Insulin Signaling Pathway Research Articles

Relationship between obesity, insulin resistance and cell membrane properties

Introduction and aim. The obesity is one of the greatest public health problems in developing countries and it is a triggering factor for diabetes associated with insulin resistance. The importance of cell membrane lipids as essential regulators of insulin resistance, since changes in the dynamic properties of the cell membrane (e.g., membrane fluidity), could be one of the events by which obesity affects insulin sensitivity. Thus, the insulin resistance may not only be a cause but also a consequence of lipid disorders such as dyslipidemia and/or cell membrane phospholipid composition change. The modification of plasma membrane lipid composition can change membrane biophysical properties and thus influencing protein-lipid interactions, enzymatic activity and regulation of surface receptors. Alterations in the lipid composition modify the fluidity of plasma membranes and the expression of membrane functions, such as receptor binding and enzyme activities. This review summarizes the current knowledge on the effects of the modulation of plasma membrane lipid composition and membrane fluidity in the functionality of membrane proteins involved in insulin activity, including the insulin receptor, glucose transport and Na + /K + ATPase and, in turn, the key features of the metabolic syndrome. Material and methods. References for that article were found through PubMed and Google Scholar, using terms: “obesity”, “insulin resistance” and “membrane properties”. The research was limited to abstracts and available full-text articles. Analysis of the literature. There is a strong relationship between dietary lipids, membrane lipid profiles and insulin resistance. The changes in the dynamic properties of the cell membrane (e.g., membrane fluidity), could be one of the events by which obesity affects insulin sensitivity. The modification of plasma membrane lipid composition can change membrane biophysical properties and thus influencing protein–lipid interactions, enzymatic activity, and regulation of surface receptors. Modifications of membrane phospholipid composition could have a role in the insulin action by altering membrane fluidity and, as a consequence, the insulin signaling pathway. Conclusion. As conclusion the membrane-lipid therapy approach can be used to treat important pathologies such as obesity and many others diseases such as : cancer, cardiovascular pathologies, neurodegenerative processes, obesity, metabolic disorders, inflammation, and infectious and autoimmune diseases. This pharmacological strategy aims to regulate cell functions by influencing lipid organization and membrane fluidity, inducing a concomitant modulation of membrane protein localization and activity which might serve to reverse the pathological state. Through this review we suggest an in-depth analysis of the membrane lipid therapy field, especially its molecular bases and its relevance to the development of innovative therapeutic approaches.

Levels of insulin pathway proteins in persons with concomitant Alzheimer’s disease dementia and type 2 diabetes mellitus

AbstractBackgroundAlzheimer’s disease (AD) is a gradual and progressive neurodegenerative disease characterized by predominant cortical atrophy in the medial temporal lobe. Since the results of the Rotterdam study in 1992, it has been known that type 2 diabetes mellitus (T2DM) increases the risk of dementia. Persons with T2DM have structural brain changes and cognitive impairment, with a high risk of developing AD. These data suggest that insulin may play a key role in brain activity and memory formation. The objective of this study was to verify if there are alterations in the levels of proteins of the insulin pathway in cognitively healthy individuals, with AD, with T2DM and with the concomitant presence of AD and T2DM.MethodThe study was approved by the UFSCar’s ethics committee (CAAE: 31634720.9.0000.5504) and recruited participants aged 60 years or older. The AD diagnosis was obtained using the criteria of the National Institute Aging Alzheimer’s Association (NIA/AA). T2DM was defined as self‐reported use of oral antidiabetic drugs. Specific inclusion and exclusion criteria and cognitive assessment of the MMSE and CDR were applied to all participants. Plasma was collected by venepuncture and protein levels of ISNR, IRS1, Akt1, PI3KCD, MAPK1, MAPK8, PTP1B and IDE (Life‐Span Biosciences) were analysed using ELISA (Enzyme Enzyme‐Linked Immunosorbent Assay).ResultSeveral proteins of the insulin pathway were found to be significantly different among patients with AD, T2DM and AD+T2DM, compared with healthy controls (figure 1), reinforcing the strong correlation between T2DM and AD. Main alterations were found for INSR, IRS1, Akt1, PIK3, MAPK, PTP1b and IDE among healthy participants and those with AD+T2DM.ConclusionThe peripheral alterations found in the levels of insulin pathway proteins confirm the possible relationship between T2DM and AD and reinforce the importance of the insulin signalling pathways, as they can play a fundamental role in AD. The clinical impact of this study is related to a new approach that could be used in the treatment of this type of dementia, also observing the metabolic and inflammatory states of the patients, in addition to contributing to a better understanding of the biology of the disease itself.

Joint Effects of Heat Stress and PM2.5 Exposure on Glucose Metabolism and Hepatic Insulin Signaling

: Heatwave events occur more frequently, accompanied by a significant increase in the ambient concentration of fine particulate matter (PM 2.5 ). Epidemiological and experimental studies have suggested that heat stress or PM 2.5 exposure would impair glucose homeostasis and insulin sensitivity. : To explore the joint effects of heat stress and PM 2.5 exposure on glucose metabolism and hepatic insulin pathway. : C57BL/6 mice were randomly divided into filtered air (FA) group, fine particulate matter (PM) group, filtered air combined with heat stress (FH) group, and PM combined with heat stress (PH) group. Mice were exposed to PM for a total of 6 weeks, and heat stress combined with PM exposure was applied at the 5th and 6th weeks via a whole-body exposure system. Systemic glucose homeostasis, insulin sensitivity, and circulating inflammatory cytokines were examined. HSP72 expression and insulin signaling in the liver were measured. : Glucose tolerance and insulin sensitivity were impaired in response to heat stress, accompanied by lessened hepatic GLUT2 expression and inhibited insulin signaling pathway. No synergistic effects of heat stress and PM 2.5 exposure on glucose homeostasis were observed, while heat-upregulated HSP72 expression was attenuated with accumulated TNFα induced by further PM 2.5 exposure. : Heat stress combined with PM 2.5 exposure induced TNFα, which could inhibit heat-elevated hepatic HSP72 expression. Elevated circulating TNFα impaired hepatic insulin signaling and GLUT2 expression. Then, glucose homeostasis was perturbed, and insulin action was impaired.

Fecal Microbiota Composition, Their Interactions, and Metagenome Function in US Adults with Type 2 Diabetes According to Enterotypes.

T2DM etiology differs among Asians and Caucasians and may be associated with gut microbiota influenced by different diet patterns. However, the association between fecal bacterial composition, enterotypes, and T2DM susceptibility remained controversial. We investigated the fecal bacterial composition, co-abundance network, and metagenome function in US adults with T2DM compared to healthy adults based on enterotypes. We analyzed 1911 fecal bacterial files of 1039 T2DM and 872 healthy US adults from the Human Microbiome Projects. Operational taxonomic units were obtained after filtering and cleaning the files using Qiime2 tools. Machine learning and network analysis identified primary bacteria and their interactions influencing T2DM incidence, clustered into enterotypes, Bacteroidaceae (ET-B), Lachnospiraceae (ET-L), and Prevotellaceae (ET-P). ET-B showed higher T2DM incidence. Alpha-diversity was significantly lower in T2DM in ET-L and ET-P (p < 0.0001), but not in ET-B. Beta-diversity revealed a distinct separation between T2DM and healthy groups across all enterotypes (p < 0.0001). The XGBoost model exhibited high accuracy and sensitivity. Enterocloster bolteae, Facalicatena fissicatena, Clostridium symbiosum, and Facalibacterium prausnitizii were more abundant in the T2DM group than in the healthy group. Bacteroides koreensis, Oscillibacter ruminantium, Bacteroides uniformis, and Blautia wexlerae were lower in the T2DM than in the healthy group regardless of the enterotypes in the XGBoost model (p < 0.0001). However, the patterns of microbial interactions varied among different enterotypes affecting T2DM risk. The interaction between fecal bacteria was more tightly regulated in the ET-L than in the ET-B and ET-P groups (p < 0.001). Metagenomic analysis revealed an inverse association between bacteria abundance in T2DM, energy utility, butanoate and propanoate metabolism, and the insulin signaling pathway (p < 0.0001). In conclusion, fecal bacteria play a role in T2DM pathogenesis, particularly within different enterotypes, providing valuable insights into the link between gut microbiota and T2DM in the US population.

Evaluation of adiponectin and TNF-α expression in diabetic patients and its relationship with cardiovascular diseases.

Diabetes is caused by peripheral insulin resistance and lack of insulin secretion due to the apoptosis of pancreatic beta cells. Tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine secreted from the tissue on the insulin signaling pathway, can play a role in causing fat resistance to insulin in type 2 diabetes patients. Adiponectin is a specific protein of adipose tissue. It belongs to the collectin family, which is present in human plasma at a high level and can protect against vascular lesions. Considering the importance of epigenetic changes in the development of multifactorial diseases, this study was conducted to investigate the methylation of TNF-α gene promoter in patients with type diabetes with cardiovascular disease and compare it with diabetic people without cardiovascular disease. Also, the serum concentration of adiponectin was investigated in diabetic patients with and without cardiovascular disease. For this purpose, 95 patients with type 2 diabetes referred to Isfahan Endocrine and Metabolism Research Center were divided into two groups: cardiovascular disease and without cardiovascular disease, based on the angiography results. Serum adiponectin level was measured by the RIA method. In addition to adiponectin, indicators such as FBS, cholesterol, triglycerides, and HDL were also measured in these patients. Then, the promoter region of the TNF-α gene was investigated by bisulfite treatment method, nested PCR, and finally, sequence determination. The results showed that the serum level of adiponectin was higher in diabetic patients without cardiovascular disease than in diabetic patients with cardiovascular disease, but this difference was not statistically significant. Also, no change was observed between men and women in TNF-α gene promoter methylation in diabetic and non-diabetic groups. In general, the decrease in adiponectin concentration in diabetic people can be a factor in causing macroangiopathy, so it can be predicted that the production of recombinant adiponectin can be helpful in the treatment and protection of cardiovascular disease in these patients. Also, it seems that the epigenetic changes of cytokines that play a role in causing insulin resistance in type 2 diabetic patients are not noticeable in the peripheral blood sample. In this regard, other tissues should probably be investigated.

NPFFR2-deficient mice fed a high-fat diet develop strong intolerance to glucose.

A previous study on neuropeptide FF receptor 2 (NPFFR2)-deficient mice has demonstrated that NPFFR2 is involved in the control of energy balance and thermogenesis. Here, we report on the metabolic impact of NPFFR2 deficiency in male and female mice that were fed either a standard diet (STD) or a high-fat diet (HFD) and each experimental group consisted of ten individuals. Both male and female NPFFR2 knockout (KO) mice exhibited severe glucose intolerance that was exacerbated by a HFD diet. In addition, reduced insulin pathway signaling proteins in NPFFR2 KO mice fed a HFD resulted in the development of hypothalamic insulin resistance. HFD feeding did not cause liver steatosis in NPFFR2 KO mice of either sex, but NPFFR2 KO male mice fed a HFD had lower body weights, white adipose tissues, and liver and lower plasma leptin levels compared with their wild-type (WT) controls. Lower liver weight in NPFFR2 KO male mice compensated for HFD-induced metabolic stress by increased liver PPARα and plasma FGF21 hepatokine, which supported fatty acid β-oxidation in the liver and white adipose tissue. Conversely, NPFFR2 deletion in female mice attenuated the expression of Adra3β and Pparγ, which inhibited lipolysis in adipose tissue.

AMPK Activation as a Protective Mechanism to Restrain Oxidative Stress in the Insulin-Resistant State in Skeletal Muscle of Rat Model of PCOS Subjected to Postnatal Overfeeding.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age, often associated with obesity and insulin resistance. Childhood obesity is an important predisposing factor for the development of PCOS later in life. Being particularly interested in the interplay between prepubertal obesity and hyperandrogenemia, we investigated the effects of early postnatal overfeeding, accomplished by reducing litter size during the period of suckling, on energy sensing and insulin signaling pathways in the gastrocnemius muscle of a rat model of PCOS-induced by 5α-dihydrotestosterone (DHT). The combination of overfeeding and DHT treatment caused hyperinsulinemia and decreased systemic insulin sensitivity. Early postnatal overfeeding induced defects at critical nodes of the insulin signaling pathway in skeletal muscle, which was associated with reduced glucose uptake in the presence of hyperandrogenemia. In this setting, under a combination of overfeeding and DHT treatment, skeletal muscle switched to mitochondrial β-oxidation of fatty acids, resulting in oxidative stress and inflammation that stimulated AMP-activated protein kinase (AMPK) activity and its downstream targets involved in mitochondrial biogenesis and antioxidant protection. Overall, a combination of overfeeding and hyperandrogenemia resulted in a prooxidative and insulin-resistant state in skeletal muscle. This was accompanied by the activation of AMPK, which could represent a potential therapeutic target in insulin-resistant PCOS patients.

Annona muricate Extract Supplementation Contributes to Improve Aberrant Multi-Organ Energy Metabolism via Muscle-Brain Connectivity in Diabetic Mice.

Type 2 diabetes mellitus (T2DM) is related with the incidence of sarcopenia and cognitive impairment that reduces quality of life in the elderly. Recent evidence has demonstrated that sarcopenia is associated with cognitive dysfunction, and muscle-derived endocrine factors might contribute to cognitive function by the skeletal muscle-brain endocrine loop. This study investigated the beneficial effects of Annona muricata (AM, graviola) on multi-organ energy metabolism with muscle-brain connectivity via brain function-related myokines in mice. Body composition, fasting blood glucose level, insulin, HbA1c%, histopathological changes, and the protein levels of insulin-signaling, energy metabolism, neuroprotection, inflammation, and protein-degradation pathways were measured. AM extract (AME) treatment selectively enhanced insulin signaling in the skeletal muscle and hippocampus of T2DM mice. Furthermore, AME treatment effectively increased muscle-derived fibroblast growth factor 21 (FGF21), cathepsin-B (CTSB), irisin, brain-derived neurotrophic factor (BDNF), and liver-derived FGF21 that contribute to whole-body energy homeostasis. In particular, AME increased the levels of circulating myokines (FGF21, BDNF, irisin, and CTSB), and these were accordance with the hippocampal neurotrophic factors (BDNF and CTSB) in T2DM mice. In conclusion, we suggest that AME would be a potential nutraceutical for improving the energy metabolism associated with muscle-brain connectivity via brain function-related myokines in T2DM.

Insulin Resistance and Impaired Branched-Chain Amino Acid Metabolism in Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD) is complicated and involves multiple contributing factors. Mounting evidence supports the concept that AD is an age-related metabolic neurodegenerative disease mediated in part by brain insulin resistance, and sharing similar metabolic dysfunctions and brain pathological characteristics that occur in type 2 diabetes mellitus (T2DM) and other insulin resistance disorders. Brain insulin signal pathway is a major regulator of branched-chain amino acid (BCAA) metabolism. In the past several years, impaired BCAA metabolism has been described in several insulin resistant states such as obesity, T2DM and cardiovascular disease. Disrupted BCAA metabolism leading to elevation in circulating BCAAs and related metabolites is an early metabolic phenotype of insulin resistance and correlated with future onset of T2DM. Brain is a major site for BCAA metabolism. BCAAs play pivotal roles in normal brain function, especially in signal transduction, nitrogen homeostasis, and neurotransmitter cycling. Evidence from animal models and patients support the involvement of BCAA dysmetabolism in neurodegenerative diseases including Huntington's disease, Parkinson's disease, and maple syrup urine disease. More recently, growing studies have revealed altered BCAA metabolism in AD, but the relationship between them is poorly understood. This review is focused on the recent findings regarding BCAA metabolism and its role in AD. Moreover, we will explore how impaired BCAA metabolism influences brain function and participates in the pathogenesis of AD.

A comprehensive review on the research progress of PTP1B inhibitors as antidiabetics.

Diabetes mellitus (DM) is a serious global health concern affecting over 500 million people. To put it simply, it is one of the most dangerous metabolic illnesses. Insulin resistance is the root cause of 90% of all instances of diabetes, all of which are classified as Type 2 DM. Untreated, it poses a hazard to civilization since it can lead to terrifying consequences and even death. Oral hypoglycemic medicines presently available act in a variety of ways, targeting various organs and pathways. The use of protein tyrosine phosphatase 1B (PTP1B) inhibitors, on the contrary, is a novel and effective method of controlling type 2 diabetes. PTP1B is a negative insulin signaling pathway regulator; hence, inhibiting PTP1B increases insulin sensitivity, glucose absorption, and energy expenditure. PTP1B inhibitors also restore leptin signaling and are considered a potential obesity target. In this review, we have compiled a summary of the most recent advances in synthetic PTP1B inhibitors from 2015 to 2022 which have scope to be developed as clinical antidiabetic drugs.

20-Hydroxyecdysone counteracts insulin to promote programmed cell death by modifying phosphoglycerate kinase 1

BackgroundThe regulation of glycolysis and autophagy during feeding and metamorphosis in holometabolous insects is a complex process that is not yet fully understood. Insulin regulates glycolysis during the larval feeding stage, allowing the insects to grow and live. However, during metamorphosis, 20-hydroxyecdysone (20E) takes over and regulates programmed cell death (PCD) in larval tissues, leading to degradation and ultimately enabling the insects to transform into adults. The precise mechanism through which these seemingly contradictory processes are coordinated remains unclear and requires further research. To understand the coordination of glycolysis and autophagy during development, we focused our investigation on the role of 20E and insulin in the regulation of phosphoglycerate kinase 1 (PGK1). We examined the glycolytic substrates and products, PGK1 glycolytic activity, and the posttranslational modification of PGK1 during the development of Helicoverpa armigera from feeding to metamorphosis.ResultsOur findings suggest that the coordination of glycolysis and autophagy during holometabolous insect development is regulated by a balance between 20E and insulin signaling pathways. Glycolysis and PGK1 expression levels were decreased during metamorphosis under the regulation of 20E. Insulin promoted glycolysis and cell proliferation via PGK1 phosphorylation, while 20E dephosphorylated PGK1 via phosphatase and tensin homolog (PTEN) to repress glycolysis. The phosphorylation of PGK1 at Y194 by insulin and its subsequent promotion of glycolysis and cell proliferation were important for tissue growth and differentiation during the feeding stage. However, during metamorphosis, the acetylation of PGK1 by 20E was key in initiating PCD. Knockdown of phosphorylated PGK1 by RNA interference (RNAi) at the feeding stage led to glycolysis suppression and small pupae. Insulin via histone deacetylase 3 (HDAC3) deacetylated PGK1, whereas 20E via acetyltransferase arrest-defective protein 1 (ARD1) induced PGK1 acetylation at K386 to stimulate PCD. Knockdown of acetylated-PGK1 by RNAi at the metamorphic stages led to PCD repression and delayed pupation.ConclusionsThe posttranslational modification of PGK1 determines its functions in cell proliferation and PCD. Insulin and 20E counteractively regulate PGK1 phosphorylation and acetylation to give it dual functions in cell proliferation and PCD.

Taurine alleviated hepatic steatosis in oleic acid-treated-HepG2 cells and rats fed a high-fat diet

Taurine has been proven in many trials to alleviate the symptoms of metabolic associated fatty liver disease. Here its protective effect for hepatic steatosis and modulation of AMP-activated protein kinase and insulin signaling pathway were investigated. Steatotic HepG2 cell established with oleic acid (0.05 mmol/L), treated with taurine (5 mmol/L), dorsomorphin (10 μmol/L) for 24 h. Sprague Dawley rats were divided into regular and high-fat diet (HFD) groups, and their corresponding taurine (70 or 350 mg/kg BW/d) groups, fed for 8 weeks. In steatotic cell, taurine reduced the TG concentration and SREBP-1c, PPARγ, FAS, ACC, SCD1 protein levels, decreased phosphorylation of mTOR, IRS1 (Ser302), increased phosphorylation of AMPKα, LKB1, PI3K, Akt, ACC. While dorsomorphin eliminated taurine's TG-lowering effect. In HFD-fed rats, taurine reduced liver TG, serum TG, ALT, AST, IL-1β, IL-4, TNF-α. The effects of taurine on the main factors of fatty acid synthesis were mostly consistent with cell experiments, and the reduction of microRNAs (451, 33, 291b) was aligned with the improvement in LKB1 and AMPK expression in HFD rats. Taurine alleviated steatosis-induced inhibition of IRS1-PI3K-Akt pathway, but suppressed its positively regulated downstream factor mTOR. In parallel, taurine reduced steatosis by activating LKB1-AMPKα pathway via phosphorylation and no-phosphorylation manner, then inhibiting SREBP-1c directly or by suppressing mTOR phosphorylation.

The positive effects of dietary arginine on juvenile hybrid snakehead (Channa maculata♀×Channa argus♂) fed high-carbohydrate diets: Liver inflammation antioxidant response, and glucose metabolism

The aim of this study was to investigate the effects of arginine supplementation on liver morphology, antioxidant capacity, inflammatory response, insulin signaling pathway and glucose metabolism in hybrid snakehead. Five experimental diets (2.31 %, 2.42 %, 2.72 %, 2.92 %, and 3.12 % arginine) were prepared by adding different levels of arginine to the basal diet containing high (27 %) level of carbohydrate. The results showed that the activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD) and glutathione peroxidase (GSH-Px) of fish fed with arginine diets were significantly higher than those in control group (p < 0.05), accompanied by the lower malondialdehyde (MDA) content in the same groups (p < 0.05). There were obvious mild inflammatory cell infiltration and increased perihepatic pancreatic space in control group, while the pathological state of the liver was relieved in fish fed with arginine diets. Dietary arginine supplementation resulted in significantly higher glucose metabolism-related genes glucokinase (GK), phosphoenolpyruvate carboxkinase (PEPCK), glycogen synthase (GS) and pyruvate kinase (PK) and insulin signaling pathway key genes insulin receptor subset-1 (IRS-1), protein kinase B (Akt) and phosphoenolpyruvate carboxykinase (PI3K)(p < 0.05). Immune-related genes transforming growth factor β (TGF-β), heat shock protein 70 (HSP70) and heat shock protein 90 (HSP90) were significantly higher in the arginine supplemented diet than in the control group (p < 0.05). Immune-related genes interleukin-8 (IL8), interleukin-1β (IL1β) and tissue tumor necrosis factor-α (TNF-α) in fish fed with arginine diets were significantly lower than those in control group (p < 0.05). In conclusion, dietary arginine can alleviate the adverse effects of high carbohydrate diet on hybrid snakeheads by improving glucose metabolism and enhancing antioxidant, anti-inflammatory and non-specific immune functions.

Elevated temperature decreases cardiovascular toxicity of nanoplastics but adds to their lethality: A case study during zebrafish (Danio rerio) development

To highlight the key role of global warming on the toxicity of contaminants, the cardiovascular toxicity of nanoparticles (NPs) was estimated in developing zebrafish (Danio rerio) at different exposure temperatures, and the toxicity mechanisms were explored via multi-omic analyses. Polystyrene NPs (50 nm) at 0.1 mg·L−1 entered zebrafish embryos at 24 h post-fertilization and caused cardiovascular toxicity in the developing zebrafish at 27 ℃. This was explained by the down-regulation of the branched-chain amino acid and insulin signaling pathways owing to induced oxidative stress. Elevated exposure temperatures promoted the accumulation of NPs in developing zebrafish, increased the levels of oxidative stress and enhanced the oxidative phosphorylation rate in mitochondria, thus resulting in an additive effect on the mortality of zebrafish larvae. Notably, elevated exposure temperatures reduced the cardiovascular toxicity of NPs, as the effective concentration of NPs for inhibiting embryonic heartbeat rate increased from 0.1 mg·L−1 at 27 ℃ to 1.0 mg·L−1 at 30 ℃. Experiments of transgenic zebrafish Tg(myl7:GFP) and multi-omic analyses revealed that elevated temperatures enhanced the myocardial contractility of larvae, thus reducing the cardiovascular toxicity of NPs. However, the health risks of enhanced myocardial contraction caused by NP exposure at elevated temperatures requires further consideration.

Angelica keiskei Impacts the Lifespan and Healthspan of Drosophila melanogaster in a Sex and Strain-Dependent Manner.

Angelica keiskei is a perennial plant, belonging to the Apiaceae family and originating from Japan. This plant has been reported to act as a diuretic, analeptic, antidiabetic, hypertensive, tumor, galactagogue, and laxative. The mechanism of action of A. keiskei is not known, but previous studies have suggested that it may act as an antioxidant. In this work, we used Drosophila melanogaster to evaluate the impact of A. keiskei on lifespan and healthspan and its potential anti-aging mechanism by conducting multiple assays on three fly strains: w1118, chico, and JIV. We observed that the extract extended lifespan and improved healthspan in a sex- and strain-dependent manner. A. keiskei extended lifespan and improved reproductive fitness in female flies and either had no effect or decreased survival and physical performance in males. The extract protected against the superoxide generator paraquat in both sexes. These sex-specific effects suggest that A. keiskei may act through age-specific pathways such as the insulin and insulin-like growth factor signaling (IIS) pathways. Upon examination, we found that the increased survival of A. keiskei-fed females was dependent on the presence of the insulin receptor substrate chico, supporting the role of IIS in the action of A. keiskei.

MiRNA expression profiles of peripheral white blood cells from beef heifers with varying reproductive potential.

Reproductive performance is the most critical factor affecting production efficiency in the cow-calf industry. Heifers with low reproductive efficiency may fail to become pregnant during the breeding season or maintain a pregnancy. The cause of reproductive failure often remains unknown, and the non-pregnant heifers are not identified until several weeks after the breeding season. Therefore, improving heifer fertility utilizing genomic information has become increasingly important. One approach is using microRNAs (miRNA) in the maternal blood that play an important role in regulating the target genes underlying pregnancy success and thereby in selecting reproductively efficient heifers. Therefore, the current study hypothesized that miRNA expression profiles from peripheral white blood cells (PWBC) at weaning could predict the future reproductive outcome of beef heifers. To this end, we measured the miRNA profiles using small RNA-sequencing in Angus-Simmental crossbred heifers sampled at weaning and retrospectively classified as fertile (FH, n = 7) or subfertile (SFH, n = 7). In addition to differentially expressed miRNAs (DEMIs), their target genes were predicted from TargetScan. The PWBC gene expression from the same heifers were retrieved and co-expression networks were constructed between DEMIs and their target genes. We identified 16 differentially expressed miRNAs between the groups (p-value ≤0.05 and absolute (log2 fold change ≥0.05)). Interestingly, based on a strong negative correlation identified from miRNA-gene network analysis with PCIT (partial correlation and information theory), we identified miRNA-target genes in the SFH group. Additionally, TargetScan predictions and differential expression analysis identified bta-miR-1839 with ESR1 , bta-miR-92b with KLF4 and KAT2B, bta-miR-2419-5p with LILRA4, bta-miR-1260b with UBE2E1, SKAP2 and CLEC4D, and bta-let-7a-5p with GATM, MXD1 as miRNA-gene targets. The miRNA-target gene pairs in the FH group are over-represented for MAPK, ErbB, HIF-1, FoxO, p53, mTOR, T-cell receptor, insulin and GnRH signaling pathways, while those in the SFH group include cell cycle, p53 signaling pathway and apoptosis. Some miRNAs, miRNA-target genes and regulated pathways identified in this study have a potential role in fertility; other targets are identified as novel and need to be validated in a bigger cohort that could help to predict the future reproductive outcomes of beef heifers.

Programming Mechanism of Adipose Tissue Expansion in the Rat Offspring of Obese Mothers Occurs in a Sex-Specific Manner.

We investigated whether excessive retroperitoneal adipose tissue (AT) expansion programmed by maternal obesity (MO) affects adipocyte size distribution and gene expression in relation to adipocyte proliferation and differentiation in male and female offspring (F1) from control (F1C) and obese (F1MO) mothers. Female Wistar rats (F0) ate a control or high-fat diet from weaning through pregnancy and lactation. F1 were weaned onto a control diet and euthanized at 110 postnatal days. Fat depots were weighed to estimate the total AT. Serum glucose, triglyceride, leptin, insulin, and the insulin resistance index (HOMA-IR) were determined. Adipocyte size and adipogenic gene expression were examined in retroperitoneal fat. Body weight, retroperitoneal AT and adipogenesis differed between male and female F1Cs. Retroperitoneal AT, glucose, triglyceride, insulin, HOMA-IR and leptin were higher in male and female F1MO vs. F1C. Small adipocytes were reduced in F1MO females and absent in F1MO males; large adipocytes were increased in F1MO males and females vs. F1C. Wnt, PI3K-Akt, and insulin signaling pathways in F1MO males and Egr2 in F1MO females were downregulated vs. F1C. MO induced metabolic dysfunction in F1 through different sex dimorphism mechanisms, including the decreased expression of pro-adipogenic genes and reduced insulin signaling in males and lipid mobilization-related genes in females.

The effects of sucrose and arsenic on muscular insulin signaling pathways differ between the gastrocnemius and quadriceps muscles.

Insulin resistance in muscle can originate from a sedentary lifestyle, hypercaloric diets, or exposure to endocrine-disrupting pollutants such as arsenic. In skeletal muscle, insulin stimulates glucose uptake by translocating GLUT4 to the sarcolemma. This study aimed to evaluate the alterations induced by sucrose and arsenic exposure in vivo on the pathways involved in insulinstimulated GLUT4 translocation in the quadriceps and gastrocnemius muscles. Male Wistar rats were treated with 20% sucrose (S), 50 ppm sodium arsenite (A), or both (A+S) in drinking water for 8 weeks. We conducted an intraperitoneal insulin tolerance (ITT) test on the seventh week of treatment. The quadriceps and gastrocnemius muscles were obtained after overnight fasting or 30 min after intraperitoneal insulin injection. We assessed changes in GLUT4 translocation to the sarcolemma by cell fractionation and abundance of the proteins involved in GLUT4 translocation by Western blot. Male rats consuming S and A+S gained more weight than control and Atreated animals. Rats consuming S, A, and A+S developed insulin resistance assessed through ITT. Neither treatments nor insulin stimulation in the quadriceps produced changes in GLUT4 levels in the sarcolemma and Akt phosphorylation. Conversely, A and A+S decreased protein expression of Tether containing UBX domain for GLUT4 (TUG), and A alone increased calpain-10 expression. All treatments reduced this muscle's protein levels of VAMP2. Conversely, S and A treatment increased basal GLUT4 levels in the sarcolemma of the gastrocnemius, while all treatments inhibited insulin-induced GLUT4 translocation. These effects correlated with lower basal levels of TUG and impaired insulin-stimulated TUG proteolysis. Moreover, animals treated with S had reduced calpain-10 protein levels in this muscle, while A and A+S inhibited insulin-induced Akt phosphorylation. Arsenic and sucrose induce systemic insulin resistance due to defects in GLUT4 translocation induced by insulin. These defects depend on which muscle is being analyzed, in the quadriceps there were defects in GLUT4 retention and docking while in the gastrocnemius the Akt pathway was impacted by arsenic and the proteolytic pathway was impaired by arsenic and sucrose.

Paliurus spina-christi Mill fruit extracts improve glucose uptake and activate the insulin signaling pathways in HepG2 insulin-resistant cells

BackgroundPaliurus spina-christi Mill. (PSC) fruit is frequently used in the treatment of diabetes mellitus in Mediterranean regions. Here, we investigated the effects of various PSC fruit extracts (PSC-FEs) on glucose consumption and some key mediators of insulin signaling pathways in high glucose and high insulin-induced insulin-resistant HepG2 cells.MethodsThe effects of methanolic, chloroform and total extracts on cell proliferation were assessed by the MTT assay. The potential of non-toxic extracts on glucose utilization in insulin-resistant HepG2 cells was checked using a glucose oxidase assay. AKT and AMP-activated protein kinase (AMPK) pathway activation and mRNA expression levels of insulin receptor (INSR), glucose transporter 1 (GLUT1), and glucose transporters 4 (GLUT4) were determined by western blotting and real-time PCR, respectively.ResultsWe found that high concentrations of methanolic and both low and high concentrations of total extracts were able to enhance glucose uptake in an insulin-resistant cell line model. Moreover, AKT and AMPK phosphorylation were significantly increased by the high strength of methanolic extract, while total extract raised AMPK activation at low and high concentrations. Also, GLUT 1, GLUT 4, and INSR were elevated by both methanolic and total extracts.ConclusionsUltimately, our results shed new light on methanolic and total PSC-FEs as sources of potential anti-diabetic medications, restoring glucose consumption and uptake in insulin-resistant HepG2 cells. These could be at least in part due to re-activating AKT and AMPK signaling pathways and also increased expression of INSR, GLUT1, and GLUT4. Overall, active constituents present in methanolic and total extracts of PCS are appropriate anti-diabetic agents and explain the use of these PSC fruits in traditional medicine for the treatment of diabetes.

Integrating Metabolomics and Network Pharmacology to Explore the Mechanism of Tongmai Yangxin Pills in Ameliorating Doxorubicin-Induced Cardiotoxicity.

Doxorubicin (DOX) is a broad-spectrum chemotherapeutic drug used in clinical treatment of malignant tumors. It has a high anticancer activity but also high cardiotoxicity. The aim of this study was to explore the mechanism of Tongmai Yangxin pills (TMYXPs) in ameliorating DOX-induced cardiotoxicity through integrated metabolomics and network pharmacology. In this study, first, an ultrahigh-performance liquid chromatography-quadrupole-time-of-flight/mass spectrometry (UPLC-Q-TOF/MS) metabonomics strategy was established to obtain metabolite information and potential biomarkers were determined after data processing. Second, network pharmacological analysis was used to evaluate the active components, drug-disease targets, and key pathways of TMYXPs to alleviate DOX-induced cardiotoxicity. Targets from the network pharmacology analysis and metabolites from plasma metabolomics were jointly analyzed to select crucial metabolic pathways. Finally, the related proteins were verified by integrating the above results and the possible mechanism of TMYXPs to alleviate DOX-induced cardiotoxicity was studied. After metabolomics data processing, 17 different metabolites were screened, and it was found that TMYXPs played a role in myocardial protection mainly by affecting the tricarboxylic acid (TCA) cycle of myocardial cells. A total of 71 targets and 20 related pathways were screened out with network pharmacological analysis. Based on the combined analysis of 71 targets and different metabolites, TMYXPs probably played a role in myocardial protection through regulating upstream proteins of the insulin signaling pathway, MAPK signaling pathway, and p53 signaling pathway, as well as the regulation of metabolites related to energy metabolism. They then further affected the downstream Bax/Bcl-2-Cyt c-caspase-9 axis, inhibiting the myocardial cell apoptosis signaling pathway. The results of this study may contribute to the clinical application of TMYXPs in DOX-induced cardiotoxicity.