multivariate analysis of variance (MANOVA, factorial model) was used for statistical analysis (p&amp;lt;0.05). Results Time domain analysis showed a decrease in RR interval (p&amp;lt;0.001) and geometrical Ti (p=0.036) in MetS animals (Figure, A-B), indicative of an increased heart rate. The rest of parameters in the time domain (SDNN, RMSSD, TINN) were not modified. Further, in the frequency domain at FFT spectrum, we did find a significant decrease in the LF band (p=0.032) in MetS animals (Figure, C). The rest of the frequency domain parameters (VLF, HF and LF/HF index) remained unchanged. Conclusion MetS decreased RR interval duration and triangular index, suggesting an increased sympathetic activity during day and night. Those changes were reflected in LF modifications, and might be attributable to a deficiency in sympathetic-parasympathetic control, which requires adjustments to maintain normal autonomic balance. Collectively, these results could give insight into the autonomic mechanisms that underlie increased atrial arrhythmia susceptibility in MetS. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Generalitat Valenciana, University of Valencia

Anthocyanins from Aristotelia chilensis Prevent Olanzapine-Induced Hepatic-Lipid Accumulation but Not Insulin Resistance in Skeletal Muscle Cells.

Type 2 diabetes and obesity are major problems worldwide and dietary polyphenols have shown efficacy to ameliorate signs of these diseases. Anthocyanins from berries display potent antioxidants and protect against weight gain and insulin resistance in different models of diet-induced metabolic syndrome. Olanzapine is known to induce an accelerated form of metabolic syndrome. Due to the aforementioned, we evaluated whether delphinidin-3,5-O-diglucoside (DG) and delphinidin-3-O-sambubioside-5-O-glucoside (DS), two potent antidiabetic anthocyanins isolated from Aristotelia chilensis fruit, could prevent olanzapine-induced steatosis and insulin resistance in liver and skeletal muscle cells, respectively. HepG2 liver cells and L6 skeletal muscle cells were co-incubated with DG 50 μg/mL or DS 50 μg/mL plus olanzapine 50 μg/mL. Lipid accumulation was determined in HepG2 cells while the expression of p-Akt as a key regulator of the insulin-activated signaling pathways, mitochondrial function, and glucose uptake was assessed in L6 cells. DS and DG prevented olanzapine-induced lipid accumulation in liver cells. However, insulin signaling impairment induced by olanzapine in L6 cells was not rescued by DS and DG. Thus, anthocyanins modulate lipid metabolism, which is a relevant factor in hepatic tissue, but do not significantly influence skeletal muscle, where a potent antioxidant effect of olanzapine was found.

Lupeol reduces M1 macrophage polarization to attenuate immunologic dissonance and fatty acid deposition in rats with diet-induced metabolic syndrome.

BackgroundThis study aimed to investigate whether lupeol could inhibit the inflammatory mediators associated with the regulation of macrophage phenotypes and functions in rats with diet-induced metabolic syndrome (MS).MethodsForty specific-pathogen-free Sprague Dawley rats were fed a high-fat diet (HFD) for 10 weeks to establish an MS model. Lupeol was prepared and administered to the rats intraperitoneally at 20, 50, or 100 mg/kg (the lupeol 20 mg/kg, lupeol 50 mg/kg, and lupeol 100 mg/kg groups respectively). After 28 days of continuous intraperitoneal administration, rats were anesthesia and euthanasia. The obesity index, blood glucose and lipid metabolism indexes of rats in each group were measured. The levels of insulin and inflammatory factors in each group were detected by enzyme-linked immunosorbent assay (ELISA) kits. The pathological changes of liver tissue in rats were observed by hematoxylin and eosin (HE) and oil red O staining. The polarization levels of M1 and M2 macrophages in peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry. The transcription levels of M1 and M2 macrophages markers were detected by qRT-PCR. The expressions of inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) proteins in heart tissues of rats in each group were analyzed by Western blotting.ResultsLupeol significantly recovered fasting blood glucose and serum insulin levels, and reduced the production of proinflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1), in the liver. It also elevated the expression of anti-inflammatory cytokines, including IL-4 and IL-10, in the MS model. Further, after treatment with lupeol, the levels of total cholesterol, triacylglycerol and low-density lipoprotein (LDL) were decreased, and high-density lipoprotein (HDL) were increased. Importantly, in the MS model group, lupeol remarkably inhibited M1 macrophages polarization (F4/80+iNOS+) while elevating M2 macrophages polarization (F4/80+CD206+) remarkably. At the same time, the levels of M1 markers, including inducible nitric oxide synthase, IL-1β, IL-6, and TNF-α, were markedly inhibited, while those of M2 markers, such as arginase-1, IL-10, CD206, and TGF-β, were markedly elevated in the MS model rats.ConclusionsLupeol might promote M2 polarization of macrophages to relieve damage caused by MS.

In Silico-Based Design and In Vivo Evaluation of an Anthranilic Acid Derivative as a Multitarget Drug in a Diet-Induced Metabolic Syndrome Model.

Metabolic syndrome (MetS) is a complex disease that affects almost a quarter of the world’s adult population. In MetS, diabetes, obesity, hyperglycemia, high cholesterol, and high blood pressure are the most common disorders. Polypharmacy is the most used strategy for managing conditions related to MetS, but it has drawbacks such as low medication adherence. Multitarget ligands have been proposed as an interesting approach to developing drugs to treat complex diseases. However, suitable preclinical models that allow their evaluation in a context closer to a clinical situation of a complex disease are needed. From molecular docking studies, compound 1b, a 5-aminoanthranilic acid derivative substituted with 4′-trifluoromethylbenzylamino and 3′,4′-dimethoxybenzamide moieties, was identified as a potential multitarget drug, as it showed high in silico affinity against targets related to MetS, including PPAR-α, PPAR-γ, and HMG-CoA reductase. It was evaluated in a diet-induced MetS rat model and simultaneously lowered blood pressure, glucose, total cholesterol, and triglyceride levels after a 14-day treatment. No toxicity events were observed during an acute lethal dose evaluation test at 1500 mg/kg. Hence, the diet-induced MetS model is suitable for evaluating treatments for MetS, and compound 1b is an attractive starting point for developing multitarget drugs.

Seaweed Dietary Fiber Sodium Alginate Suppresses the Migration of Colonic Inflammatory Monocytes and Diet-Induced Metabolic Syndrome via the Gut Microbiota.

Metabolic syndrome (MetS) is a multifactorial chronic metabolic disorder that affects approximately one billion people worldwide. Recent studies have evaluated whether targeting the gut microbiota can prevent MetS. This study aimed to assess the ability of dietary fiber to control MetS by modulating gut microbiota composition. Sodium alginate (SA) is a seaweed-derived dietary fiber that suppresses high-fat diet (HFD)-induced MetS via an effect on the gut microbiota. We observed that SA supplementation significantly decreased body weight gain, cholesterol levels, and fat weight, while improving glucose tolerance in HFD-fed mice. SA changed the gut microbiota composition and significantly increased the abundance of Bacteroides. Antibiotic treatment completely abolished the suppressive effects of SA on MetS. Mechanistically, SA decreased the number of colonic inflammatory monocytes, which promote MetS development, in a gut microbiota-dependent manner. The abundance of Bacteroides was negatively correlated with that of inflammatory monocytes and positively correlated with the levels of several gut metabolites. The present study revealed a novel food function of SA in preventing HFD-induced MetS through its action on gut microbiota.