Glucose Tolerance In HFD-fed Mice Research Articles

TLR7 activation by imiquimod worsens glycemic control in female FVB/N mice consuming a high-fat diet.

Toll-like receptor-7 (TLR7) activation promotes autoimmunity, and metabolic syndrome (MetS) is a common comorbidity in patients with autoimmune disease. We previously demonstrated hyperinsulinemia in TLR7 agonist imiquimod (IMQ)-treated, high-fat diet (HFD)-fed female C57BL/6 mice. Since mouse strains differ in susceptibility to MetS and target organ damage, this study investigated whether 12 weeks of exposure to HFD and IMQ promoted MetS, autoimmunity, and target organ damage in female FVB/N mice. Supporting early-stage autoimmunity, spleen-to-tibia ratio, and anti-nuclear antibodies (ANA) were significantly increased by IMQ. No significant effect of IMQ on urinary albumin excretion or left ventricular hypertrophy was observed. HFD increased liver-to-tibia ratio, which was further exacerbated by IMQ. HFD increased fasting blood glucose levels at the end of 12 weeks, but there was no significant effect of IMQ treatment on fasting blood glucose levels at 6 or 12 weeks of treatment. However, oral glucose tolerance testing at 12 weeks revealed impaired glucose tolerance in HFD-fed mice compared to control diet mice together with IMQ treatment exacerbating the impairment. Accordingly, these data suggest TLR7 activation also exacerbates HFD-induced dysregulation of glucose handling FVB/N mice, supporting the possibility that endogenous TLR7 activation may contribute to dysglycemia in patients with autoimmune disease.

Dietary Tomato Pectin Attenuates Hepatic Insulin Resistance and Inflammation in High-Fat-Diet Mice by Regulating the PI3K/AKT Pathway

Chronic metabolic disease is a serious global health issue, which is accompanied by impaired insulin resistance. Tomato pectin (TP) is a naturally soluble complex hetero-polysaccharide with various biological functions. However, the impact of TP on hepatic insulin resistance in a high-fat diet (HFD) and its potential mechanism remains largely unknown. The results revealed that TP treatment significantly decreased the liver weight, hepatic fat accumulation and hepatic injury in HFD-fed mice. TP also improved fasting blood glucose levels and glucose tolerance in HFD-fed mice. The underlying mechanisms involved in the inflammation, oxidative stress and insulin signaling in the liver were also investigated by RT-qPCR and western blot, which indicated that TP ameliorated hepatic insulin resistance by regulating the PI3K/AKT/GSK-3β pathway, increasing the expression of GLUT4, decreasing the expression of PECK and G6P as well as restoring antioxidant activities and suppressing the inflammation statues in HFD-fed mice. Our data showed that dietary TP has profound effects on hepatic insulin resistance, inflammation and oxidative stress, demonstrating that TP might be a promising therapeutic agent against insulin resistance and related chronic metabolic disease.

Glucokinase activator improves glucose tolerance and induces hepatic lipid accumulation in mice with diet-induced obesity

Background and aimsType 2 diabetes mellitus remains a substantial medical problem with increasing global prevalence. Pharmacological research is becoming increasingly focused on personalized treatment strategies. Drug development based on glucokinase (GK) activation is an important strategy for lowering blood glucose. This study aimed to investigate the effect of GK activation on glucose and lipid metabolism in diet-induced obese mice. Materials and methodsMice were fed with a high-fat diet (HFD) for 16 weeks to induce obesity, followed by a GK activator (GKA, AZD1656) or vehicle treatment by gavage for 4 weeks. The effect of GKA treatment on glucose metabolism was evaluated using glucose and insulin tolerance tests. Hepatic lipid accumulation was assessed by hematoxylin and eosin staining, Oil Red O staining, and transmission electron microscopy. The underlying mechanism of GK activation in glucose and lipid metabolism in the liver was studied using transcriptomic analysis, with a mechanistic study in mouse livers in vivo and AML12 cells in vitro. ResultsGK activation by GKA treatment improved glucose tolerance in HFD-fed mice while increasing hepatic lipid accumulation. Transcriptomic analysis of liver tissues indicated the lipogenesis and protein kinase RNA-like endoplasmic reticulum kinase (PERK)-unfolded protein response (UPR) pathway activations in GKA-treated HFD-fed mice. Inhibition of the ACC activity, which is an important protein in lipogenesis, attenuated GKA treatment-induced lipid accumulation and PERK-UPR activation in vitro. ConclusionsGK activation improved glucose tolerance and insulin sensitivity while inducing hepatic lipid accumulation by increasing the lipogenic gene expression, which subsequently activated the hepatic PERK-UPR signaling pathway.

Sulfosuccinimidyl oleate ameliorates the high-fat diet-induced obesity syndrome by reducing intestinal and hepatic absorption.

Background: A high-fat Western diet is a risk factor for obesity and steatosis. Reducing intestinal absorption of a high-fat diet (HFD) is a feasible strategy to control obesity. Sulfosuccinimidyl oleate (SSO) inhibits intestinal fatty acid transport. Therefore, the aim of this study was to investigate the effects of SSO on HFD-induced glucose and lipid metabolism in mice and its possible underlying mechanisms. Methods: Male C57/BL were fed a HFD (60% calories) for 12weeks and were administered an oral dose of SSO (50mg/kg/day). The expression of lipid absorption genes (CD36, MTTP, and DGAT1) and the serum levels of triglycerides (TGs), total cholesterol (TC), and free fatty acids (FFAs) were detected. Lipid distribution in the liver was detected by oil red and hematoxylin and eosin staining. In addition, serum levels of inflammatory factors, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured to detect side effects. Results: SSO was effective in the treatment of obesity and metabolic syndrome induced by HFD in mice. It attenuated the assembly of intestinal epithelial chylomicrons by inhibiting intestinal epithelial transport and absorption of fatty acids, thereby reducing the gene expression levels of MTTP and DGAT1, resulting in decreased plasma TG and FFA levels. At the same time, it inhibited the transport of fatty acids in the liver and improved the steatosis induced by a HFD. The results of oil red staining showed that SSO treatment can reduce lipid accumulation in the liver by 70%, with no drug-induced liver injury detected on the basis of interleukin-6, C-reactive protein, ALT, and AST levels. In addition, SSO treatment significantly improved insulin resistance, decreased fasting blood glucose levels, and improved glucose tolerance in HFD-fed mice. Conclusion: SSO is effective in the treatment of obesity and metabolic syndrome induced by a HFD in mice. SSO reduces intestinal fatty acid absorption by reducing the inhibition of intestinal CD36 expression, followed by decreased TG and FFA levels, which attenuates HFD-induced fatty liver.

Pancreas-derived DPP4 is not essential for glucose homeostasis under metabolic stress

Mice systemically lacking dipeptidyl peptidase-4 (DPP4) have improved islet health, glucoregulation, and reduced obesity with high-fat diet (HFD) feeding compared to wild-type mice. Some, but not all, of this improvement can be linked to the loss of DPP4 in endothelial cells (ECs), pointing to the contribution of non-EC types. The importance of intra-islet signaling mediated by α to β cell communication is becoming increasingly clear; thus, our objective was to determine if β cell DPP4 regulates insulin secretion and glucose tolerance in HFD-fed mice by regulating the local concentrations of insulinotropic peptides. Using β cell double incretin receptor knockout mice, β cell- and pancreas-specific Dpp4-/- mice, we reveal that β cell incretin receptors are necessary for DPP4 inhibitor effects. However, although β cell DPP4 modestly contributes to high glucose (16.7mM)-stimulated insulin secretion in isolated islets, it does not regulate whole-body glucose homeostasis.

The human symbiont Bacteroides thetaiotaomicron promotes diet-induced obesity by regulating host lipid metabolism.

The gut microbiome plays an important role in lipid metabolism. Consumption of a high-fat diet (HFD) alters the bacterial communities in the gut, leading to metabolic disorders. Several bacterial species have been associated with diet-induced obesity, nonalcoholic fatty liver disease, and metabolic syndrome. However, the mechanisms underlying the control of lipid metabolism by symbiotic bacteria remain elusive. Here, we show that the human symbiont Bacteroides thetaiotaomicron aggravates metabolic disorders by promoting lipid digestion and absorption. Administration of B. thetaiotaomicron to HFD-fed mice promoted weight gain, elevated fasting glucose levels, and impaired glucose tolerance. Furthermore, B. thetaiotaomicron treatment upregulated the gene expression of the fatty acid transporter and increased fatty acid accumulation in the liver. B. thetaiotaomicron inhibits expression of the gene encoding a lipoprotein lipase inhibitor, angiopoietin-like protein 4 (ANGPTL4), thereby increasing lipase activity in the small intestine. In particular, we found that B. thetaiotaomicron induced the expression of hepcidin, the master regulator of iron metabolism and an antimicrobial peptide, in the liver. Hepcidin treatment resulted in a decrease in ANGPTL4 expression in Caco-2 cells, whereas treatment with an iron chelator restored ANGPTL4 expression in hepcidin-treated cells. These results indicate that B. thetaiotaomicron-mediated regulation of iron storage in intestinal epithelial cells may contribute to increased fat deposition and impaired glucose tolerance in HFD-fed mice.

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.

Bifidobacterium longum counters the effects of obesity: Partial successful translation from rodent to human.

BackgroundThe human gut microbiota has emerged as a key factor in the development of obesity. Certain probiotic strains have shown anti-obesity effects. The objective of this study was to investigate whether Bifidobacterium longum APC1472 has anti-obesity effects in high-fat diet (HFD)-induced obese mice and whether B. longum APC1472 supplementation reduces body-mass index (BMI) in healthy overweight/obese individuals as the primary outcome. B. longum APC1472 effects on waist-to-hip ratio (W/H ratio) and on obesity-associated plasma biomarkers were analysed as secondary outcomes.MethodsB. longum APC1472 was administered to HFD-fed C57BL/6 mice in drinking water for 16 weeks. In the human intervention trial, participants received B. longum APC1472 or placebo supplementation for 12 weeks, during which primary and secondary outcomes were measured at the beginning and end of the intervention.FindingsB. longum APC1472 supplementation was associated with decreased bodyweight, fat depots accumulation and increased glucose tolerance in HFD-fed mice. While, in healthy overweight/obese adults, the supplementation of B. longum APC1472 strain did not change primary outcomes of BMI (0.03, 95% CI [-0.4, 0.3]) or W/H ratio (0.003, 95% CI [-0.01, 0.01]), a positive effect on the secondary outcome of fasting blood glucose levels was found (-0.299, 95% CI [-0.44, -0.09]).InterpretationThis study shows a positive translational effect of B. longum APC1472 on fasting blood glucose from a preclinical mouse model of obesity to a human intervention study in otherwise healthy overweight and obese individuals. This highlights the promising potential of B. longum APC1472 to be developed as a valuable supplement in reducing specific markers of obesity.FundingThis research was funded in part by Science Foundation Ireland in the form of a Research Centre grant (SFI/12/RC/2273) to APC Microbiome Ireland and by a research grant from Cremo S.A.

SAT-LB106 Metabolic and Brown Adipose Tissue-Specific Effects of the Novel Non-Steroidal Mineralocorticoid Receptor Antagonist Finerenone in a Mouse Model of Diet-Induced Obesity

In this work we studied the metabolic effects of the novel non-steroidal MR antagonist Finerenone (FIN) in mice fed a high-fat diet (HFD, 60% kcal as fat). We also investigated the signaling pathways underlying the beneficial metabolic effects of MR antagonism. After 3 months of HFD, mice treated with FIN showed an improvement of glucose tolerance compared to control mice as shown by intraperitoneal glucose tolerance tests. Despite this metabolic improvement, FIN-treated mice did not show a reduction in body weight compared to control mice. In order to elucidate the favourable effect of FIN on glucose tolerance we performed histological and molecular analyses at level of different adipose depots. We did not observe significant differences in classical white adipose depots (subcutaneous and visceral) between control and FIN-treated mice. Interestingly, interscapular brown adipose tissue (iBAT) of FIN-treated mice showed an increased multilocularity and a reduced size of lipid droplets, suggesting an iBAT-specific effect of FIN. We than analyzed mRNA and protein expression of uncoupling protein 1 (UCP-1) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PCG1-alpha), showing a significant increase of both markers at iBAT level in FIN-treated mice. Furthermore, leptin and adenylate cyclase 5 (Adyc5) (specific white adipose tissue markers) mRNA expression was reduced at level of iBAT in FIN-treated mice. Finally, we demonstrated that FIN-induced MR antagonism determined an increased activation of AMP-activated protein kinase (AMPK) which, in turn, stimulated adipose triglyceride lipase (ATGL) activity, with subsequent up-regulation of genes involved in fatty acids oxidation, tricarboxylic acid cycle and thermogenesis, in iBAT. In summary, our study shows that FIN protects from iBAT dysfunction and improves glucose tolerance in HFD-fed mice. Importantly, FIN effects on iBAT are mediated by a MR-AMPK-ATGL-UCP-1 signaling cascade. Therefore, MR antagonism by FIN in clinical settings might offer metabolic advantages, on top of its anti-fibrotic action, in multi-morbid cardiorenal patients.

Receptor for advanced glycation end products modulates oxidative stress and mitochondrial function in the soleus muscle of mice fed a high-fat diet.

Accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) are implicated in the progression of pathologies associated with aging, chronic inflammation, diabetes, and cellular stress. RAGE activation is also implicated in cardiovascular complications of type 2 diabetes, such as nephropathy, retinopathy, accelerated vascular diseases, and cardiomyopathy. Studies investigating the effects of AGE/RAGE axis activation on skeletal muscle oxidative stress and metabolism are more limited. We tested whether a high-fat diet (HFD) would alter circulating AGE concentration, skeletal muscle AGE accumulation, and oxidative stress in wild-type and RAGE-deficient mice. The physiological significance of AGE/RAGE axis activation in HFD-fed mice was evaluated in terms of exercise tolerance and mitochondrial respiratory chain complex activity. HFD elicited adiposity, abnormal fat distribution, and oral glucose intolerance. HFD also induced accumulation of Nε-carboxymethyl-l-lysine, increased protein carbonyl levels, and impaired respiratory chain complex activity in soleus muscle. Ablation of RAGE had no effects on weight gain and oral glucose tolerance in HFD-fed mice. Peak aerobic capacity and mitochondrial cytochrome-c oxidase activity were restored in HFD-fed RAGE-/- mice. We concluded that RAGE signaling plays an important role in skeletal muscle homeostasis of mice under metabolic stress. Novelty HFD in mice induces accumulation of AGEs, oxidative stress, and mitochondrial dysfunction in the soleus muscle. RAGE, the multi-ligand receptor for AGEs, modulates oxidative stress and mitochondrial electron transport chain function in the soleus muscle of HFD-fed mice.

Beneficial effects of a chlorophyll-rich spinach extract supplementation on prevention of obesity and modulation of gut microbiota in high-fat diet-fed mice

Abstract Obesity has become a serious public health threat worldwide and recent evidence demonstrates that gut microbiota plays an important role in obesity. To the best of our knowledge, no research has been presented demonstrating the effects of a chlorophyll-rich spinach extract supplementation on obesity and associated changes in gut microflora of mice. The present study found that a chlorophyll-rich spinach extract supplementation effectively alleviated body weight gain and low-grade inflammation, and improved the glucose tolerance in HFD-fed mice (p

Blocking Ca2+ Channel β3 Subunit Reverses Diabetes

SummaryVoltage-gated Ca2+ channels (Cav) are essential for pancreatic beta cell function as they mediate Ca2+ influx, which leads to insulin exocytosis. The β3 subunit of Cav (Cavβ3) has been suggested to regulate cytosolic Ca2+ ([Ca2+]i) oscillation frequency and insulin secretion under physiological conditions, but its role in diabetes is unclear. Here, we report that islets from diabetic mice show Cavβ3 overexpression, altered [Ca2+]i dynamics, and impaired insulin secretion upon glucose stimulation. Consequently, in high-fat diet (HFD)-induced diabetes, Cavβ3-deficient (Cavβ3−/−) mice showed improved islet function and enhanced glucose tolerance. Normalization of Cavβ3 expression in ob/ob islets by an antisense oligonucleotide rescued the altered [Ca2+]i dynamics and impaired insulin secretion. Importantly, transplantation of Cavβ3−/− islets into the anterior chamber of the eye improved glucose tolerance in HFD-fed mice. Cavβ3 overexpression in human islets also impaired insulin secretion. We thus suggest that Cavβ3 may serve as a druggable target for diabetes treatment.

Mangiferin ameliorates fatty liver via modulation of autophagy and inflammation in high-fat-diet induced mice

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally. The progression of NAFLD is complex and associated with inflammation, oxidative stress, autophagy, endoplasmic reticulum stress, and insulin resistance. Mangiferin, a natural C-glucosyl xanthone, has been reported to show multiple biological activities. The aim of this study was to investigate the therapeutic effect of mangiferin on NAFLD and the underlying molecular mechanism. We established a mouse model of NAFLD using a high-fat diet (HFD), and injected the mice with different doses of mangiferin (15, 30, and 60mg/kg, intraperitoneal) for 12 weeks. Liver tissue was assessed to evaluate changes in inflammatory responses, autophagy, and glycolipid metabolism. We found that mangiferin decreased body weight, as well as the levels of triglycerides and total cholesterol in plasma and the liver. It also increased glucose tolerance in HFD-fed mice. In addition, mangiferin decreased inflammatory responses by inhibiting the activities of nuclear factor kappa B and c-Jun N-terminal kinase, regulated autophagy via the AMP-activated protein kinase/mechanistic target of rapamycin signaling pathway, and improved glycolipid metabolism via modulation of the insulin receptor substrate/phosphoinositide 3-kinase/protein kinase B signaling pathway. This study demonstrated that mangiferin significantly ameliorates NAFLD development in HFD-fed mice by inhibiting inflammatory responses, activating autophagy, and improving glycolipid metabolism.

A casein hydrolysate protects mice against high fat diet induced hyperglycemia by attenuating NLRP3 inflammasome-mediated inflammation and improving insulin signaling.

Activation of the nod-like receptor protein 3 (NLRP3) inflammasome is required for IL-1β release and is a key component of obesity-induced inflammation and insulin resistance. This study hypothesized that supplementation with a casein hydrolysate (CH) would attenuate NLRP3 inflammasome mediated IL-1β secretion in adipose tissue (AT) and improve obesity-induced insulin resistance. J774.2 macrophages were LPS primed (10 ng/mL) and stimulated with adenosine triphosphate (5 mM) to assess NLRP3 inflammasome activity. Pretreatment with CH (1 mg/mL; 48 h) reduced caspase-1 activity and decreased IL-1β secretion from J774.2 macrophages in vitro. 3T3-L1 adipocytes cultured with conditioned media from CH-pretreated J774.2 macrophages demonstrated increased phosphorylated (p)AKT expression and improved insulin sensitivity. C57BL/6JOLaHsd mice were fed chow or high fat diet (HFD) for 12 wk ± CH resuspended in water (0.5% w/v). CH supplementation improved glucose tolerance in HFD-fed mice as determined by glucose tolerance test. CH supplementation increased insulin-stimulated pAKT protein levels in AT, liver, and muscle after HFD. Cytokine secretion was measured from AT and isolated bone marrow macrophages cultured ex vivo. CH supplementation attenuated IL-1β, tumor necrosis factor alpha (TNF-α) and IL-6 secretion from AT and IL-1β, IL-18, and TNF-α from bone marrow macrophages following adenosine triphosphate stimulation ex vivo. This novel CH partially protects mice against obesity-induced hyperglycemia coincident with attenuated IL-1β secretion and improved insulin signaling.

The inhibiting effect of the Coptis chinensis polysaccharide on the type II diabetic mice.

In this paper, we investigated the effects of Coptis chinensis polysaccharide (CCP) on hyperglycemia and glucose intolerance in high-fat diet (HFD)-induced diabetic C57BL/6J mice. CCP was prepared by extraction from Coptis chinensis and oral given to the mice. C57BL/6J mice in each of the 5 groups (eight mice per group) were given either the normal diet (ND) (D12450B, 10% kcal% fat; Research diet, New Brunswick, NJ, USA), HFD (D12451, 45% kcal% fat; Research diet, New Brunswick, NJ, USA), or HFD with CCP of differing hardness (500, 1000, and 2000ppm) for 20 weeks. Mice given an HFD with CCP showed lowered fasting plasma glucose levels compared to HFD-fed mice. Oral and intraperitoneal glucose tolerance tests showed that CCP improves impaired glucose tolerance in HFD-fed mice. Histopathological evaluation of the pancreas showed that CCP recovers the size of the pancreatic islets of Langerhans, and increases the secretion of insulin and glucagon in HFD-fed mice. Quantitative reverse transcription polymerase chain reaction results revealed that the expression of hepatic genes involved in glucogenesis, glycogenolysis and glucose oxidation were suppressed, while those in glucose uptake, β-oxidation, and glucose oxidation in muscle were increased in mice fed HFD with CCP. CCP increased AMP-dependent kinase (AMPK) phosphorylation in 3T3-L1 pre- and mature adipocytes and improved impaired AMPK phosphorylation in the muscles and livers of HFD-induced diabetic mice. CCP stimulated phosphoinositol-3-kinase and AMPK pathway-mediated glucose uptake in 3T3-L1 adipocytes. Taken together, these results suggest that CCP has potential as an anti-diabetic agent, given its ability to suppress hyperglycemia and improve glucose intolerance by increasing glucose uptake.

Fish oil ameliorates trimethylamine N-oxide-exacerbated glucose intolerance in high-fat diet-fed mice.

Trimethylamine N-oxide (TMAO), a component commonly present in seafood, has been found to have a harmful impact on glucose tolerance in high-fat diet (HFD)-fed mice. However, seafood also contains fish oil (FO), which has been shown to have beneficial effects on metabolism. Here, we investigated the effect of FO on TMAO-induced impaired glucose tolerance in HFD-fed mice. Male C57BL/6 mice were randomly assigned to the high fat (HF), TMAO, and fish oil groups. The HF group was fed a diet containing 25% fat, the TMAO group was fed the HFD plus 0.2% TMAO, and the FO group was fed the HFD plus 0.2% TMAO and 2% fish oil for 12 weeks. After 10 weeks of feeding, oral glucose tolerance tests were performed. Dietary FO improved the fasting glucose level, the fasting insulin level, HOMA-IR value, QUICKI score and ameliorated TMAO-induced exacerbated impaired glucose tolerance in HFD-fed mice. These effects were associated with the expression of genes related to the insulin signalling pathway, glycogen synthesis, gluconeogenesis, and glucose transport in peripheral tissues. Dietary fish oil also decreased TMAO-aggravated adipose tissue inflammation. Our results suggested that dietary FO ameliorated TMAO-induced impaired glucose tolerance, insulin signal transduction in peripheral tissue, and adipose tissue inflammation in HFD-fed mice.

Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet

Trimethylamine N-oxide (TMAO) is an oxidation product of trimethylamine (TMA) and is present in many aquatic foods. Here, we investigated the effects of TMAO on glucose tolerance in high fat diet (HFD)-fed mice. Male C57BL/6 mice were randomly assigned to the control, high fat (HF), and TMAO groups. The HF group was fed a diet containing 25% fat, and the TMAO group was fed the HFD plus 0.2% TMAO for 4 weeks. After 3 weeks of feeding, oral glucose tolerance tests were performed. Dietary TMAO increased fasting insulin levels and homeostasis model assessment-estimated insulin resistance (HOMA-IR) and exacerbated the impaired glucose tolerance in HFD-fed mice. These effects were associated with the expression of genes related to the insulin signal pathway, glycogen synthesis, gluconeogenesis and glucose transport in liver. mRNA levels of the pro-inflammatory cytokine MCP-1 increased significantly and of the anti-inflammatory cytokine IL-10 greatly decreased in adipose tissue. Our results suggest that dietary TMAO exacerbates impaired glucose tolerance, obstructs the hepatic insulin signaling pathway, and causes adipose tissue inflammation in mice fed a high fat diet.

Anti-Diabetic Effect of Balanced Deep-Sea Water and Its Mode of Action in High-Fat Diet Induced Diabetic Mice

In this study, we investigated the effects of balanced deep-sea water (BDSW) on hyperglycemia and glucose intolerance in high-fat diet (HFD)-induced diabetic C57BL/6J mice. BDSW was prepared by mixing deep-sea water (DSW) mineral extracts and desalinated water to give a final hardness of 500–2000. Mice given an HFD with BDSW showed lowered fasting plasma glucose levels compared to HFD-fed mice. Oral and intraperitoneal glucose tolerance tests showed that BDSW improves impaired glucose tolerance in HFD-fed mice. Histopathological evaluation of the pancreas showed that BDSW recovers the size of the pancreatic islets of Langerhans, and increases the secretion of insulin and glucagon in HFD-fed mice. Quantitative reverse transcription polymerase chain reaction results revealed that the expression of hepatic genes involved in glucogenesis, glycogenolysis and glucose oxidation were suppressed, while those in glucose uptake, β-oxidation, and glucose oxidation in muscle were increased in mice fed HFD with BDSW. BDSW increased AMP-dependent kinase (AMPK) phosphorylation in 3T3-L1 pre- and mature adipocytes and improved impaired AMPK phosphorylation in the muscles and livers of HFD-induced diabetic mice. BDSW stimulated phosphoinositol-3-kinase and AMPK pathway-mediated glucose uptake in 3T3-L1 adipocytes. Taken together, these results suggest that BDSW has potential as an anti-diabetic agent, given its ability to suppress hyperglycemia and improve glucose intolerance by increasing glucose uptake.

Selective Pharmacological Inhibition of S6K1 Improves Glucose Metabolism In Vitro and In Vivo in High-Fat-Fed Obese Mice

The mammalian target of rapamycin (RAP) complex 1 (mTORC1) and its downstream effector S6K (p70 S6 kinase) have emerged as critical signaling components in the development of obesity-linked insulin resistance (IR). The pathway is triggered by nutrients and operates a negative feedback loop toward the IRS/PI3K/Akt axis to downregulate insulin's metabolic actions. Recently, some studies have showed that S6K knockdown improves insulin sensitivity in mice fed a high-fat diet (HFD). Here, we tested whether chronic pharmacological S6K1 inhibition can improve insulin sensitivity and glucose metabolism. Mice fed HFD (12 weeks) were treated chronically (7 days) with PF-4708671 (S6K1 inhibitor) (35 mg/kg/day) or RAP (2 mg/kg/day). No significant changes in body weight or food intake were observed. PF-4708671 reduced fasting glucose and improved glucose tolerance in HFD-fed mice, whereas RAP induced fasting hyperglycemia, hyperinsulinemia and glucose intolerance in the same model. Liver, eWAT and muscle tissues were analyzed for insulin signalling and we found that the S6K1 inhibitor increases AKT phosphorylation in HFD mouse while RAP amplifies the disruptive effects of HFD on insulin signalling. In vitro, we observed that hepatocytes (FAO) chronically treated with PF-4708671 (10 uM) had lower basal glucose production, but did not further increase insulin-mediated suppression of glucose production. In L6 myotubes, PF-4708671 was able to increase both basal- and insulin-mediated glucose uptake. Conversely, chronic RAP (25nM) treatment increased hepatic glucose production and decreased glucose uptake. These results suggest that pharmacological S6K1 inhibition may represent a potential therapeutic strategy for combating IR and type 2 diabetes.