Diet-induced Mice Research Articles

Lipid- and gut microbiota-modulating effects of graphene oxide nanoparticles in high-fat diet-induced hyperlipidemic mice.

Graphene oxide (GO) suspensions can act as a good dispersant and drug delivery system for effective dispersion and drug sustained release. In this study, we investigated the impact of GO on blood/liver lipids and gut microbiota structure in high-fat diet (HFD)-induced hyperlipidemic mice. Oral administration of GO for 28 days remarkably decreased the lipid levels in blood and liver. GO did not decrease the total number of gut bacteria but increased the relative abundance of short-chain fatty acid (SCFA)-producing bacteria such as Clostridium clusters IV and Allobaculum spp. GO also enhanced the copying of bacterial butyryl coenzyme A transferase (BcoA), a key butyrate-producing gene. Although further pharmacological studies are still needed, these results provided an interesting hint that GO may exert beneficial effects on the host's metabolism via selective modulation of SCFA-producing gut microbes.

JAZF1 Inhibits Adipose Tissue Macrophages and Adipose Tissue Inflammation in Diet-Induced Diabetic Mice.

Background Juxtaposed with another zinc finger gene 1 (JAZF1) affects gluconeogenesis, insulin sensitivity, lipid metabolism, and inflammation, but its exact role in chronic inflammation remains unclear. This study aimed to examine JAZF1 overexpression in vivo on adipose tissue macrophages (ATMs). Methods Mouse models of high-fat diet- (HFD-) induced insulin resistance were induced using C57BL/6J and JAZF1-overexpressing (JAZF1-OX) mice. The mice were randomized (8–10/group) to C57BL/6J mice fed regular diet (RD) (NC group), C57BL/6J mice fed HFD (HF group), JAZF1-OX mice fed RD (NJ group), and JAZF1-OX mice fed HFD (HJ group). Adipose tissue was harvested 12 weeks later. ATMs were evaluated by flow cytometry. Inflammatory markers were evaluated by ELISA. Results JAZF1-OX mice had lower blood lipids, blood glucose, body weight, fat weight, and inflammatory markers compared with HF mice (all P < 0.05). JAZF1 overexpression decreased ATM number and secretion of proinflammatory cytokines. JAZF1 overexpression decreased total CD4+ T cells, active T cells, and memory T cells and increased Treg cells. JAZF1 overexpression downregulated IFN-γ and IL-17 levels and upregulated IL-4 levels. JAZF1 overexpression decreased MHCII, CD40, and CD86 in total ATM, CD11c+ ATM, and CD206+ ATM. Conclusions JAZF1 limits adipose tissue inflammation by limiting macrophage populations and restricting their antigen presentation function.

세리포리아 락세라타 균사체 배양물이 고지방식이로 급이된 당뇨병 마우스의 인슐린 저항성에 미치는 영향

세리포리아 락세라타 균사체 배양물이 고지방식이로 급이된 당뇨병 마우스의 인슐린 저항성에 미치는 영향

D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, small molecule synthetic peptide leptin mimetics, improve glycemic control in diet-induced obese (DIO) mice

We have previously shown that following oral delivery in dodecyl maltoside (DDM), [D-Leu-4]-OB3 and its myristic acid conjugate, MA-[D-Leu-4]-OB3, improved energy balance and glucose homeostasis in genetically obese/diabetic mouse models. More recently, we have provided immunohistochemical evidence indicating that these synthetic peptide leptin mimetics cross the blood-brain barrier and concentrate in the area of the arcuate nucleus of the hypothalamus in normal C57BL/6J and Swiss Webster mice, in genetically obese ob/ob mice, and in diet-induced obese (DIO) mice. In the present study, we describe the effects of oral delivery of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on glycemic control in diet-induced (DIO) mice, a non-genetic rodent model of obesity and its associated insulin resistance, which more closely recapitulates common obesity and diabetes in humans. Male C57BL/6J and DIO mice, 17, 20, and 28 weeks of age, were maintained on a low-fat or high-fat diet and given vehicle (DDM) alone or [D-Leu-4]-OB3 or MA-[D-Leu-4]-OB3 in DDM by oral gavage for 12 or 14 days. Body weight gain, food and water intake, fasting blood glucose, oral glucose tolerance, and serum insulin levels were measured. Our data indicate that (1) [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 restore glucose tolerance in male DIO mice maintained on a high-fat diet to levels comparable to those of non-obese C57BL/6J wild-type mice of the same age and sex maintained on a low-fat diet; and (2) the influence of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on glycemic control appears to be independent of their effects on energy balance. These results suggest that [D-Leu-4]-OB3 and/or MA-[D-Leu-4]-OB3 may have application to the management of the majority of cases of common obesity in humans, a state characterized at least in part, by leptin resistance resulting from a defect in leptin transport across the blood-brain barrier. They further suggest that these small molecule synthetic peptide leptin mimetics, through their influence on glycemic control, may prevent the pre-diabetic state associated with most cases of common obesity from escalating into overt type 2 diabetes mellitus.

P53 modulates hepatic insulin sensitivity through NF-κB and p38/ERK MAPK pathways

Besides its well-established oncosuppressor activity, the role of p53 in regulating metabolic pathways has been recently identified. Nevertheless, the function of p53 with respect to insulin resistance appears highly controversial. To address this issue, we investigated the expression of p53 in experimental model of insulin resistance. Then we used activator (nutlin-3α) and inhibitor (pifithrin-α, PFT-α) of p53 in HepG2 cell. Here we showed that p53 protein level was decreased in the hepatic tissue of high-fat diet-induced insulin resistance mice, genetically diabetic ob/ob mice and palmitate (PA) treated HepG2 cells. And high expression of phosphor-p38, ERK1/2 and nuclear factor kappa B (NF-κB) p65 accompanied with low expression of p53. But activation of p53 with nutlin-3α prevented PA-induced reduction of glucose consumption and suppression of insulin signaling pathways. At the same time, nutlin-3α downregulated the activation of NF-κB, p38 and ERK1/2 pathways upon stimulation with PA. In contrast, inhibition of p53 with PFT-α decreased glucose consumption and suppressed insulin signaling pathway. Furthermore, PFT-α activated NF-κB, p38 and ERK1/2 pathways in HepG2 cells. Overall, these results suggest that p53 is involved in improving insulin sensitivity of hepatic cells via inhibition of mitogen-activated protein kinases (MAPKs) and NF-κB pathways.

Baicalin attenuates non-alcoholic steatohepatitis by suppressing key regulators of lipid metabolism, inflammation and fibrosis in mice

AimsBaicalin (BA), an active flavonoid compound originating from the herb of Scutellaria baicalensis Georgi, has been previously shown to exert anti-inflammation and anti-oxidant effects in liver diseases. However, the potential role of BA in the regulation of non-alcoholic steatohepatitis (NASH) remains elusive. In this study, we newly explored the hepatoprotective effects of BA in MCD diet-induced NASH by ameliorating hepatic steatosis, inflammation, fibrosis and apoptosis. Main methodsNASH was induced in mice fed a methionine and choline-deficient (MCD) diet for 4weeks. The mice were simultaneously treated with or without BA for 4weeks. Serum liver functional markers and inflammatory indicators were assessed by biochemical and ELISA methods, respectively. The livers were histologically examined using H&E, Oil Red O and Masson's trichrome staining methods. The qRT-PCR, IHC and Western blotting assays were applied to analyze mechanisms underlying BA protection. Key findingsBA treatment significantly attenuated MCD diet-induced hepatic lipid accumulation partly through regulating the expression of SREBP-1c, FASN, PPARα and CPT1a. BA treatment dramatically suppressed MCD diet-induced hepatic inflammation, which was associated with decrease in serum TNF-α, IL-1β and MCP-1 production, macrophage influx and suppression of nuclear factor-κB activation. Additionally, BA was proved to prevent liver fibrosis, which appears to be mediated by inhibition of α-SMA, TGF-β1 and Col1A1. Furthermore, BA markedly inhibited hepatocyte apoptosis and cleaved caspase-3 protein expression in MCD diet-induced mice. SignificanceThese results provide a possible basis of the underlying mechanism for the application of BA in the treatment of NASH.

RETRACTED: PRMT1 mediates podocyte injury and glomerular fibrosis through phosphorylation of ERK pathway

Diabetic nephropathy (DN) is characterized by a change of glomerular structure and dysfunction of filtration barrier, which significantly accompanied by podocytes apoptosis and glomerular fibrosis. Angiotensin Ⅱ(Ang Ⅱ) induced activation of ERK1/2 signaling plays important roles in causing apoptosis of podocytes in DN kidneys. Previous studies have shown that PRMT1 have a pro-inflammatory function through activating ERK1/2 signaling pathway during development of chronic pulmonary disease, however, its role in DN development has not been investigated. Here, we detected a higher expression of PRMT1 in podocytes of kidneys from DN patients compared with normal kidneys. High glucose administration induced elevation of PRMT1 expression in podocytes, accompanied with higher phosphorylation of ERK and cleaved caspase-3. AMI-1, a selective inhibitor for PRMT1, could block these effects caused by glucose treatment. Administration of AMI-1 also attenuated apoptosis of podocytes during DN development of high-fatty diet-induced diabetic mice. Epithelial to mesenchymal transition during DN development, which characterized by extracellular matrix deposition in podocytes, was also restrained by AMI-1 treatment. Collectively, this study firstly demonstrated that PRMT1 exert podocyte-injury effects in mouse glomerulus through Ang Ⅱ/ERK pathway, which reveals a potential therapeutic target for DN.

The RBM14/CoAA-interacting, long intergenic non-coding RNA Paral1 regulates adipogenesis and coactivates the nuclear receptor PPAR\u03b3

Adipocyte differentiation and function relies on a network of transcription factors, which is disrupted in obesity-associated low grade, chronic inflammation leading to adipose tissue dysfunction. In this context, there is a need for a thorough understanding of the transcriptional regulatory network involved in adipose tissue pathophysiology. Recent advances in the functional annotation of the genome has highlighted the role of non-coding RNAs in cellular differentiation processes in coordination with transcription factors. Using an unbiased genome-wide approach, we identified and characterized a novel long intergenic non-coding RNA (lincRNA) strongly induced during adipocyte differentiation. This lincRNA favors adipocyte differentiation and coactivates the master adipogenic regulator peroxisome proliferator-activated receptor gamma (PPARγ) through interaction with the paraspeckle component and hnRNP-like RNA binding protein 14 (RBM14/NCoAA), and was therefore called PPARγ-activator RBM14-associated lncRNA (Paral1). Paral1 expression is restricted to adipocytes and decreased in humans with increasing body mass index. A decreased expression was also observed in diet-induced or genetic mouse models of obesity and this down-regulation was mimicked in vitro by TNF treatment. In conclusion, we have identified a novel component of the adipogenic transcriptional regulatory network defining the lincRNA Paral1 as an obesity-sensitive regulator of adipocyte differentiation and function.

Exposure to cigarette smoke disturbs adipokines secretion causing intercellular damage and insulin resistance in high fructose diet-induced metabolic disorder mice

A large amount of fructose intake along with smoking is associated with increased incidence of diseases linked to metabolic syndrome. More research is necessary to understand the complex mechanism that ultimately results in metabolic syndrome and the effect, if any, of high fructose dietary intake and smoking on individual health. In this study, we investigated changes in ER-Golgi network and disturbance to secretion of adipokines induced by cigarette smoking (CS) and excess fructose intake and their contribution to the disruption of metabolic homeostasis. We used high fructose-induced metabolic disorder mice model by feeding them with high fructose diet for 8 weeks. For CS exposure experiment, these mice were exposed to CS for 28 days according to OECD guideline 412. Our results clearly showed that the immune system was suppressed and ER stress was induced in mice with exposure to CS and fed with high fructose. Furthermore, their concentrations of adipokines including leptin and adiponectin were aberrant. Such alteration in secretion of adipokines could cause insulin resistance which may lead to the development of type 2 diabetes.

Salidroside, A Natural Antioxidant, Improves β-Cell Survival and Function via Activating AMPK Pathway.

Aim: The enhanced oxidative stress contributes to progression of type 2 diabetes mellitus (T2DM) and induces β-cell failure. Salidroside is a natural antioxidant extracted from medicinal food plant Rhodiola rosea. This study was aimed to evaluate protective effects of salidroside on β-cells against diabetes associated oxidative stress.Methods and Results: In diabetic db/db and high-fat diet-induced mice, we found salidroside ameliorated hyperglycemia and relieved oxidative stress. More importantly, salidroside increased β-cell mass and β-cell replication of diabetic mice. Mechanism study in Min6 cells revealed that, under diabetic stimuli, salidroside suppressed reactive oxygen species production and restore mitochondrial membrane potential (ΔΨm) via reducing NOX2 expression and inhibiting JNK–caspase 3 apoptotic cascade subsequently to protect β-cell survival. Simultaneously, diabetes associated oxidative stress also activated FOXO1 and triggered nuclear exclusion of PDX1 which resulted in β-cell dysfunction. This deleterious result was reversed by salidroside by activating AMPK-AKT to inhibit FOXO1 and recover PDX1 nuclear localization. The efficacy of salidroside in improving β-cell survival and function was further confirmed in isolated cultured mouse islets. Moreover, the protective effects of salidroside on β-cells against diabetic stimuli can be abolished by an AMPK inhibitor compound C, which indicated functions of salidroside on β-cells were AMPK activation dependent.Conclusion: These results confirmed beneficial metabolic effects of salidroside and identified a novel role for salidroside in preventing β-cell failure via AMPK activation. Our finding highlights the potential value of Rhodiola rosea as a dietary supplement for diabetes control.

Effect of methanol extract of Salviae miltiorrhizae Radix in high-fat diet-induced hyperlipidemic mice

BackgroundThe dried root of Salvia miltiorrhiza, Salviae miltiorrhizae Radix (SR), is one of the most popular medicinal herbs in Asian countries such as China and Korea. In Asian traditional medicine, SR is considered to have a bitter flavor, be slightly cold in nature, and exert therapeutic actions in the heart and liver meridians. Thus, SR has been used to control symptoms related to cardiovascular diseases. Hyperlipidemia is recognized as the main cause of cerebrovascular and heart diseases; consequently, therapeutic strategies for hyperlipidemia have been widely studied. In this study, the effects and molecular targets of methanol extract of SR (SRme) in hyperlipidemic mice were investigated.MethodsHigh-fat diet was fed to mice to induce hyperlipidemia, and measurement of blood cholesterol and triglycerides were conducted to evaluate the effect of SRme on hyperlipidemic mice, and gene expression in mice liver was analyzed to identify key molecules which could be potential targets for developing anti-hyperlipidemic herbal medicines.ResultsThere was no significant effect on the body weight gain of hyperlipidemic mice, but the triglyceride content in blood was significantly reduced by the administration of SRme to hyperlipidemic mice. Proteins such as minichromosome maintenance (Mcm) family which play a key role in DNA replication were identified as molecular targets in the amelioration of hyperlipidemia.ConclusionsSRme ameliorated hyperlipidemia in high-fat diet fed mice by inhibiting increase of blood serum level of triglycerides. And several proteins such as Mcm proteins were deduced to be molecular targets in treating hyperlipidemia.

The α-lipoic acid improves high-fat diet-induced cerebral damage through inhibition of oxidative stress and inflammatory reaction

This study is to clarify the protective role of α-lipoic acid in high-fat diet-induced cerebral damage mice. The mice were divided into 5 groups: normal control group, high-fat diet (HFD) group, low-dose α-lipoic acid group for prevention, high-dose α-lipoic acid group for prevention, and high-dose α-lipoic acid group for treatment. The groups’ weights and blood glucose changes were monitored. We used HE staining to observe morphological changes in the cerebral cortex. The expression levels of the oxidative stress proteins SOD2, catalase, and the inflammatory pathway proteins p-JNK, p-ERK were measured by western blot and immunochemistry. Compared with the control group, the quantity of cortical neurons in the HFD group was decreased, and the samples exhibited retrogression. However, the lipoic acid significantly protected and promoted the cortical neurons survival. Moreover, compared with the HFD group, the expression levels of SOD2 and catalase in the three α-lipoic acid obtained groups were significantly increased. However, the expression levels of the inflammatory pathway proteins p-JNK and p-ERK were significantly decreased. These results indicate that theα-lipoic acid greatly protects the cortical neurons, and inhibited the oxidative stress and inflammatory reactions in the high-fat diet mice.

The role and underlying mechanism of CITED2-mediated insulin signaling pathway in the pathogenesis of diabetic vascular diseases

It is well established that cardiovascular diseases are the leading causes of diabetes-related death. Endothelial dysfunction is widely accepted as the initial and critical factor contributing to diabetic vascular diseases. Insulin resistance may result in vascular endothelial dysfunction, which in turn aggravates diabetic vascular diseases. Via PI3K/Akt signaling pathway, insulin inhibits the function of FoxOs, which, endothelial FoxO1 especially, exerts an important role in atherosclerosis and angiogenesis. In this regard, Wang et al. characterized 10 FoxO1 target genes regulated by insulin in endothelial cells, among which, CITED2, a transcriptional coregulator, was selected to extensively investigate its role and the underlying mechanism of insulin-regulated angiogenesis. CITED2 was significantly increased in vascular endothelial cells in diet-induced mice, ob/ob mice, as well as obese type 2 diabetic patients, all of those models or subjects are accompanied by insulin resistance. In endothelial cells, insulin significantly down-regulated CITED2 expression through insulin receptor-PI3K-Akt-FoxO1 pathway. Inhibition of CITED2 resulted in significant increases in proliferation and tube formation of endothelial cells. Overexpression of CITED2, however, repressed the transactivation of HIF. The study on the mouse model with hind limb ischemia showed that endothelial CITED2 deficiency gave rise to significant increases of expression of endothelin-1, a well-known HIF target gene, induced by ischemia or hypoxia, suggesting that CITED2 inhibited endothelial angiogenesis via suppressing HIF transactivation. In summary, insulin resistance accompanying obesity and type 2 diabetes leads to enhanced CITED2 expression, consequently impairing HIF signaling and proangiogenic capacity in endothelial cells. Inhibition of CITED2 will be a promising novel way to deal with ischemic cardiovascular diseases in diabetic patients. (Chin J Endocrinol Metab, 2017, 33: 637-643) Key words: Endothelial cell; Insulin signaling pathway; FoxO1; CITED2; Angiogenesis

Alfalfa-derived HSP70 administered intranasally improves insulin sensitivity in mice.

Heat shock protein (HSP) 70 is an abundant cytosolic chaperone protein that is deficient in insulin-sensitive tissues in diabetes and unhealthy aging, and is considered a longevity target. It is also protective in neurological disease models. Using HSP70 purified from alfalfa and administered as an intranasal solution, we tested in whether the administration of Hsp70 to diet-induced diabetic mice would improve insulin sensitivity. Both the 10 and 40μg given three times per week for 26days significantly improved the response to insulin. The HSP70 was found to pass into the olfactory bulbs within 4-6hours of a single dose. These results suggest that a relatively inexpensive, plentiful source of HSP70 administered in a simple, non-invasive manner, has therapeutic potential in diabetes.

L-Homocysteine-induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia.

Vascular inflammation, including the expression of inflammatory cytokines in endothelial cells, plays a critical role in hyperhomocysteinaemia-associated vascular diseases. Cathepsin V, specifically expressed in humans, is involved in vascular diseases through its elastolytic and collagenolytic activities. The aim of this study was to determine the effects of cathepsin V on l-homocysteine-induced vascular inflammation. A high methionine diet-induced hyperhomocysteinaemic mouse model was used to assess cathepsin V expression and vascular inflammation. Cultures of HUVECs were challenged with l-homocysteine and the cathepsin L/V inhibitor SID to assess the pro-inflammatory effects of cathepsin V. Transfection and antisense techniques were utilized to investigate the effects of cathepsin V on the dual-specificity protein phosphatases (DUSPs) and MAPK pathways. Cathepsin L (human cathepsin V homologous) was increased in the thoracic aorta endothelial cells of hyperhomocysteinaemic mice; l-homocysteine promoted cathepsin V expression in HUVECs. SID suppressed the activity of cathepsin V and reversed the up-regulation of inflammatory cytokines (IL-6, IL-8 and TNF-α), adhesion and chemotaxis of leukocytes and vascular inflammation induced by l-homocysteine in vivo and in vitro. Increased cathepsin V promoted the degradation of DUSP6 and DUSP7, phosphorylation and subsequent nuclear translocation of ERK1/2, phosphorylation of STAT1 and expression of IL-6, IL-8 and TNF-α. This study has identified a novel mechanism, which shows that l-homocysteine-induced upregulation of cathepsin V mediates vascular endothelial inflammation under high homocysteine condition partly via ERK1/2 /STAT1 pathway. This mechanism could represent a potential therapeutic target in hyperaemia-associated vascular diseases. This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Metabolomics study of the therapeutic mechanism of Schisandra Chinensis lignans in diet-induced hyperlipidemia mice

BackgroundSchisandra, a globally distributed plant, has been widely applied for the treatment of diseases such as hyperlipidemia, fatty liver and obesity in China. In the present work, a rapid resolution liquid chromatography coupled with quadruple-time-of-flight mass spectrometry (RRLC-Q-TOF-MS)-based metabolomics was conducted to investigate the intervention effect of Schisandra chinensis lignans (SCL) on hyperlipidemia mice induced by high-fat diet (HFD).MethodsHyperlipidemia mice were orally administered with SCL (100 mg/kg) once a day for 4 weeks. Serum biochemistry assay of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) was conducted to confirm the treatment of SCL on lipid regulation. Metabolomics analysis on serum samples was carried out, and principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were carried out for the pattern recognition and characteristic metabolites identification. The relative levels of critical regulatory factors of liver lipid metabolism, sterol regulatory element-binding proteins (SREBPs) and its related gene expressions were measured by quantitative real-time polymerase chain reaction (RT-PCR) for investigating the underlying mechanism.ResultsOral administration of SCL significantly decreased the serum levels of TC, TG and LDL-c and increased the serum level of HDL-c in the hyperlipidemia mice, and no effect of SCL on blood lipid levels was observed in control mice. Serum samples were scattered in the PCA scores plots in response to the control, HFD and SCL group. Totally, thirteen biomarkers were identified and nine of them were recovered to the normal levels after SCL treatment. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, the anti-hyperlipidemia mechanisms of SCL may be involved in the following metabolic pathways: tricarboxylic acid (TCA) cycle, synthesis of ketone body and cholesterol, choline metabolism and fatty acid metabolism. Meanwhile, SCL significantly inhibited the mRNA expression level of hepatic lipogenesis genes such as SREBP-1c, fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), and decreased the mRNA expression of liver X receptor α (LXRα). Moreover, SCL also significantly decreased the expression level of SREBP-2 and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in the liver of hyperlipidemia mice.ConclusionAnti-hyperlipidemia effect of SCL was confirmed by both serum biochemistry and metabolomics analysis. The mechanism may be related to the down-regulation of LXRα/SREBP-1c/FAS/ACC and SREBP2/HMGCR signaling pathways.

Free form astaxanthin from yeast Phaffia rhodozyma fermentation reduces plasmatic triglycerides in a pre-obesity diet-induced dyslipidaemia mouse model

Previous work have indicated a lipid-lowering effect of esterified astaxanthin (AX) from algae Haematococcus pluvialis. The aim of this study was to set up a murine model of pre-obesity diet-induced dyslipidaemia to investigate the lipid-lowering effect of free-form AX from yeast Phaffia rhodozyma fermentation. After 6 weeks on high-fat diet, 32 male C57BL/6 mice were divided into 4 groups fed (1) a standard or (2–4) a high-fat diet (HFD) supplemented or not with AX at 0.03% or 0.06% for 8 weeks. Animals were anesthetized and sacrificed and biological samples (plasma and internal organs) collected and stored at −80°C. The plasma concentrations of triglycerides and cholesterol were determined and gene expression measured for markers of energy metabolism in the liver and adipose tissue. Statistical analyses were performed using SPSS software and the significance set at p<0.05. Primary results showed a lowering effect on the triglyceride levels (−35 to −45%, p<0.05) in the groups fed high-fat-diet supplemented with AX, but no effect on cholesterol. Genetic expression showed a modulation of various mechanisms of energy regulation, from lipid transporters to beta-oxidation pathways and insulin resistance. The associated effects could also have implications for the prevention of metabolic syndrome.

Plantago asiatica L. Seed Extract Improves Lipid Accumulation and Hyperglycemia in High-Fat Diet-Induced Obese Mice.

Obesity and its common association with type 2 diabetes, dyslipidemia, and cardiovascular diseases are worldwide epidemics. Currently, to prevent or treat obesity and associated metabolic disorders, herbal dietary supplements or medicines have attracted more and more attention owing to their relative effectiveness with fewer significant side effects. We investigate the therapeutic effects and underlying mechanisms of Plantago asiatica L. seed extract (PSE) on obesity and associated metabolic disorders in high-fat (HF) diet-induced mice. Our results displayed that PSE did not modify food intake or body weight but decreased abdominal white adipose tissue ratio, white/brown adipocyte size, serum total cholesterol, triglyceride (TG), low density lipoprotein cholesterol, free fatty acid, and hepatic TG concentrations when compared with the HF group. The levels of fasting blood glucose and glucose tolerance were improved in the PSE group when compared with the HF group. Furthermore, PSE upregulated mRNA expressions of peroxisome proliferator activated receptors (PPARs) and target genes related to fatty acid metabolism and energy expenditure in liver and adipose tissue of obese mice when compared with the HF group. PSE treatment effectively improved lipid and glucose metabolism in HF diet-induced obese mice. These effects might be attributed to the upregulation of PPAR signaling

Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice

This study assessed the metabolic and neuroprotective actions of the sodium glucose cotransporter-2 inhibitor dapagliflozin in combination with the GLP-1 agonist liraglutide in dietary-induced diabetic mice. Mice administered low-dose streptozotocin (STZ) on a high-fat diet received dapagliflozin, liraglutide, dapagliflozin-plus-liraglutide (DAPA-Lira) or vehicle once-daily over 28 days. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin sensitivity, hormone and biochemical analysis, dual-energy X-ray absorptiometry densitometry, novel object recognition, islet and brain histology were examined. Once-daily administration of DAPA-Lira resulted in significant decreases in body weight, fat mass, glucose and insulin concentrations, despite no change in energy intake. Similar beneficial metabolic improvements were observed regarding glucose tolerance, insulin sensitivity, HOMA-IR, HOMA-β, HbA1c and triglycerides. Plasma glucagon, GLP-1 and IL-6 levels were increased and corticosterone concentrations decreased. DAPA-Lira treatment decreased alpha cell area and increased insulin content compared to dapagliflozin monotherapy. Recognition memory was significantly improved in all treatment groups. Brain histology demonstrated increased staining for doublecortin (number of immature neurons) in dentate gyrus and synaptophysin (synaptic density) in stratum oriens and stratum pyramidale. These data demonstrate that combination therapy of dapagliflozin and liraglutide exerts beneficial metabolic and neuroprotective effects in diet-induced diabetic mice. Our results highlight important personalised approach in utilising liraglutide in combination with dapagliflozin, instead of either agent alone, for further clinical evaluation in treatment of diabetes and associated neurodegenerative disorders.

Encapsulation of 16-Hydroxycleroda-3,13-Dine-16,15-Olide in Mesoporous Silica Nanoparticles as a Natural Dipeptidyl Peptidase-4 Inhibitor Potentiated Hypoglycemia in Diabetic Mice.

Natural supplements comprise good efficacy with less adverse effects as against diabetic therapy, but their advancement as anti-diabetic agents is unsatisfactory with regard to the delivery system. Dipeptidyl peptidase-4 (DPP4)/CD26) can degrade glucagon-like pepetide-1 (GLP-1) which renders a decrease of blood glucose levels. 16-hydroxycleroda-3,13-dine-16,15-olide (HCD) extracted from Polyalthia longifolia, exhibits numerous medicinal potentials including hypoglycemic potential. On consideration of HCD application, the bioavailability is affected by low solubility. Extended experiments of anti-diabetic efficacy confirmed HCD biocompatible with mesoporous silica nanoparticles (MSNs) encapsulation resulted in a sustained release property in delivering HCD for the inhibition of DPP4 via the activity and protein levels of DPP4 analysis. In the enzymatic activity assay, MSN-HCD directly changed DPP4 activity. Moreover, MSN-HCD nanoparticles were treated with Caco-2 cells and the protein levels of DPP4 determined within the cells. The results revealed that MSN-HCD caused reduction of DPP4 activity in a time- and dose-dependent fashion. Orally administered MSN-HCD in diet-induced diabetic mice alleviated blood glucose via an oral glucose tolerance test. In addition, administration of MSN-HCD for five weeks revealed that the biochemical cues such as pyruvate transaminase (GPT), glutamate oxaloacetate transaminase (GOT), triglycerides (TG), cholesterol (CHO), and glycated hemoglobin (HbA1c) in mice were commendable as further confirmation of MSN-HCD efficacy and less adverse effects in down-regulation of hyperglycemia. Furthermore, this formulation effectively controlled blood glucose and significantly decreased the body weight of mice, suggesting that MSN-HCD exerts natural DPP4 inhibitor as a potential clinical drug for the treatment of diabetes.