Pampus argenteus, a species distributed throughout the Indo-West Pacific, plays a significant role in the yield of aquaculture species. However, cultured P. argenteus has always been characterised by unbalanced growth synchronisation among individuals, slow growth rate, and lack of excellent germplasm resources. Therefore, we conducted mass selection for fast-growing strain P. argenteus for several consecutive years. Various genetic improvement programs have modified its genome sequence through selective pressure, leaving nucleotide signals that can be detected at the genomic level. In the present study, we combined bulked segregant analysis and transcriptome sequencing to identify candidate single nucleotide polymorphisms (SNPs) and key genes for growth-related traits in P. argenteus. A total of 7,280,936 SNPs and 2,212,379 insertions/deletions were identified in the extreme phenotypes of the fast-growing and slow-growing groups. Based on the examination of SNP frequency differences and sliding-window analysis, 42 SNPs were identified as candidate markers. Moreover, 14 of the 42 SNPs linked to growth-related traits were confirmed to be credible SNPs, and eight growth-related genes were screened, namely myb-binding protein 1 A, insulin A/B chains, α-1B adrenoceptor, engulfment and cell motility protein 3, myosin light chain kinase family member 4, insulin receptor located, unconventional myosin-9b, and matrilin-1. An optimal three-factor model (SNP4&SNP12&SNP14) was constructed using the generalized multifactor dimensionality reduction method, and its accuracy was verified as 67.72 %. These results may benefit genetic studies and accelerate genetic improvement of fast-growing strains of P. argenteus.

Numerous studies have focused on nutrient-driven regulation of muscle metabolism/homeostasis through the mammalian target of rapamycin complex 1 (mTORC1) pathway, but their results fail to converge, perhaps due to differences in mTORC1 pathway protein studied, muscle type, and/or sex. The aim of this work was to study the influence of these factors on mTORC1 pathway activation in response to food intake. Rats (16 male and 16 female) were fasted for 20 h and then were randomized into two groups: a postabsorptive group in which the animals were euthanized in the fasted state and a postprandial group in which the animals were euthanized 30 min after food intake (10 g). Plasma glucose, insulin, and amino acids were assayed. Muscles (extensor digitorum longus, tibialis, soleus, gastrocnemius and plantaris) were removed and Western blotted to analyze the activation of the mTORC1 pathway [phosphorylation of Akt, 4E-binding protein 1 (4E-BP1), and S6K1]. Levels of Akt, 4E-BP1, and S6K1 activation were compared between muscles and by sex in different nutritional states, and a Kruskal-Wallis test was performed to find statistically significant differences.Food intake led to an increase in plasma concentrations of glucose, insulin, and total amino acids (P < 0.0001). Levels of Akt, 4E-BP1, and S6K1 activation differed significantly between muscles and by sex and nutritional state. Different phosphorylation sites in the same muscle were not correlated with each other. These results suggest that mTORC1 activation level is sensitive to muscle type, sex, and nutritional state. Studies on this signal transduction pathway therefore require an individualized approach, considering all the factors that may affect it.NEW & NOTEWORTHY This work demonstrates the complexity of the regulation of the mTOR pathway depending on the protein, muscle, sex, and nutritional status studied. This systemic approach is very little/not considered in the articles.

A series of 38 phthalazinone-triazole compounds were synthesized using Click chemistry to identify potential antidiabetic agents. These compounds were systematically tested for their ability to promote glucose transporter type 4 (GLUT4) translocation in skeletal muscle cells. Among the 38 derivatives, 11 compounds (i.e., 12k, 13a-13c, 13e-13i, 13s, and 13v) showed significant potential to stimulate GLUT4 translocation in skeletal muscle cells, with compound 13a exhibiting most promising activity. Further, treatment with 13a induced a concentration-dependent increase in GLUT4 translocation in L6 skeletal muscle cells through the activation of wortmannin-sensitive PI-3-K-dependent signaling and AMPK-dependent signaling pathways. The in vivo studies further demonstrated that compound 13a effectively lowered blood glucose levels in STZ-induced diabetic rats and displayed favorable pharmacokinetic properties, making it a promising candidate for further development as an antidiabetic agent.

This meta-analysis aimed to evaluate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) when compared to metformin and placebo in the management of body weight, glucose homeostasis and hormone levels in women polycystic ovary syndrome (PCOS). A systematic search of "PubMed", "EMBASE", "Cochrane Library", "Web of Science" and "Google Scholar" was conducted up to October 2024 for randomized controlled trials involving adult women with PCOS treated with GLP-1RAs compared to metformin or placebo. The primary outcomes were changes in body mass index (BMI), body weight, waist circumference (WC), waist-to-hip ratio (WHR) and abdominal girth (AG). Secondary outcomes included glucose homeostasis (fasting glucose, fasting insulin, OGTT results and HOMA-IR), hormone levels (DHEAS, SHBG, total and free testosterone and FAI), lipid profiles (total cholesterol, HDL, LDL and triglycerides) and safety. GLP-1RAs significantly reduced BMI, body weight, WC, WHR and AG (P < 0.0001 in all cases). For glucose homeostasis, GLP-1RAs significantly reduced fasting insulin, glucose level at 2 h after OGTT, and HOMA-IR. There was also a reduction in HDL. All the other parameters measured were unchanged. In addition, GLP-1RAs increased nausea (P = 0.02), vomiting (0.04) and dizziness (0.03). GLP-1RAs effectively reduced body weight, BMI and insulin resistance in patients with PCOS, although they were accompanied by nausea, vomiting and dizziness. Further studies are needed to explore their long-term effects on glucose homeostasis and lipid profiles.

Phloretin, a natural dihydrochalcone, exhibits significant potential in modulating lipid metabolism both in vitro and in vivo. This study investigated the effects of phloretin on lipid accumulation in HepG2 cells and Caenorhabditis elegans. In HepG2 cells, phloretin reduced lipid accumulation, ROS levels, and lipid peroxidation while ameliorating mitochondrial dysfunction. It downregulated lipid synthesis genes (SREBP, FASN) and upregulated PI3K-AKT pathway genes (AKT, FOXO, MTOR). In C. elegans, phloretin alleviated lipid accumulation-induced growth and locomotor impairments, reduced lipofuscin, ROS, glucose, and triglyceride levels, and modulated amino acid and lipid metabolism pathways. Gene expression analysis revealed downregulation of sbp-1, mdt-15, fat-5, fat-6, and fat-7, and upregulation of daf-16, age-1, and skn-1. Mutant studies confirmed that phloretin's lipid-lowering effects were mediated through the IIS and sbp-1/SREBP pathways. These findings suggest phloretin is a promising candidate for regulating lipid metabolism and preventing hyperlipidemia.

Contrasting almost all other mammalian wintering strategies, Eurasian common shrews, Sorex araneus, endure winter by shrinking their brain, skull, and most organs, only to then regrow to breeding size the following spring. How such tiny mammals achieve this unique brain size plasticity while maintaining activity through the winter remains unknown. To discover potential adaptations underlying this trait, we analyzed seasonal differential gene expression in the shrew hypothalamus, a brain region that both regulates metabolic homeostasis and drastically changes size, and compared hypothalamus gene expression across species. We discovered seasonal variation in suites of genes involved in energy homeostasis and apoptosis, shrew-specific upregulation of genes involved in the development of the hypothalamic blood-brain barrier and calcium signaling, as well as overlapping seasonal and comparative gene expression divergence in genes implicated in the development and progression of human neurological and metabolic disorders, including CCDC22. With high metabolic rates and facing harsh winter conditions, S. araneus have evolved both adaptive and plastic mechanisms to sense and regulate their energy budget. Many of these changes mirrored those identified in human neurological and metabolic disease, highlighting the interactions between metabolic homeostasis, brain size plasticity, and longevity.

The prepartum rise in cortisol promotes cardiac development and maturation. Here, we investigated the impact of elevated circulating cortisol during mid-late gestation on cardiac growth and metabolism in fetal sheep. Saline or cortisol (2-3 mg in 4.4 mL/24 h) was infused into the fetal jugular vein from 109 to 116 days gestation (dG, term = 150 dG), and fetal heart tissue was collected at 116 dG. Glucocorticoid concentrations, gene and protein expression were measured in fetal left ventricle (LV) tissue. Intrafetal cortisol infusion increased cardiac cortisol concentration but downregulated the protein abundance of glucocorticoid receptor (GR) isoforms (GRα-A, GR-P, GR-A, GRα-D2 and GRα-D3). The gene and protein expression of markers of cardiac hyperplastic growth (IGF1, IGF-1R, TGFβ and AGT) were downregulated, while a protein marker of DNA replication (proliferating cell nuclear antigen) was upregulated by cortisol infusion. Cardiac protein and/or gene expression of complex I of the electron transport chain, SOD2, GLUT-4 (gene and protein), and phosphorylated IRS-1, were upregulated in response to elevated fetal cortisol concentration. Intrafetal cortisol infusion downregulated gene expression of PDK4, which mediates the metabolic switch from glucose to fatty acid metabolism. Cardiac expression of molecular markers involved in cardiovascular protection (SIRT-1, HO1, LAMP1 and SK1) were also downregulated in the cortisol group. In conclusion, these findings suggest that chronic cortisol exposure in preterm fetuses alters heart development, promoting cardiac maturation and potentially increasing the risk of cardiovascular disease later in life if these changes persist into adulthood.

Type 2 diabetes mellitus (T2DM) is a medical disorder characterized by high blood sugar levels resulting from a lack of insulin caused by impaired activity of 𝛽-cells and/or the inability of insulin to efficiently transport glucose from the bloodstream into cells, a condition referred to as insulin resistance. This occurs not only in insulin-sensitive tissues such as muscles, adipose tissue, and the liver, but also in the gastrointestinal tract, which may be caused by a defect in the insulin signaling pathway. MicroRNAs (miRNAs) are RNA molecules that do not code for proteins and play a role in multiple pathways. Several studies have suggested that specific miRNAs could potentially be used as biomarkers for diagnosing diabetes. These miRNAs regulate the formation of pancreatic islets, the differentiation of β-cells, the secretion of insulin, and the control of glucose metabolism. miRNA-mediated pathways are associated with human genetic illnesses resulting from mutations in the maturation process of miRNAs. The changes in miRNAs impact their ability to bind to mRNA targets, hence modifying gene expression. This review provides a concise overview of the latest studies investigating the correlation between miRNA expression and the regulation of glucose levels in cases of β-cell malfunction and insulin resistance.

Chicken Primordial Germ Cells (PGCs) are one of the few germ cells that can be cultured for a long time in vitro, but challenges remain such as low culture efficiency and unclear roles of nutrient factors and signaling pathways.

In this study, protein kinase B (AKT) pathway activator insulin-like growth factor 1 (IGF-1) was screened for its ability to promote cell proliferation by transcriptome results using various inhibitors of pathway activation. The effects of IGF-1 on PGCs were evaluated through EdU assays, qRT-PCR, flow cytometry, and migration experiments.

This study systematically examined the effects of insulin and IGF-1 on the proliferation, cell cycle, ferroptosis, migration capacity, and establishment efficiency of PGCs. The findings demonstrated that IGF-1 exhibited comparable effects to insulin and could effectively replace insulin in PGC culture systems.

The research results are expected to provide a solid theoretical basis for optimizing the chicken PGC cultivation system and promoting its practical application.

Allosteric regulation is a pivotal mechanism governing a wide array of cellular functions. Essential to this process is a flexible biomolecule allowing distant sites to interact through coordinated or sequential conformational shifts. Phosphoinositide-dependent kinase 1 (PDK1) possesses a conserved allosteric binding site, the PIF-pocket, which regulates the kinase's ATP binding, catalytic activity, and substrate interactions. We elucidated the allosteric mechanisms of PDK1 by comparing conformational ensembles of the kinase bound with different small-molecule allosteric modulators in the PIF-pocket with that of the modulator-free kinase. Analysis of over 48 μs of simulations consistently shows that the allosteric modulators predominantly influence the conformational dynamics of specific distal regions from the PIF-pocket, driving allosteric activation. Furthermore, a recently developed advanced difference contact network community analysis is employed to elucidate allosteric communications. This approach integrates multiple conformational ensembles into a single community network, offering a valuable tool for future studies aimed at identifying function-related dynamics in proteins.

A library of 30 novel quinazolinone-dihydropyrimidinone derivatives was synthesized employing a diversity-oriented approach for the identification of potential anti-diabetic therapeutic lead. In vitro evaluation revealed that seven compounds (5d, 5e, 5i, 5j, 5l, 5m and 5s) significantly enhanced the rate of GLUT4 translocation to the cell surface in L6-GLUT4myc myotubes. Out of these, compound, 5m exhibited promising potency to stimulate GLUT4 translocation in skeletal muscle cells via activating AMPK-dependent pathway, but independent to PI-3-K/AKT signaling. Under in vivo conditions, treatment with 5m demonstrated a marked 39.5 % (p < 0.001) reduction in blood glucose levels in a streptozotocin-induced diabetic rat model after 5 h of treatment. Pharmacokinetic analysis indicated compound 5m shows favourable pharmacokinetic properties. Overall, the compound 5m emerged as a promising lead compound for subsequent structural modification and optimization to develop a novel and potent anti-hyperglycemic agent.

Chronic obstructive pulmonary disease (COPD) is a progressive and debilitating condition characterized by airflow limitations and systemic inflammation. The interaction between the metabolic and inflammatory pathways plays a key role in disease progression, with leptin and insulin emerging as pivotal metabolic regulators. Leptin, an adipokine that regulates energy homeostasis, and insulin, the primary regulator of glucose metabolism, are both altered in COPD patients. This narrative review provides an in-depth examination of the roles of leptin and insulin in COPD pathogenesis, focusing on the molecular mechanisms through which these metabolic regulators interact with inflammatory pathways and how their dysregulation contributes to a spectrum of extrapulmonary manifestations. These disturbances not only exacerbate COPD symptoms but also increase the risk of comorbidities such as metabolic syndrome, diabetes, cardiovascular disease, or muscle wasting. By exploring the underlying mechanisms of leptin and insulin dysregulation in COPD, this review underscores the significance of the metabolic-inflammatory axis, suggesting that restoring metabolic balance through leptin and insulin modulation could offer novel therapeutic strategies for improving clinical outcomes.

The mevalonate (MVA) pathway plays a critical role in cholesterol biosynthesis, protein prenylation, and metabolic reprogramming, all of which contribute to cancer progression and therapy resistance. Targeting the MVA pathway with statins and other inhibitors has shown promise in preclinical studies; however, clinical outcomes remain controversial, raising concerns about translating these findings into effective treatments. Additionally, the interaction between the MVA pathway and radiation therapy (RT) is not yet fully understood, as RT upregulates the pathway, which can enhance tumor cell survival. This review summarizes the current literature on MVA pathway inhibition in cancer therapy, focusing on its potential to enhance the efficacy of RT. A better understanding of the pathway's role in radiation responses will be essential to translate combination therapies that target this pathway.

While statins are effective at managing lipid levels, there is growing evidence for new-onset diabetes mellitus (NODM). The insulin signalling pathway (ISP) inhibited by statins is one of the potential mechanisms; however, most studies have been limited to in vitro settings. Therefore, this study aimed to identify the genetic associations within the ISP-related genes and NODM.

We performed a retrospective analysis of samples collected prospectively from February 2021 to May 2021. Among ISP-related genes, we selected 11 candidate genes (IGF1, IGF2, IGF1R, INSR, IRS1, IRS2, PIK3CA, PIK3CB, PIK3R1, AKT1 and AKT2). An additional analysis was conducted comparing patients with DM prior to statin therapy and controls to determine whether the single nucleotide polymorphisms (SNPs) are specific to statin.

A total of 602 patients were analysed, including 71 (11.8%) with statin-induced NODM. After adjustment, IGF1R rs2715439, INSR rs1799817, INSR rs2059807 and PIK3R1 rs3730089 were found to be independently associated with NODM. In an additional analysis, all SNPs that demonstrated an association with statin-induced NODM lost their significance in patients with DM prior to statin therapy.

This study revealed the ISP-related genetic effects, specifically involving genes such as INSR, IGF1R and PIK3R1, in the development of statin-induced NODM. Our findings suggest a potential mechanism of statin-induced NODM related to ISP-related genetic variants.

BackgroundBrain insulin signaling has been associated with both Alzheimer's disease (AD) pathology and cognitive decline, but the mechanisms remain unclear.ObjectiveTo examine whether AD-related cortically-expressed proteins modify the association of brain insulin signaling and cognitive decline.MethodsParticipants included 116 autopsied members of the Religious Orders Study (58 with diabetes matched to 58 without, by age at death, sex, and education) who had both postmortem brain (prefrontal cortex) insulin signaling (by ELISA and immunohistochemistry, including RAC-alpha serine/threonine-protein kinase or AKT1) and AD-related cortical protein measurements. Levels of five AD-related proteins including insulin-like growth factor-binding protein-5 (IGFBP-5) and inositol-tetrakisphosphate 1-kinase (ITPK1) were measured using quantitative proteomics. We conducted adjusted linear mixed model analyses to examine associations of insulin signaling measures and AD-related proteins with longitudinally assessed cognitive function.ResultsHigher levels of IGFBP-5 and lower levels of ITPK1 were each associated with higher levels of AKT1 phosphorylation (pT308AKT1 /total AKT1). Additionally, higher levels of AKT1 phosphorylation were associated with faster decline in global cognition and most cognitive domains. IGFBP-5 partially mediated the association of AKT1 phosphorylation with the decline rate of global cognition and cognitive domains including perceptual speed and visuospatial abilities. Further, ITPK1 had an interaction with AKT1 phosphorylation on decline of global cognition and domains including episodic memory, perceptual speed, and visuospatial abilities.ConclusionsAD-related proteins IGFBP-5 and ITPK1 are each associated with insulin signaling AKT1 phosphorylation in the postmortem human brain. Moreover, IGFBP-5 mediates, while ITPK1 moderates, the association between AKT1 phosphorylation and late-life cognitive decline.

Activated immune cells are highly susceptible to human immunodeficiency virus (HIV) infection. Vitamin D (VitD) induces antimicrobial responses and reduces cellular activation. We investigated VitD effects on HIV-1 replication, glucose uptake, and gene regulation using computational and in vitro approaches. CD4+ T cells from healthy male donors were treated with VitD and infected with HIV-1. After 72 h, p24 protein was measured to assess viral replication. VitD effects on anti- and pro-HIV genes were analyzed by a Boolean network model based on curated databases and the literature. CCR5 and CXCR4 coreceptor expression, AKT phosphorylation, and glucose uptake were evaluated by flow cytometry, and expression of some model-identified genes was quantified by qPCR. VitD reduced p24 by 53.2% (p = 0.0078). Boolean network modeling predicted that VitD upregulates antiviral, migration, and cell-differentiation related genes, while downregulating genes related to cellular activation, proliferation, glucose metabolism, and HIV replication, notably AKT1, CCNT1, SLC2A1, HIF1A, and PFKL. In vitro, VitD reduced AKT phosphorylation by 26.6% (p = 0.0156), transcription of CCNT1 by 22.7% (p = 0.0391), and glucose uptake by 22.8% (p = 0.0039) without affecting classic antiviral genes or coreceptor expression. These findings suggest an anti-HIV effect of VitD, mediated through AKT and glucose metabolism downmodulation, both involved in cell activation and HIV-1 replication.

Gastrodin (gas) has been shown to promote neuroprotection and reverse Alzheimer's disease (AD) pathology. However, its high effective dose limits its potential in treating AD. In this study, a bioassay system using PC12 cells and the nerve growth factor (NGF)-mimic effect was employed to investigate the structure-activity relationship of gas derivatives. Among the synthesized compounds, GAD037 demonstrated the highest NGF-mimic activity, surpassing gas. Additionally, GAD037 exhibited significant neuroprotective effects, reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels, thereby improving the survival of PC12 cells under oxidative stress. It also protected cells from Aβ-induced toxicity. Target protein identification and mechanistic studies revealed that insulin receptor (INSR) and alpha-actinin-4 (ACTN4) are potential targets of GAD037, confirmed through specific inhibitors, small interfering RNA (siRNA) analysis, a cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). Moreover, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and rat sarcoma (Ras)/protooncogene serine-threonine protein kinase (Raf)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways were found to be involved in the NGF-mimic activity of GAD037. In conclusion, GAD037 exhibits superior NGF-mimic and neuroprotective activities compared to gas, suggesting its potential as a lead compound for anti-AD applications.

We examined the acute effects of intranasal insulin on cognitive function and brain glutathione (GSH), a central factor in resistance to oxidative stress, in both participants with early psychosis and healthy control (HC) participants.

Twenty-one patients with early-stage psychotic disorders and 18 HC participants underwent magnetic resonance spectroscopy (MRS) scans and cognitive assessments before and after administration of intranasal insulin 40 IU. We conducted proton MRS (1H-MRS) in the prefrontal cortex at 4T to measure GSH and glutamate metabolites. We assessed cognition using the Brief Assessment of Cognition in Schizophrenia symbol coding, digit sequencing, and verbal fluency tasks, in addition to the Stroop task.

The mean (SD) age of participants was 25.7 (4.6) years; 51.3% were female. There were no significant group differences at baseline in age, sex, body mass index, homeostatic model assessment of insulin resistance (HOMA-IR), or cognition. Patients had higher baseline GSH (p < .001) and glutamate (p = .007). After insulin administration, GSH increased in HC participants (mean change, 0.15; 95% CI 0.03 to 0.26; p = .015), but not in patients. Symbol coding improved in both patients (0.74; 95% CI 0.37 to 1.11; p < .001) and HC participants (0.83; 95% CI 0.58 to 1.09; p < .001), and verbal fluency improved in HC participants (0.43; 95% CI 0.14 to 0.72; p = .006). Lower baseline HOMA-IR was associated with greater change in GSH (coefficient -0.22; 95% CI -0.40 to -0.04; p = .017).

Intranasal insulin increased brain GSH in HC participants, but not in patients with early psychotic disorders. These novel findings demonstrate that intranasal insulin enhances antioxidant capacity and resilience to oxidative stress in HC individuals in contrast to an absent antioxidant response in those with early psychotic disorders.

Vascular endothelium is integral to the regulation of vascular homeostasis and maintenance of normal arterial function in healthy individuals. Endothelial dysfunction is a significant contributor to the advancement of atherosclerosis, which can precipitate cardiovascular complications. A notable correlation exists between diabetes and endothelial dysfunction, wherein chronic hyperglycemia and acute fluctuations in glucose levels exacerbate oxidative stress. This results in diminished nitric oxide synthesis and heightened production of endothelin-1, ultimately leading to endothelial impairment. In clinical settings, it is imperative to implement appropriate therapeutic strategies aimed at enhancing endothelial function to prevent and manage diabetes-associated vascular complications. Various antidiabetic agents, including insulin, GLP-1 receptor agonists, sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, α-glucosidase inhibitors, thiazolidinediones (TZDs), and metformin, are effective in mitigating blood glucose variability and improving insulin sensitivity by lowering postprandial glucose levels. Additionally, traditional Chinese medicinal compounds, such as turmeric extract, resveratrol, matrine alkaloids, tanshinone, puerarin, tanshinol, paeonol, astragaloside, berberine, and quercetin, exhibit hypoglycemic properties and enhance vascular function through diverse mechanisms. Consequently, larger randomized controlled trials involving both pharmacological and herbal interventions are essential to elucidate their impact on endothelial dysfunction in patients with diabetes. This article aims to explore a comprehensive approach to the treatment of diabetic endothelial dysfunction based on an understanding of its pathophysiology.

RNA N6-methyladenosine (m6A) is one of the most common and widespread reversible epigenetic modifications of mRNAs, and m6A has been shown to play a positive role in regulating follicular development. However, the role of RNA m6A methylation in chicken ovaries and egg production has not been fully studied. In this study, we comprehensively analyzed the m6A transcriptome profiles of high- and low-yield Gushi chickens at 43 weeks of age (43 w). We found that m6A modification differed between the two groups. The m6A peak was positively correlated with the gene expression level, indicating that m6A may play an important role in regulating chicken egg production. In total, 9008 and 15,415 m6A peaks were separately identified in the two groups, including 2241 differential m6A peaks. In addition, seven candidate genes related to egg laying that were significantly enriched in the KEGG pathway related to ovary development and egg laying were identified. In summary, we constructed the first m6A modification map of ovarian tissue of Gushi chickens, and the differences in egg laying in 43 w Gushi chickens may originate from the effect of RNA methylation on the expression of egg-related genes. These findings provide new insights into the regulatory mechanisms of m6A methylation during egg production in Gushi chickens.

Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.

The liver plays an important role in the control of glucose homeostasis. When insulin levels are low, such as in the fasting state, gluconeogenesis and glycogenolysis are stimulated to maintain the blood glucose levels. Conversely, in the presence of increased insulin levels, such as after a meal, synthesis of glycogen and lipid occurs to maintain the blood glucose levels within normal range. Insulin receptor signaling regulates glycogenesis, gluconeogenesis and lipogenesis through downstream pathways such as the insulin receptor substrate (IRS)-phosphoinositide 3 (PI3) kinase-Akt pathway. IRS-1 and IRS-2 are abundantly expressed in the liver and are thought to be responsible for transmitting the insulin signal from the insulin receptor to the intracellular effectors involved in the regulation of glucose and lipid homeostasis. Impaired insulin receptor signaling can cause hepatic insulin resistance and lead to type 2 diabetes. In the present study, we focus on a concept called "selective insulin resistance," which has received increasing attention recently: the frequent coexistence of hyperglycemia and hepatic steatosis in people with type 2 diabetes and obesity suggests that it is possible for the insulin signaling regulating gluconeogenesis to be impaired even while that regulating lipogenesis is preserved, suggestive of selective insulin resistance. In this review, we review the progress in research on the insulin actions and insulin signaling in the liver.

Extracellular vesicles (EVs) have emerged as novel blood-based biomarkers for various pathologies. The development of methods to enrich cell-specific EVs from biofluids has enabled us to monitor difficult-to-access organs, such as the brain, in real time without disrupting their function, thus serving as liquid biopsy. Burgeoning evidence indicates that the contents of neuron-derived EVs (NDEs) in blood reveal dynamic alterations that occur during neurodegenerative pathogenesis, including Alzheimer's disease (AD), reflecting a disease-specific molecular signature. Among these AD-specific molecular changes is brain insulin-signaling dysregulation, which cannot be assessed clinically in a living patient and remains an unexplained co-occurrence during AD pathogenesis. This review is focused on delineating how NDEs in the blood may begin to close the gap between identifying molecular changes associated with brain insulin dysregulation reliably in living patients and its connection to AD. This approach could lead to the identification of novel early and less-invasive diagnostic molecular biomarkers for AD. HIGHLIGHTS: Neuron-derived extracellular vesicles (NDEs) could be isolated from peripheral blood. NDEs in blood reflect the molecular signature of Alzheimer's disease (AD). Brain insulin-signaling dysregulation plays a critical role in AD. NDEs in blood could predict brain insulin-signaling dysregulation. NDEs offer novel early and less-invasive diagnostic biomarkers for AD.

Choline is an essential nutrient required for proper functioning of organs and serves as a methyl donor. In liver where choline metabolism primarily occurs, glucose homeostasis is regulated through insulin receptor substrates (IRS) 1 and 2. The objective of this research was to determine the role of prenatal choline as a modulator of metabolic health and DNA methylation in liver of offspring and dams. Pregnant Wistar rat dams were fed an AIN-93G diet and received drinking water either with supplemented 0.25% choline (w/w) as choline bitartrate or untreated control. All offspring were weaned to a high-fat diet for 12 weeks. Prenatal choline supplementation led to higher insulin sensitivity in female offspring at weaning as well as lower body weight and food intake and higher insulin sensitivity in female and male adult offspring compared to offspring from untreated dams. Higher hepatic betaine concentrations were observed in dams and female offspring of choline-supplemented dams at weaning and higher glycerophosphocholine in female and male offspring at postweaning compared to the untreated control, suggestive of sustaining different choline pathways. Hepatic gene expression of Irs2 was higher in dams at weaning and female offspring at weaning and postweaning, whereas Irs1 was lower in male offspring at postweaning. Gene-specific DNA methylation of Irs2 was lower in female offspring at postweaning and Irs1 methylation was higher in male offspring at postweaning that exhibited an inverse relationship between methylation and gene expression. In conclusion, prenatal choline supplementation contributes to improved parameters of insulin signaling but these effects varied across time and offspring sex.

The blood-brain barrier (BBB) is a highly selective, semipermeable barrier critical for maintaining brain homeostasis. The BBB regulates the transport of essential nutrients, hormones, and signaling molecules between the bloodstream and the central nervous system (CNS), while simultaneously protecting the brain from potentially harmful substances and pathogens. This selective permeability ensures that the brain is nourished and shielded from toxins. An exception to this are brain regions, such as the hypothalamus and circumventricular organs, which are irrigated by fenestrated capillaries, allowing rapid and direct response to various blood components. We overview the metabolic functions of the BBB, with an emphasis on the impact of altered glucose metabolism and insulin signaling on BBB in the pathogenesis of neurodegenerative diseases. Notably, endothelial cells constituting the BBB exhibit distinct metabolic characteristics, primarily generating ATP through aerobic glycolysis. This occurs despite their direct exposure to the abundant oxygen in the bloodstream, which typically supports oxidative phosphorylation. The effects of insulin on astrocytes, which form the glial limitans component of the BBB, show a marked sexual dimorphism. BBB nutrient sensing in the hypothalamus, along with insulin signaling, regulates systemic metabolism. Insulin modifies BBB permeability by regulating the expression of tight junction proteins, angiogenesis, and vascular remodeling, as well as modulating blood flow in the brain. The disruptions in glucose and insulin signaling are particularly evident in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, where BBB breakdown accelerates cognitive decline. This review highlights the critical role of normal glucose metabolism and insulin signaling in maintaining BBB functionality and investigates how disruptions in these pathways contribute to the onset and progression of neurodegenerative diseases.

Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular pattern recognition receptor that detects injury signals and initiates inflammatory responses and host defense. Furthermore, NOD1 serves as a metabolic mediator by influencing the metabolism of various tissues, including adipose tissue, liver, cardiovascular tissue, pancreatic β cells, adrenal glands, and bones through diverse mechanisms. It has been discovered that activated NOD1 is associated with the pathological mechanisms of certain metabolic diseases. This review presents a comprehensive summary of the impact of NOD1 on tissue-specific metabolism.

Glucose homeostasis is maintained by insulin. Insulin resistance is caused by multiple factors including hereditary factors and diet. The molecular mechanism underlying insulin resistance (IR) is not completely understood. Hyperinsulinemia often precedes insulin resistance and Type 2 diabetes. We had previously shown that prolonged exposure of insulin-responsive cells to insulin in the absence of high levels of glucose led to insulin resistance. In the present study, we show that the underlying cause for the impaired insulin signalling is the defective PI3K/AKT pathway. The observed insulin resistance is likely due to epigenetic alterations, as it can be maintained for several generations even when insulin is not provided, and epigenetic modifiers can reverse it. We also show that liver cell line (BRL-3A) developed impaired insulin signalling upon prolonged exposure to insulin in the absence of high levels of glucose. Transcriptomic analysis of the insulin-sensitive and resistance cells uncover altered signalling networks involved in chromatin remodelling, Rho GTPases, and ubiquitination. Furthermore, trimethylation of histone H3 at lysine 4 (H3K4me3) is increased in insulin-resistant cells. We extended these studies to mice, and show that mice injected with low doses of insulin when fasting develop insulin resistance with impaired glucose tolerance and increased HOMA-IR index. Altogether, these findings suggest that dysregulated synthesis of insulin in the absence of glucose stimulus could lead to epigenetic alterations that may ultimately result in insulin resistance.

Aphids exhibit a unique reproductive strategy known as pseudoplacental viviparity, in which embryos develop internally and are thought to receive nutrients such as sugars and amino acids directly from the maternal hemolymph through an ovariole sheath, bypassing the need for traditional yolk storage. This system enables viviparous aphids to adapt to diverse and potentially stressful environments by transmitting maternal environmental cues that influence transgenerational plasticity. However, the mechanisms underlying this nutrient-mediated plasticity are poorly understood. This study focused on the role of trehalose, a primary sugar in the maternal hemolymph, in facilitating adaptive plasticity. Trehalose serves as an energy source and may act as a carrier of environmental information from the mother to offspring, potentially influencing resilience and adaptability. The results showed that winged adult aphids have higher levels of trehalose than wingless morphs, and that these elevated trehalose levels are inherited by their first-instar nymphs. This transfer may help the offspring of winged aphids survive in resource-poor environments after migration. Gene expression analysis showed the upregulation of trehalose metabolism genes in winged adults, possibly to meet the increased energy demands of flight and reproduction. However, trehalose metabolism in embryos appears to be regulated independently of postnatal nutrient uptake. In vitro studies further suggested that trehalose can directly penetrate the oocyte sheath and embryo membrane, supporting a direct pathway for trehalose transfer. These findings highlight the adaptive role of trehalose in aphid development and suggest a potential mechanism for nutrient-based transgenerational plasticity in aphids.

The sheer amplitude of biological actions of insulin-like growth factor I (IGF-1) affecting all types of cells in all tissues suggests a vast signaling landscape for this ubiquitous humoral signal. While the canonical signaling pathways primarily involve the Ras/MAPK and PI3K/AKT cascades, the evolutionary conservation of insulin-like peptides (ILPs) and their pathways hints at the potential for novel functions to emerge over time. Indeed, the evolutionary trajectory of ILPs opens the possibility of either novel functions for these two pathways, novel downstream routes, or both. Evidence supporting this notion includes observations of neofunctionalization in bony fishes or crustaceans, and the involvement of ILPs pathways in invertebrate eusociality or in vertebrate bone physiology, respectively. Such evolutionary processes likely contribute to the rich diversity of ILPs signaling observed today. Moreover, the interplay between conserved signaling pathways, such as those implicated in aging (predominantly involving the PI3K-AKT route), and lesser known pathways, such as those mediated by biased G-protein coupled receptors and others even less known, may underpin the context-dependent actions characteristic of ILPs signaling. While canonical IGF-1 signaling is often assumed to account for the intracellular pathways utilized by this growth factor, a comprehensive analysis of all the pathways mediated by the IGF-1 receptor (IGF-1R) remains lacking. This review aims to explore both canonical and non-canonical routes of IGF-1R action across various cell types, offering a detailed examination of the mechanisms underlying IGF-1 signaling and highlighting the significant gaps in our current understanding.

Leptin is an adipose tissue-derived hormone that plays a crucial role in body weight, appetite, and behaviour regulation. Leptin controls energy balance as an indicator of adiposity levels and as a modulator of the reward system, which is associated with liking palatable foods. Obesity is characterized by expanded adipose tissue mass and consequently, elevated concentrations of leptin in blood. Leptin's therapeutic potential for most forms of obesity is hampered by leptin resistance and a narrow dose-response window.

This review describes the current knowledge of the brain regions and intracellular pathways through which leptin promotes negative energy balance and restrains neural circuits affecting food reward. We also describe mechanisms that hinder these biological responses in obesity and highlight potential therapeutic interventions.

Additional research is necessary to understand how pathways engaged by leptin in different brain regions are interconnected in the control of energy balance.

The worldwide epidemic of obesity has drastically worsened with the increase in more sedentary lifestyles and increased consumption of fatty foods. Increased blood free fatty acids, often observed in obesity, lead to impaired insulin action, and promote the development of insulin resistance and type 2 diabetes mellitus. c-Jun N-terminal kinase (JNK), inhibitor of kappa B (IκB) kinase (IKK)-nuclear factor-kappa B (NF-κB), and signal transducer and activator of transcription 3 (STAT3) are known to be involved in skeletal muscle insulin resistance. We reported previously that carnosic acid (CA) and rosmarinic acid (RA) attenuated the palmitate-induced skeletal muscle insulin resistance, an effect that was associated with increased AMPK activation and reduced mammalian target of rapamycin-p70S6K signaling. In the present study, we examined the effects of CA and RA on JNK, IKK-NF-κB, and STAT3. Exposure of cells to palmitate increased the phosphorylation/activation of JNK, IKKα/β, IκBα, NF-κBp65, and STAT3. Importantly, CA and RA attenuated the deleterious effects of palmitate. Our data indicate that CA and RA have the potential to counteract the palmitate-induced skeletal muscle cell insulin resistance by modulating JNK, IKK-NF-κB, and STAT3 signaling.

UpToDate, no drugs have been approved to treat nonalcoholic steatohepatitis, the advanced stage of the most prevalent liver disease, non-alcoholic fatty liver disease. The present study was conducted to explore the potential influences of L-carnitine on the pathomechanisms of hepatic injury that mediate progression to non-alcoholic steatohepatitis in dexamethasone-toxified rats.

Male Wistar rats were allocated as follows: dexamethasone group, rats received dexamethasone (8 mg/kg/day, intraperitoneally) for 6 days; DEXA-LCAR300, DEXA-LCAR500, and DEXA-MET groups, rats administered L-carnitine (300 or 500 mg/kg/day, IP) or metformin (500 mg/kg/day, orally) one week prior to dexamethasone injection (8 mg/kg/day, IP) and other six days alongside dexamethasone administration. Two groups of age-matched normal rats received either the drug vehicle (the control group) or the higher dose of L-carnitine (the drug-control group). At the end of the experiment, sets of biochemical, histological, and immunohistochemical examinations were performed.

L-carnitine (mainly at the dose of 500 mg/kg/day) markedly abolished dexamethasone-induced alterations in glucose tolerance, hepatic histological features, and serum parameters of hepatic function and lipid profile. Moreover, it significantly ameliorated dexamethasone-induced elevations of hepatic oxidative stress, SREBP-1 and p-MLKL protein levels, and nuclear FOXO1, LC3, P62, and caspase-3 immunohistochemical expression. Furthermore, it markedly diminished dexamethasone-induced suppression of hepatic Akt phosphorylation and Bcl2 immunohistochemical expression. The effects of L-carnitine (500 mg/kg/day) were comparable to those of metformin in most assessments and better than its corresponding lower dose.

These findings introduce L-carnitine as a potential protective drug that may mitigate the rate of disease progression in non-alcoholic fatty liver disease patients with early stages or those at the highest risks.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by insulin resistance and impaired beta-cell secretory function. Since existing treatments often present side effects based on different mechanisms, alternative therapeutic options are needed. In this scenario, the present study first evaluates the cytotoxicity of decoctions from the leaves, stems, and roots of Cucumis prophetarum L. on HepG2 and L6C5 cells. The extracts were chemically investigated by UV-Vis and ATR-FTIR spectroscopic techniques and by ultra high-performance chromatographic techniques, coupled with high-resolution mass spectrometry. Briefly, decoctions from the leaves and stems were mainly composed of apigenin C-glycosides, while the root decoction was rich in raffinose and cucumegastigmane II. To evaluate the insulin-sensitizing properties of the extracts in insulin-resistant L6 myoblasts, an evaluation by Western blot analysis of the proteins in the insulin signaling pathway was then performed. Particularly, key proteins of insulin signaling were investigated, i.e., insulin receptor substrate (IRS-1), protein kinase B (PKB/AKT), and glycogen synthase kinase-3 (GSK-3β), which have gained considerable attention from scientists for the treatment of diabetes. Under all conditions tested, the three decoctions showed low cytotoxicity. The stem and root decoction (300 μg/mL) resulted in a significant increase in the levels of p-IRS-1 (Tyr612), GSK3β (Ser9), and p-AMPK (Thr172) compared to those of the palmitic acid-treated group, and the leaf decoction resulted an increase in the level of p-IRS-1 (Tyr612) and p-AMPK (Thr172) and a decrease in p-GSK3β (Ser9) compared to the levels for the palmitic acid-treated group. The root decoction also reduced the level of p-mToR (Ser2448). Overall, the acquired data demonstrate the effect of reducing insulin resistance induced by the investigated decoctions, opening new scenarios for the evaluation of these effects aimed at counteracting diabetes and related diseases in animal models.

In this study, the full-length cDNA sequences of the phosphatidylinositol-3-kinase p85 alpha (PI3KR1) and serine/threonine kinase 1 (AKT1) genes in largemouth bass (Micropterus salmoides) were obtained using the rapid amplification of cDNA ends (RACE) method. Sequence analysis revealed that the cloned sequences of PI3KR1 and AKT1 are 4170 bp and 3672 bp in length, with open reading frames (ORFs) of 1389 bp and 1422 bp encoding 462 and 473 amino acids, respectively. Sequence alignment and evolutionary tree analysis indicated their close relationship to other teleosts, especially those with similar feeding habits. Tissue distribution demonstrated widespread distribution of both genes in various tissues, with the highest abundance in the liver. Further results found that the upregulation of the expression of p-PI3KR1, p-AKT1, p-FoxO1, and GLUT2 proteins by insulin, while suppressing the expression of the total FoxO1 protein, effectively triggers a significant activation of the PI3KR1-AKT1 insulin signaling pathway. Meanwhile, the mRNA levels of the key glycolytic genes, including glucokinase (gk), pyruvate kinase (pk), and phosphofructokinase liver type (pfkl), have been enhanced evidently. In contrast, the expression of gluconeogenic genes such as phosphoenolpyruvate carboxykinase (pepck), glucose-6-phosphatase catalytic subunit (g6pc), and fructose-1,6-bisphosphatase-1 (fbp1) has been notably down-regulated. In addition, insulin treatment promoted the phosphorylation of glycogen phosphorylase (PYGL) and the dephosphorylation of glycogen synthase (GS), and the glycogen content in the insulin-treated group was remarkably reduced compared to the control group. Overall, our study indicates that the activation of PI3KR1-AKT1 insulin signaling pathway represses the hepatic glycogen deposition via the regulation of glycolysis and gluconeogenesis, which provides some new insights into nutritional strategy to effectively regulate the glucose metabolism in carnivorous fish.

Tumor necrosis factor alpha (TNF-α)/hypoxia-treated 3T3-L1 adipocytes have been used to model inflamed and insulin-resistant adipose tissue: this study examines gaps in the model. We tested whether modulating TNF-α/hypoxia treatment time could reduce cell death while still inducing inflammation and insulin resistance. Adipocytes were treated with TNF-α (12 h or 24 h) and incubated in a hypoxic chamber for 24 h. To examine maintenance of the phenotype over time, glucose and FBS were added at 24 h post initiation of treatment, and the cells were maintained for an additional 48 h. Untreated adipocytes were used as a control. Viability, insulin resistance, and inflammation were assessed using Live/Dead staining, RT-qPCR, ELISA, and glucose uptake assays. Treatment for 12 h with TNF-α in the presence of hypoxia resulted in an increase in the percentage of live cells compared to 24 h treated cells. Importantly, insulin resistance and inflammation were still induced in the 12 h treated adipocytes: the expression of the insulin sensitive and inflammatory genes was decreased and increased, respectively. In 72 h treated adipocytes, no significant differences were found in the viability, glucose uptake or insulin-sensitive and inflammatory gene expression. This study provides a modified approach to in vitro odeling adipocyte inflammation and insulin resistance.        .

Lipid droplets (LDs) are highly specialized energy storage organelles involved in the maintenance of lipid homoeostasis by regulating lipid flux within white adipose tissue (WAT). The physiological function of adipocytes and LDs can be compromised by mutations in several genes, leading to NEFA-induced lipotoxicity, which ultimately manifests as metabolic complications, predominantly in the form of dyslipidemia, ectopic fat accumulation, and insulin resistance. In this review, we delineate the effects of mutations and deficiencies in genes - CIDEC, PPARG, BSCL2, AGPAT2, PLIN1, LIPE, LMNA, CAV1, CEACAM1, and INSR - involved in lipid droplet metabolism and their associated pathophysiological impairments, highlighting their roles in the development of lipodystrophies and metabolic dysfunction.

The insulin receptor (IR) and insulin like growth factor-1 receptor (IGF-1R) are heterodimers consisting of two extracellular α-subunits and two transmembrane β -subunits. Insulin αβ and insulin like growth factor-1 αβ hemi-receptors can heterodimerize to form hybrids composed of one IR αβ and one IGF-1R αβ. The function of hybrids in the endothelium is unclear. We sought insight by developing a small molecule capable of reducing hybrid formation in endothelial cells.

We performed a high-throughput small molecule screening, based on a homology model of the apo hybrid structure. Endothelial cells were studied using western blotting and qPCR to determine the effects of small molecules that reduced hybrid formation.

Our studies unveil a first-in-class quinoline-containing heterocyclic small molecule that reduces hybrids by >50% in human umbilical vein endothelial cells (HUVECs) with no effects on IR or IGF-1R. This small molecule reduced expression of the negative regulatory p85α subunit of phosphatidylinositol 3-kinase, increased basal phosphorylation of the downstream target Akt and enhanced insulin/insulin-like growth factor-1 and shear stress-induced serine phosphorylation of Akt. In primary saphenous vein endothelial cells (SVEC) from patients with type 2 diabetes mellitus undergoing coronary artery bypass (CABG) surgery, hybrid receptor expression was greater than in patients without type 2 diabetes mellitus. The small molecule significantly reduced hybrid expression in SVEC from patients with type 2 diabetes mellitus.