Intergenerational inheritance induced by a high-fat diet causes hyperphagia and reduced hypothalamic sensitivity to insulin and leptin in the second-generation of rats.

OBJECTIVE: The aim was to investigate the intergenerational inheritance induced by a high-fat diet on sensitivity to insulin and leptin in the hypothalamic control of satiety in second-generation offspring, which were fed a control diet. METHODS: Progenitor rats were fed a high-fat or a control diet for 59 d until weaning. The first-generation and second-generation offspring were fed the control diet until 90 d of age. Body mass and adiposity index of the progenitors fed the high-fat diet and the second-generation offspring from progenitors fed the high-fat diet were evaluated as were the gene expression of DNA methyltransferase 3a, angiotensin-converting enzyme type 2, angiotensin II type 2 receptor, insulin and leptin signaling pathway (insulin receptor, leptin receptor, insulin receptor substrate 2, protein kinase B, signal transducer and transcriptional activator 3, pro-opiomelanocortin, and neuropeptide Agouti-related protein), superoxide dismutase activity, and the concentration of carbonyl protein and satiety-regulating neuropeptides, pro-opiomelanocortin and neuropeptide Agouti-related protein, in the hypothalamus. RESULTS: The progenitor group fed a high-fat diet showed increased insulin resistance and reduced insulin-secreting beta-cell function and reduced food intake, without changes in caloric intake. The second-generation offspring from progenitors fed a high-fat diet, compared with second-generation offspring from progenitors fed a control diet group, had decreased insulin-secreting beta-cell function and increased food and caloric intake, insulin resistance, body mass, and adiposity index. Furthermore, second-generation offspring from progenitors fed a high-fat diet had increased DNA methyltransferase 3a, neuropeptide Agouti-related protein, angiotensin II type 1 receptor, and nicotinamide adenine dinucleotide phosphate oxidase p47phox gene expression, superoxide dismutase activity, and neuropeptide Agouti-related protein concentration in the hypothalamus. In addition, there were reduced in gene expression of the insulin receptor, leptin receptor, insulin receptor substrate 2, pro-opiomelanocortin, angiotensin II type 2 receptor, angiotensin-converting enzyme type 2, and angiotensin-(1-7) receptor and pro-opiomelanocortin concentration in the second-generation offspring from progenitors fed the high-fat diet. CONCLUSIONS: Overall, progenitors fed a high-fat diet induced changes in the hypothalamic control of satiety of the second-generation offspring from progenitors fed the high-fat diet through intergenerational inheritance. These changes led to hyperphagia, alterations in the hypothalamic pathways of insulin, and leptin and adiposity index increase, favoring the occurrence of different cardiometabolic disorders in the second-generation offspring from progenitors fed the high-fat diet fed only with the control diet.

The crucial role and mechanism of insulin resistance in metabolic disease.

Insulin resistance (IR) plays a crucial role in the development and progression of metabolism-related diseases such as diabetes, hypertension, tumors, and nonalcoholic fatty liver disease, and provides the basis for a common understanding of these chronic diseases. In this study, we provide a systematic review of the causes, mechanisms, and treatments of IR. The pathogenesis of IR depends on genetics, obesity, age, disease, and drug effects. Mechanistically, any factor leading to abnormalities in the insulin signaling pathway leads to the development of IR in the host, including insulin receptor abnormalities, disturbances in the internal environment (regarding inflammation, hypoxia, lipotoxicity, and immunity), metabolic function of the liver and organelles, and other abnormalities. The available therapeutic strategies for IR are mainly exercise and dietary habit improvement, and chemotherapy based on biguanides and glucagon-like peptide-1, and traditional Chinese medicine treatments (e.g., herbs and acupuncture) can also be helpful. Based on the current understanding of IR mechanisms, there are still some vacancies to follow up and consider, and there is also a need to define more precise biomarkers for different chronic diseases and lifestyle interventions, and to explore natural or synthetic drugs targeting IR treatment. This could enable the treatment of patients with multiple combined metabolic diseases, with the aim of treating the disease holistically to reduce healthcare expenditures and to improve the quality of life of patients to some extent.

Insulin Receptor Substrates Regulation and Clinical Responses Following Vanadium-Enriched Yeast Supplementation in Obese Type 2 Diabetic Patients: a Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Increasing evidence suggests that organic vanadium compounds are bioavailable and safe therapeutic agents with insulin-mimetic and insulin-enhancing features. The objective of the current study was to examine the effect of vanadium-enriched yeast (VEY) supplementation on the gene expression level of insulin receptor substrates and clinical manifestations of obese type 2 diabetic mellitus (T2DM) patients. In this randomized, double-blind, placebo-controlled clinical trial, 44 obese T2DM patients were randomly allocated into either VEY (0.9 mg/day vanadium pentoxide) or placebo group for 12 weeks. The mRNA expression level of protein tyrosine phosphatase 1B (PTP1B), phosphatase and tensin homolog (PTEN), mitogen-activated protein kinase (MAPK), ribosomal protein S6 kinase (S6K), and nuclear factor kappa-light-chain-enhancer of activated B cells (NFƘB) genes in the peripheral blood mononuclear cells, serum levels of metabolic parameters, anthropometric indices, as well as the quality of life, and dietary intake were collected at pre- and post-intervention phases. Analysis of covariance was performed to obtain the corresponding effect size. Results showed that VEY administration significantly decreased anthropometric indices and glycemic parameters and increased insulin sensitivity after adjusting for potential covariates (p < 0.05), in comparison to the placebo group. Additionally, VEY supplementation was significantly effective on MAPK, PTP1B, and NFƘB gene expression level, compared to the placebo group. No significant changes were noticed for dietary intake, quality of life, and lipid profile in the VEY group, compared to the placebo group. Overall, VEY supplementation can be considered as a promising safe adjunct therapy for improving anthropometric indices and glycemic parameters in T2DM patients.

Combination of chronic stress with fructose diet increases AMP-activated protein kinase phosphorylation and affects agouti-related protein and proopiomelanocortin expression in the hypothalamus of male Wistar rats.

Appetite regulation in the hypothalamus is dependent on hormonal signals from the periphery, such as insulin and leptin, and can be modulated by both sugar-rich diet and stress. Our aim was to explore the effects of 9-week feeding with 20% fructose solution combined with 4-week chronic unpredictable stress, on appetite-regulating neuropeptides and modulatory role of leptin and insulin signalling in the hypothalamus of male Wistar rats. Energy intake, body mass and adiposity, as well as circulatory leptin and insulin concentrations were assessed. Hypothalamic insulin signalling was analysed at the level of glucose transporters, as well as at the protein level and phosphorylation of insulin receptor, insulin receptor supstrate-1, Akt and ERK. Phosphorylation of AMP-activated protein kinase (AMPK), level of protein tyrosine phosphatase 1B (PTP1B) and expression of leptin receptor (ObRb) and suppressor of cytokine signalling 3 (SOCS3) were also analysed, together with the expression of orexigenic agouti-related protein (AgRP) and anorexigenic proopiomelanocortin (POMC) neuropeptides. The results revealed that stress decreased body mass and adiposity, blood leptin level and expression of ObRb, SOCS3 and POMC, while combination with fructose diet led to marked increase of AgRP, associated with AMPK phosphorylation despite increased plasma insulin. Reduced Akt, enhanced ERK activity and elevated PTP1B were also observed in the hypothalamus of these animals. In conclusion, our results showed that joint effects of fructose diet and stress are more deleterious than the separate ones, since inappropriate appetite control in the hypothalamus may provide a setting for the disturbed energy homeostasis in the long run.

Participation of Magnesium in the Secretion and Signaling Pathways of Insulin: an Updated Review.

Several studies have demonstrated the participation of various minerals in mechanisms involving insulin. Magnesium, in particular, plays an important role in the secretion and action of this hormone. Therefore, this review aimed to examine the latest insights into the biochemical and molecular aspects of the participation of magnesium in insulin sensitivity. Magnesium plays a vital role in the activity of intracellular proteins involved in insulin secretion in ß-pancreatic cells, such as glucokinase, ATPase, and protein kinase C. In addition, evidence suggests that this mineral participates directly in insulin sensitivity and signaling in peripheral tissues, acting in the phosphorylation of the receptor tyrosine kinase and the insulin receptor substrates 1, insulin receptor substrates 2, phosphatidylinositol 3-kinase, and protein kinase B, and indirectly by reducing oxidative stress and chronic low-grade inflammation, which also lead to insulin resistance. Thus, magnesium deficiency is associated with glucose intolerance, while magnesium supplementation stimulates insulin secretion in pancreatic cells and improves insulin sensitivity in peripheral tissues. However, studies must consider assess short- and long-term nutritional status of mineral before performing intervention, the relevance of the balance of other nutrients that influence hormone secretion and sensibility, and health status of the assessed population.

Elimination of Vitamin D Signaling Causes Increased Mortality in a Model of Overactivation of the Insulin Receptor: Role of Lipid Metabolism.

Vitamin D (VD) deficiency has been associated with cancer and diabetes. Insulin signaling through the insulin receptor (IR) stimulates cellular responses by activating the PI3K/AKT pathway. PTEN is a tumor suppressor and a negative regulator of the pathway. Its absence enhances insulin signaling leading to hypoglycemia, a dangerous complication found after insulin overdose. We analyzed the effect of VD signaling in a model of overactivation of the IR. We generated inducible double KO (DKO) mice for the VD receptor (VDR) and PTEN. DKO mice showed severe hypoglycemia, lower total cholesterol and increased mortality. No macroscopic tumors were detected. Analysis of the glucose metabolism did not show clear differences that would explain the increased mortality. Glucose supplementation, either systemically or directly into the brain, did not enhance DKO survival. Lipidic liver metabolism was altered as there was a delay in the activation of genes related to ß-oxidation and a decrease in lipogenesis in DKO mice. High-fat diet administration in DKO significantly improved its life span. Lack of vitamin D signaling increases mortality in a model of overactivation of the IR by impairing lipid metabolism. Clinically, these results reveal the importance of adequate Vitamin D levels in T1D patients.

Antidiabetic efficacy of Trifolium alexandrinum extracts hesperetin and quercetin in ameliorating carbohydrate metabolism and activating IR and AMPK signaling in the pancreatic tissues of diabetic rats.

Diabetes is a metabolic disease that is mainly characterized by hyperglycemia. The present work investigated the efficacy of the flavanones hesperetin (HES) and quercetin (Q) extracted from Trifolium alexandrinum (TA) to treat type 2 diabetic rats. Wistar albino rats were supplemented with a high fat diet (HFD) for 2 weeks and then administered streptozotocin to induce diabetes. Diabetic rats were orally treated with Q, HES, and TA extract at concentrations of 40, 50, and 200 mg/kg BW, respectively, for 4 weeks. Various biochemical, molecular, and histological analysis were performed to evaluate the antidiabetic effects of these treatments. Q, HES, and TA extract treatments all significantly improved diabetic rats' levels of serum glucose, insulin, glucagon, liver function enzymes, hepatic glycogen, α-amylase, lipase enzymes, lipid profiles, oxidative stress indicators, and antioxidant enzymes as compared with control diabetic untreated rats. In addition, supplementation with Q, HES, and TA extract attenuated the activities of glucose-6-phosphate; fructose-1,6-bisphospahate; 6-phosphogluconate dehydrogenase; glucose-6-phosphate dehydrogenase; glucokinase; and hexokinase in pancreatic tissue, and they improved the levels of glucose transporter 2 and glucose transporter 4. Furthermore, these treatments modulated the expressions levels of insulin receptor (IR), phosphoinositide 3-kinase (PI3K), AMP-activated protein kinase (AMPK), caspase-3, and interleukin-1ß (IL-1ß). Enhancement of the histological alterations in pancreatic tissues provided further evidence of the ability of Q, HES, and TA extract to exert antidiabetic effects. Q, HES, and TA extract remedied insulin resistance by altering the IR/PI3K and AMPK signaling pathways, and they attenuated type 2 diabetes by improving the antioxidant defense system.

Zinc Levels Affect the Metabolic Switch of T Cells by Modulating Glucose Uptake and Insulin Receptor Signaling.

SCOPE: T cell activation requires a metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis to rapidly provide substrates for biosynthesis. An individual's zinc status plays an important role in balancing the activation of T cells and is required for a proper function of immune cells. Furthermore, zinc plays an important role during effector T cell polarization to T helper cell subsets or regulatory T cells, with effector T cells relying on glycolysis and regulatory T cells on oxidative phosphorylation. Therefore, the study aims to analyze if zinc also impacts on T cell activation on the level of intracellular metabolism. METHODS AND RESULTS: Mixed lymphocyte culture and anti-CD3/CD28 stimulation is used as in vitro models for T cell activation to investigate the effect of zinc supplementation and deprivation on metabolic switching. Promoted glucose uptake, insulin receptor expression, and signaling in both zinc conditions are observed, whereas key metabolic enzymes are stimulated mainly by zinc deprivation. Alterations in cytokine production suggest an immune-activating effect of zinc deprivation and a balancing effect of zinc supplementation. CONCLUSION: The results suggest a supportive effect of both zinc supplementation and deprivation on the metabolic switch during T cell activation, adding another level of immune regulation by zinc.

Differential impact of cold and hot tea extracts on tyrosine phosphatases regulating insulin receptor activity: a focus on PTP1B and LMW-PTP.

PURPOSE: The impact of tea constituents on the insulin-signaling pathway as well as their antidiabetic activity are still debated questions. Previous studies suggested that some tea components act as Protein Tyrosine Phosphatase 1B (PTP1B) inhibitors. However, their nature and mechanism of action remain to be clarified. This study aims to evaluate the effects of both tea extracts and some of their constituents on two main negative regulators of the insulin-signaling pathway, Low-Molecular-Weight Protein Tyrosine Phosphatase (LMW-PTP) and PTP1B. METHODS: The effects of cold and hot tea extracts on the enzyme activity were evaluated through in vitro assays. Active components were identified using gas chromatography-mass spectrometry (GC-MS) analysis. Finally, the impact of both whole tea extracts and specific active tea components on the insulin-signaling pathway was evaluated in liver and muscle cells. RESULTS: We found that both cold and hot tea extracts inhibit LMW-PTP and PTP1B, even if with a different mechanism of action. We identified galloyl moiety-bearing catechins as the tea components responsible for this inhibition. Specifically, kinetic and docking analyses revealed that epigallocatechin gallate (EGCG) is a mixed-type non-competitive inhibitor of PTP1B, showing an IC50 value in the nanomolar range. Finally, in vitro assays confirmed that EGCG acts as an insulin-sensitizing agent and that the chronic treatment of liver cells with tea extracts results in an enhancement of the insulin receptor levels and insulin sensitivity. CONCLUSION: Altogether, our data suggest that tea components are able to regulate both protein levels and activation status of the insulin receptor by modulating the activity of PTP1B.

Hypothalamic miR-1983 Targets Insulin Receptor ß and the Insulin-mediated miR-1983 Increase Is Blocked by Metformin.

MicroRNAs (miRNAs) expressed in the hypothalamus are capable of regulating energy balance and peripheral metabolism by inhibiting translation of target messenger RNAs (mRNAs). Hypothalamic insulin resistance is known to precede that in the periphery, thus a critical unanswered question is whether central insulin resistance creates a specific hypothalamic miRNA signature that can be identified and targeted. Here we show that miR-1983, a unique miRNA, is upregulated in vitro in 2 insulin-resistant immortalized hypothalamic neuronal neuropeptide Y-expressing models, and in vivo in hyperinsulinemic mice, with a concomitant decrease of insulin receptor ß subunit protein, a target of miR-1983. Importantly, we demonstrate that miR-1983 is detectable in human blood serum and that its levels significantly correlate with blood insulin and the homeostatic model assessment of insulin resistance. Levels of miR-1983 are normalized with metformin exposure in mouse hypothalamic neuronal cell culture. Our findings provide evidence for miR-1983 as a unique biomarker of cellular insulin resistance, and a potential therapeutic target for prevention of human metabolic disease.

Insulin signalling in tanycytes gates hypothalamic insulin uptake and regulation of AgRP neuron activity.

Insulin acts on neurons and glial cells to regulate systemic glucose metabolism and feeding. However, the mechanisms of insulin access in discrete brain regions are incompletely defined. Here we show that insulin receptors in tanycytes, but not in brain endothelial cells, are required to regulate insulin access to the hypothalamic arcuate nucleus. Mice lacking insulin receptors in tanycytes (IR∆Tan mice) exhibit systemic insulin resistance, while displaying normal food intake and energy expenditure. Tanycytic insulin receptors are also necessary for the orexigenic effects of ghrelin, but not for the anorexic effects of leptin. IR∆Tan mice exhibit increased agouti-related peptide (AgRP) neuronal activity, while displaying blunted AgRP neuronal adaptations to feeding-related stimuli. Lastly, a highly palatable food decreases tanycytic and arcuate nucleus insulin signalling to levels comparable to those seen in IR∆Tan mice. These changes are rooted in modifications of cellular stress responses and of mitochondrial protein quality control in tanycytes. Conclusively, we reveal a critical role of tanycyte insulin receptors in gating feeding-state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance.

Stevioside Attenuates Insulin Resistance in Skeletal Muscle by Facilitating IR/IRS-1/Akt/GLUT 4 Signaling Pathways: An In Vivo and In Silico Approach.

Type-2 diabetes mellitus (T2DM), the leading global health burden of this century majorly develops due to obesity and hyperglycemia-induced oxidative stress in skeletal muscles. Hence, developing novel drugs that ameliorate these pathological events is an immediate priority. The study was designed to analyze the possible role of Stevioside, a characteristic sugar from leaves of Stevia rebaudiana (Bertoni) on insulin signaling molecules in gastrocnemius muscle of obesity and hyperglycemia-induced T2DM rats. Adult male Wistar rats rendered diabetic by administration of high fat diet (HFD) and sucrose for 60 days were orally administered with SIT (20 mg/kg/day) for 45 days. Various parameters were estimated including fasting blood glucose (FBG), serum lipid profile, oxidative stress markers, antioxidant enzymes and expression of insulin signaling molecules in diabetic gastrocnemius muscle. Stevioside treatment improved glucose and insulin tolerances in diabetic rats and restored their elevated levels of FBG, serum insulin and lipid profile to normalcy. In diabetic gastrocnemius muscles, Setvioside normalized the altered levels of lipid peroxidase (LPO), hydrogen peroxide (H2O2) and hydroxyl radical (OH*), antioxidant enzymes (CAT, SOD, GPx and GSH) and molecules of insulin signaling including insulin receptor (IR), insulin receptor substrate-1 (IRS-1) and Akt mRNA levels. Furthermore, Stevioside enhanced glucose uptake (GU) and oxidation in diabetic muscles by augmenting glucose transporter 4 (GLUT 4) synthesis very effectively in a similar way to metformin. Results of molecular docking analysis evidenced the higher binding affinity with IRS-1 and GLUT 4. Stevioside effectively inhibits oxidative stress and promotes glucose uptake in diabetic gastrocnemius muscles by activating IR/IRS-1/Akt/GLUT 4 pathway. The results of the in silico investigation matched those of the in vivo study. Hence, Stevioside could be considered as a promising phytomedicine to treat T2DM.

Role of Epigallocatechin Gallate in Glucose, Lipid, and Protein Metabolism and L-Theanine in the Metabolism-Regulatory Effects of Epigallocatechin Gallate.

Epigallocatechin gallate (EGCG) and L-theanine (LTA) are important bioactive components in tea that have shown promising effects on nutrient metabolism. However, whether EGCG alone or combined with LTA can regulate the glucose, lipid, and protein metabolism of healthy rats remains unclear. Therefore, we treated healthy rats with EGCG or the combination of EGCG and LTA (EGCG+LTA) to investigate the effects of EGCG on nutrient metabolism and the role of LTA in the metabolism-regulatory effects of EGCG. The results showed that compared with the control group, EGCG activated insulin and AMP-activated protein kinase (AMPK) signals, thus regulating glucose, lipid, and protein metabolism. Compared with EGCG, EGCG+LTA enhanced hepatic and muscle glycogen levels and suppressed phosphorylation of AMPK, glycogen synthase 2, mammalian target of rapamycin, and ribosomal protein S6 kinase. In addition, EGCG+LTA inhibited the expression of liver kinase B1, insulin receptor and insulin receptor substrate, and promoted the phosphorylation level of acetyl-CoA carboxylase. Furthermore, both EGCG and EGCG+LTA were harmless for young rats. In conclusion, EGCG activated AMPK and insulin pathways, thereby promoting glycolysis, glycogen, and protein synthesis and inhibiting fatty acid (FA) and cholesterol synthesis. However, LTA cooperated with EGCG to promote glycogen metabolism and suppressed the effect EGCG on FA and protein synthesis via AMPK signals.

Insulin Signaling in Arthritis.

Inflammatory arthritis is burdened by an increased risk of metabolic disorders. Cytokines and other mediators in inflammatory diseases lead to insulin resistance, diabetes and hyperlipidemia. Accumulating evidence in the field of immunometabolism suggests that the cause-effect relationship between arthritis and metabolic abnormalities might be bidirectional. Indeed, the immune response can be modulated by various factors such as environmental agents, bacterial products and hormones. Insulin is produced by pancreatic cells and regulates glucose, fat metabolism and cell growth. The action of insulin is mediated through the insulin receptor (IR), localized on the cellular membrane of hepatocytes, myocytes and adipocytes but also on the surface of T cells, macrophages, and dendritic cells. In murine models, the absence of IR in T-cells coincided with reduced cytokine production, proliferation, and migration. In macrophages, defective insulin signaling resulted in enhanced glycolysis affecting the responses to pathogens. In this review, we focalize on the bidirectional cause-effect relationship between impaired insulin signaling and arthritis analyzing how insulin signaling may be involved in the aberrant immune response implicated in arthritis and how inflammatory mediators affect insulin signaling. Finally, the effect of glucose-lowering agents on arthritis was summarized.

Systematic investigation of the pharmacological mechanism for renal protection by the leaves of Eucommia ulmoides Oliver using UPLC-Q-TOF/MS combined with network pharmacology analysis.

Bark is the traditional medicinal component of Eucommia ulmoides Oliver (E. ulmoides). However, the demand for E. ulmoides medicinal materials seriously limits their sustainability. To alleviate resource constraints, the bioactivity of E. ulmoides leaves and its pharmacodynamic basis were investigated. In the present study, extracts of E. ulmoides leaves were found to display potential renal protective properties in rat glomerular mesangial (HBZY-1) cells treated with high levels of glucose, suggesting that they possess potential factors capable of treating diabetic nephropathy. Ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was used to comprehensively characterize the chemical components of E. ulmoides leaves. A total of 83 possible chemical components, including 12 iridoids, 13 flavonoids, 14 lignans, 20 phenylpropanoids, 14 phenolic acids, and 10 additional components, were identified in E. ulmoides leaves. Network pharmacology was used for a preliminary exploration of the potential mechanism of action of renal protection afforded by E. ulmoides leaves towards diabetic nephropathy. The network pharmacology results were verified using a series of biological experiments. The present study provided the basis for the comprehensive development and utilization of E. ulmoides leaves and the discovery of potential drugs.

Activation of Insulin Signaling by Botanical Products.

Type 2 diabetes (T2D) is a worldwide health problem, ranked as one of the leading causes for severe morbidity and premature mortality in modern society. Management of blood glucose is of major importance in order to limit the severe outcomes of the disease. However, despite the impressive success in the development of new antidiabetic drugs, almost no progress has been achieved with regard to the development of novel insulin-sensitizing agents. As insulin resistance is the most eminent factor in the patho-etiology of T2D, it is not surprising that an alarming number of patients still fail to meet glycemic goals. Owing to its wealth of chemical structures, the plant kingdom is considered as an inventory of compounds exerting various bioactivities, which might be used as a basis for the development of novel medications for various pathologies. Antidiabetic activity is found in over 400 plant species, and is attributable to varying mechanisms of action. Nevertheless, relatively limited evidence exists regarding phytochemicals directly activating insulin signaling, which is the focus of this review. Here, we will list plants and phytochemicals that have been found to improve insulin sensitivity by activation of the insulin signaling cascade, and will describe the active constituents and their mechanism of action.

Aurantio-obtusin improves obesity and insulin resistance induced by high-fat diet in obese mice.

Aurantio-obtusin (AUR) is the main bioactive compound among the anthraquinones, from Cassia seed extract. This study was conducted to identify whether AUR could improve obesity and insulin resistance, induced by a high-fat diet in obese mice. Mice were fed a high-fat diet for 6 weeks and were then assigned to the high-fat diet (HFD) control group, the AUR 5 mg/kg group, or the AUR 10 mg/kg group. AUR improves glucose by activating the expression of PI3K, Akt and GLUT4, GLUT2. AUR altered the expression levels of several lipid metabolism-related and adipokine genes. AUR decreased the mRNA expression of PPAR-γ, FAS and increased the mRNA expression of PPAR-α in liver. AUR lowered SREBP-1c, FAS, SCD-1, inflammatory cytokines, and increased the expression of PPAR-γ, PPAR-α, CPT-1, and adiponectin in white adipose tissue (WAT). AUR docking with the insulin receptor showed that the residues of the insulin receptor, ectodomain, were the same as those around the emodin. The effect of AUR may be elicited by regulating the activity of the insulin signaling pathway, expression of lipid metabolism-related genes, and expression of inflammatory cytokine markers to improve adiposity, insulin resistance, and dyslipidemia.

An In Silico Approach Towards Investigation of Possible Effects of Essential Oils Constituents on Receptors Involved in Cardiovascular Diseases (CVD) and Associated Risk Factors (Diabetes Mellitus and Hyperlipidemia).

AIM: Aromatherapy products, hydrosol beverages and distillates containing essential oils are widely used for cardiovascular conditions. Investigation of the possible activity of their major constituents with the cardiovascular-related receptors may lead to developing new therapeutics. It also may prevent unwanted side effects and drug-herb interactions. MATERIALS AND METHODS: A list of 243 volatile molecules (mainly monoterpene and sesquiterpene) was prepared from a literature survey in Scopus and PubMed (2000-2019) on hydrosols and essential oils which are used for Cardiovascular Diseases (CVD) and its risk factors (diabetes mellitus and hyperlipidemia). The PDB files of the receptors (229 native PDB files) included alpha-glucosidase, angiotensin- converting enzymes, beta-2 adrenergic receptor, glucocorticoid, HMG-CoA reductase, insulin, mineralocorticoid, potassium channel receptors and peroxisome proliferator-activated receptoralpha, were downloaded from Protein Data Bank. An in silico study using AutoDock 4.2 and Vina in parallel mode was performed to investigate possible interaction of the molecules with the receptors. Drug likeliness of the most active molecules was investigated using DruLiTo software. RESULTS: Spathulenol, bisabolol oxide A, bisabolone oxide, bergapten, bergamotene, dill apiole, pcymene, methyl jasmonate, pinocarveol, intermedeol, α-muurolol, S-camphor, ficusin, selinen-4-ol, iso-dihydrocarveol acetate, 3-thujanone, linanool oxide and cadinol isomers made a better interaction with some of the named receptors. All of the named molecules had an acceptable dug likeliness except for α-bergamotene. In addition, all of the named molecules had the ability to pass the bloodbrain barrier and it is possible to produce unwanted side effects. CONCLUSION: Some ingredients of essential oils might be active on cardiovascular-related receptors.

Acteoside-improved streptozotocin-induced learning and memory impairment by upregulating hippocampal insulin, glucose transport, and energy metabolism.

Alzheimer's disease (AD), a neurodegenerative disease, has been, by and large, correlated to insulin pathway, glucose level, and energy metabolism in the brain. Intracerebroventricular administration of streptozotocin (ICV-STZ) leads to glucose and energy metabolism dysfunction, cognitive impairment, and increased oxidative stress in the brain. Acteoside has a myriad of pharmacological effects on the brain, namely, neuroprotection and recuperation of cognitive functions. The primary focus of the current study was to examine the effect of acteoside on insulin, glucose transport, and energy metabolism in the hippocampal area of the brain. The behavioral experiments such as spatial memory, active learning, and passive memory suggested that acetoside ameliorated the ICV-STZ-induced learning and cognitive impairment. The acteoside induced increase in the protein expression of glucose transporters (Glu T1, Glu T3, and Glu T4), glucose, and insulin levels in the hippocampus for maintaining normal learning and memory function were demonstrated by Western blot. In addition, acteoside's long-term oral administration increased the the ratio of ATP content divided by ADP content (ATP/ADP) ratio, which, in turn, reduced the reactiveoxygen species (ROS) level and improved the cellular oxidative stress response. Compared with the model group, the above results show significant differences in different degrees (p < .05 or p < .01). This study suggests that acteoside can ameliorate the ICV-STZ-induced learning and memory impairment caused due to insulin receptor, insulin receptor substrate 1, Glu T1, Glu T3, and Glu T4 pathways by triggering intracerebral metabolism.

Effects of Heshouwuyin on gene expression of the insulin/IGF signalling pathway in rat testis and spermatogenic cells.

CONTEXT: The Chinese herbal formula Heshouwu decoction (Heshouwuyin) has protective effects on testicular function in aging male rats, but the mechanism is unknown. OBJECTIVE: This study investigated whether Heshouwuyin affects the testicular function of aging rats by regulating the insulin/IGF signalling pathway. MATERIALS AND METHODS: Sixteen-month-old male Wistar rats in the Heshouwuyin group and the natural-aging group were orally administered Heshouwuyin granules (0.056 g/kg) or equivalent normal saline for 60 d. The testicular tissue of 12-month-old male Wistar rats was removed as a young control group (n = 10). The testicular tissue and spermatogenic cells were studied. RESULTS: The immunofluorescence results revealed that the insulin receptor (INSR)- (0.056 ± 0.00548), insulin receptor substrate 1(IRS1)- (0.251 ± 0.031), IRS2 (0.230 ± 0.019)- and insulin-like growth factor 1 (IGF1)-positive cell rate (0.33 ± 0.04) in the aging group was higher than that in the young control group (0.116 ± 0.011, 0.401 ± 0.0256, 0.427 ± 0.031, 0.56 ± 0.031; p < 0.01), and the IGF-binding protein 3 (IGFBP3)-positive cell rate (0.42 ± 0.024) was lower than that (0.06 ± 0.027) in the young group (p < 0.01). The intervention of Heshouwuyin reversed the above phenomena. The qPCR and immunoblot results were consistent with those of the immunofluorescence. The same results were obtained in spermatogenic cells. CONCLUSIONS: Our research shows that Heshouwuyin can regulate the insulin/IGF signalling pathway to improve testicular function, and provides an experimental basis for further clinical use.