Search Results (284)

Chronic low-grade inflammation is a hallmark of both metabolic and neurodegenerative diseases. In recent years, several studies have highlighted the pivotal role of systemic metabolic dysfunction, particularly insulin resistance, in shaping neuroinflammatory processes and contributing to impaired cognitive performance. Among metabolic disorders, type 2 diabetes mellitus has emerged as a major risk factor for the development of age-related neurodegenerative conditions, suggesting a complex and bidirectional crosstalk between peripheral metabolic imbalance and central nervous system function. This review aims to explore the cellular and molecular mechanisms underlying the interaction between metabolic dysregulation and brain inflammation. By integrating current findings from endocrinology, immunology, and neuroscience, this work provides a comprehensive overview of how chronic metabolic inflammation may contribute to the onset and progression of neurodegenerative conditions. This interdisciplinary approach could offer novel insights into potential therapeutic strategies targeting both metabolic and neuroinflammatory pathways. Full article

Intermittent fasting (IF) and caloric restriction (CR) have garnered attention for their potential to enhance cognitive function, particularly in aging and metabolically compromised populations. This narrative review critically examines whether the cognitive benefits of IF are attributable to its specific fasting patterns or are instead mediated by the production of weight loss, fat loss, and improvements in insulin sensitivity. Evidence from human trials suggests that reductions in body weight, especially visceral adiposity, and improvements in insulin resistance are key factors linked to enhanced cognitive performance. Comparisons between the results of IF and CR trials show comparable cognitive outcomes, supporting the idea that negative energy balance, rather than fasting or altered eating patterns, drive these effects. However, further investigation of specific types of IF patterns, as well as possible cognitive domains to be affected, may identify mechanisms through which IF can yield benefits on neurocognitive health beyond those of loss of body fat and its accompanying inflammatory state. Full article

Insulin-degrading enzyme (IDE) plays a critical role in regulating insulin levels in various tissues, including the brain, liver, and kidneys. In type 2 diabetes mellitus (T2DM), key features include insulin resistance, elevated insulin levels in the blood, and hyperglycemia. In this context, the function of IDE becomes particularly important; however, in T2DM, IDE’s function can be impaired. Notably, individuals with T2DM have a higher risk of developing Alzheimer’s disease (AD), suggesting that impaired IDE function may contribute to both diabetes and neurodegeneration. IDE has been studied for its ability to degrade Amyloid-β peptides, the primary constituents of amyloid plaques in AD. However, its role in Aβ clearance in vivo remains debated due to limited enzymatic efficacy under physiological conditions and differences in subcellular localization between IDE and its putative substrate. Other proteases, such as neprilysin, appear to play a more prominent role in preventing plaque formation. Additionally, the long-standing hypothesis that insulin competes with Aβ for IDE activity has been questioned, as brain insulin levels are too low to inhibit Aβ degradation significantly. Genetic variants in the IDE gene have been associated with increased AD risk, although the mechanisms by which they alter enzyme function are not yet fully understood. A deeper understanding of IDE’s role in the context of both metabolic and neurodegenerative diseases may provide valuable insights for the development of new therapeutic strategies. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental condition frequently associated with gastrointestinal symptoms, gut dysbiosis, and metabolic dysfunctions such as insulin resistance (IR). Recent evidence suggests that the gut microbiota may influence both metabolic and neurological processes through the gut–brain–metabolic axis. This review explores the molecular mechanisms linking dysbiosis, IR, and ASD, focusing on pathways such as TLR/NF-κB activation, PI3K/Akt/mTOR disruption, and the action of microbial metabolites, like short-chain fatty acids (SCFAs), lipopolysaccharide (LPS), and γ-aminobutyric acid (GABA). We discuss how dysbiosis may contribute to increased intestinal permeability, systemic inflammation, and neuroimmune activation, ultimately affecting brain development and behavior. Common microbial alterations in ASD and IR—including increased Clostridium, Desulfovibrio, and Alistipes, and reduced Bifidobacterium and butyrate-producing genera—suggest a shared pathophysiology. We also highlight potential therapeutic strategies, such as microbiota modulation, insulin-like growth factor 1 (IGF-1) treatment, and dietary interventions. Understanding these interconnected mechanisms may support the development of microbiota-targeted approaches for individuals with ASD metabolic comorbidities. Full article

Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in the regulation of synaptic plasticity and metabolic processes, including glucose metabolism and insulin sensitivity. In patients with obstructive sleep apnea (OSA), recurrent episodes of intermittent hypoxia may stimulate BDNF expression as a compensatory neuroprotective response. OSA is associated with metabolic disturbances, such as increased insulin resistance and a higher risk of type 2 diabetes. Continuous positive airway pressure (CPAP) therapy may influence both BDNF levels and metabolic outcomes. The aim of this study was to evaluate changes in BDNF concentration and glucose metabolism in patients with OSA, with particular emphasis on the effect of long-term CPAP therapy. Sixty-six adult patients with OSA confirmed by polysomnography were enrolled and divided into severe (s-OSA) and non-severe (ns-OSA) groups. Fasting blood samples were collected to measure glucose, insulin, and BDNF concentrations. Patients with s-OSA were re-evaluated after 12 months of CPAP therapy and further classified as compliant (sc-OSA) or non-compliant (snc-OSA) based on recorded device usage. The same biochemical parameters were assessed after the 12-month follow-up. Baseline BDNF levels were significantly higher in the s-OSA group compared to the ns-OSA group (20.1 ng/mL vs. 8.1 ng/mL, p = 0.02) and correlated with the apnea–hypopnea index (AHI, r = 0.38, p = 0.02). In the nsc-OSA group, BDNF concentrations increased significantly after 12 months (16.2 ng/mL vs. 35.5 ng/mL, p < 0.001), while no significant change was observed in the sc-OSA group (24.4 ng/mL vs. 27.4 ng/mL, p = 0.33). Among sc-OSA patients, a significant improvement in insulin resistance was noted, although no significant changes were observed in fasting glucose or insulin levels. Increased BDNF levels were observed in patients with s-OSA compared to ns-OSA. Compliant CPAP therapy was associated with reduced insulin resistance and no further BDNF increase, in contrast to non-compliance, suggesting a beneficial effect of CPAP on glucose metabolism and BDNF regulation. These findings support the hypothesis that both neurotrophic and metabolic responses in OSA may be modulated by disease severity and therapy adherence. Full article

Obesity is characterized by excessive fat accumulation that triggers chronic low-grade inflammation and systemic immune dysregulation, significantly increasing the risk of metabolic disorders including insulin resistance, type 2 diabetes, and cardiovascular disease. This review examines the bidirectional relationship between obesity and immune dysfunction, focusing on how immune cell infiltration in adipose tissue drives inflammatory processes. We highlight the phenotypic shifts in key immune populations—macrophages polarized toward proinflammatory M1 phenotypes, T cell exhaustion occurrs, and alterations appear in B cells, natural killer (NK) cells, and dendritic cells—that collectively contribute to metabolic deterioration. The gut microbiome emerged as a critical mediator in this relationship, influencing both immune responses and metabolic regulation through gut–liver and gut–brain axes. We explore emerging immunomodulatory therapeutic strategies, including anti-inflammatory agents, microbiota interventions, and targeted immune therapies such as innovative nanomedicine approaches. The review also addresses the challenges of immunotherapy in obesity, particularly the paradoxical effects observed in cancer immunotherapy outcomes and the need for personalized treatment approaches. Artificial intelligence is highlighted as a potential tool to enhance patient stratification and treatment optimization in future immunomodulatory interventions. Understanding these immunometabolic interactions provides a foundation for developing more effective therapeutic strategies that could transform obesity management and reduce the burden of obesity-related metabolic diseases. Full article

This study investigates the health benefits of supplementing Asian seabass diets with hot water crude extract from the sea lettuce Ulva rigida (Ur-HWCE). The extract’s proximate composition consists of 57.63% carbohydrates, 6.75% protein, 31.96% ash, and 6.01% sulfate polysaccharides, as confirmed by FTIR spectrum analysis. It also exhibits significant antioxidant properties, including total antioxidants, ABTS, DPPH, and reducing power. The study involved four groups fed Ur-HWCE at 0.5, 1.0, and 5 g/kg compared to a control group, with feed prepared daily and given twice at 5% of body weight for 4 weeks. Ur-HWCE supplementation did not negatively impact growth performance. It significantly upregulated insulin-like growth factor 1 (igf1) in the brain and liver, enhancing growth processes. Ur-HWCE reduced oxidative stress markers, such as malondialdehyde (MDA). Enhanced immune responses were observed, including increased bactericidal activity, serum IgM levels, and the upregulation of immune-related genes (dcs, c3, ighm, lyz, il8, il10). Gut microbiota analyses showed increased beneficial aerobic and natural probiotic Bacillus spp., particularly Bacillus amyloliquefaciens, enhancing gut health by reducing pathogenic bacteria. Blood biochemical parameters remained stable, and no histopathological alterations were found in the liver and intestine tissues, confirming the supplement’s safety. Fish fed with Ur-HWCE showed significantly higher survival rates and relative percent survival (RPS) against Vibrio vulnificus AAHM-VV2312 compared to the control group, demonstrating improved disease resistance. The study concludes that Ur-HWCE is a promising dietary supplement for enhancing the health, growth, and disease resistance of Asian seabass, supporting its potential in sustainable aquaculture practices. Full article

Retinoic acid (RA) exerts biological effects through RA receptors (RARs) to regulate transcription. RA also elicits rapid, RAR-independent (noncanonical) activities mediated by Cellular RA Binding Protein 1 (CRABP1) to modulate cytosolic signaling. CRABP1 functions by forming protein complexes, named CRABP1 signalosomes, to modulate signal propagation in a cell type-specific manner. This review summarizes multiple CRABP1 signalosomes and their physiological functions. CRABP1 knockout (CKO) mice develop multiple phenotypes progressively throughout the lifespan. These include altered brain function, obesity, and insulin resistance starting at young adult stages, increased vulnerability to heart failure and altered serum exosome profiles in midlife, and motor deterioration and thyroid dysfunction (hypothyroidism) in later life. The mouse Crabp1 gene is tightly regulated by multiple epigenetic mechanisms, whereas human CRABP1 gene dysregulation is associated with multiple human diseases in which age is an important factor. Further, CRABP1 expression in human and mouse thyroid glands gradually increases with aging. This underscores the clinical relevance of CRABP1 signalosomes in maintaining health and the functions of certain cells/organ systems, especially in the thyroid and during the aging process. The CRABP1 sequence is highly conserved, likely due to its functional constraint in forming various signalosomes; its tight regulation ensures proper expression of CRABP1 required for the forming of various signalosomes critical to the health and functions of multiple cell types/organ systems. Finally, CRABP1-specific (without activating RARs) signaling pathway-selective compounds have been designed. It may be an attractive therapeutic strategy to exploit these CRABP1-specific compounds to modulate selective signaling pathways in certain disease conditions, such as thyroid dysfunction, to maximize efficacy while minimizing retinoid toxicity. Full article

Glucagon-like peptide-1 receptor agonists, originally developed for the treatment of metabolic disorders, have recently emerged as promising candidates for the management of substance use disorders. This review synthesizes preclinical, clinical, and translational evidence on the effects of glucagon-like peptide-1 receptor agonists across addiction models involving alcohol, nicotine, psychostimulants, and opioids. In animal studies, glucagon-like peptide-1 receptor agonists consistently reduce drug intake, attenuate dopamine release in reward circuits, and decrease relapse-like behavior. Clinical and observational studies provide preliminary support for these findings, particularly among individuals with comorbid obesity or insulin resistance. However, several translational barriers remain, including limited blood–brain barrier penetration, species differences in pharmacokinetics, and variability in treatment response due to genetic and metabolic factors. Ethical considerations and methodological heterogeneity further complicate clinical translation. Future directions include the development of central nervous system penetrant analogues, personalized medicine approaches incorporating pharmacogenomics, and rigorously designed trials in diverse populations. Glucagon-like peptide-1 receptor agonists may offer a novel therapeutic strategy that addresses both metabolic and neuropsychiatric dimensions of addiction, warranting further investigation to define their role in the evolving landscape of substance use disorder treatment. Full article

Autism spectrum disorder (ASD) is a pervasive condition of neurodevelopmental origin with an increasing burden on society. Idiopathic ASD is notorious for its heterogeneous behavioral manifestations, and despite substantial efforts, its etiopathology is still unclear. An increasing amount of data points to the causative role of critical developmental alterations in the first year of life, although the contribution of fetal, environmental, and genetic factors cannot be clearly distinguished. This review attempts to propose a narrative starting from neuropathological findings in ASD, involving insulin-like growth factor 1 (IGF-1) as a key modulator and demonstrates how the most consistent gestational risk factors of ASD–maternal insulin resistance and fetal growth insufficiency–converge at the perinatal dysregulation of offspring anabolism in the critical period of early development. A unifying hypothesis is derived, stating that the co-occurrence of these gestational conditions leads to postnatal biphasic dysregulation of IGF-1 tone in the offspring, leading first to insulin-dependent accelerated development, then to subsequent arrest of growth and brain maturation in ASD as an etiologic process. This hypothesis is tested for its explanation of various widely reported risk factors and observations of idiopathic ASD, including early postnatal growth abnormalities, the pervasive spectrum of symptoms, familial predisposition, and male susceptibility. Finally, further directions of research are outlined. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and synaptic dysfunction. The accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau protein leads to neuronal dysfunction, neuroinflammation, and glial cell activation. Emerging evidence suggests that peripheral insulin resistance and chronic inflammation, often associated with type 2 diabetes (T2D) and obesity, promote increased proinflammatory cytokines, oxidative stress, and immune cell infiltration. These conditions further damage the blood–brain barrier (BBB) integrity and promote neurotoxicity and chronic glial cell activation. This induces neuroinflammation and impaired neuronal insulin signaling, reducing glucose metabolism and exacerbating Aβ accumulation and tau hyperphosphorylation. Indeed, epidemiological studies have linked T2D and obesity with an increased risk of developing AD, reinforcing the connection between metabolic disorders and neurodegeneration. This review explores the relationships between peripheral insulin resistance, inflammation, and BBB dysfunction, highlighting their role in glial activation and the exacerbation of AD pathology. Full article

Alterations in sympathetic nervous activity are evident in response to changes in body weight. Sympathetic nervous activity and sympathetic responses to weight change are regionalized, with alterations in end organ function dependent on the changes occurring in the brain regulatory pathways invoked and in the effector organs engaged. The obesity-induced activation of the sympathetic nervous system likely contributes to the initiation and worsening of cardiometabolic risk factors, including elevated blood pressure, cardiac dysfunction, dyslipidaemia, increased fasting blood glucose, insulin resistance, and non-alcoholic steatohepatitis. Unintended weight loss, as occurs in cachexia, is driven, at least in part, by the activation of sympathetic nervous-stimulated thermogenesis. The complexity of sympathetic nervous regulation renders the use of global measures of sympathetic activity problematic and the development of targeted therapies difficult, but these are not without promise or precedent. Knowledge of the central and peripheral pathways involved in sympathetic nervous regulation has opened up opportunities for pharmacological, surgical, and device-based approaches to mitigating the burden of disease development and progression. In this narrative review, we elaborate on sympathetic activity in response to changes in body weight, the brain pathways involved, and the cardiovascular and metabolic risks associated with perturbations in regional sympathetic activity. Full article

The Alzheimer’s disease (AD)-affected brain is known to be deficient in the utilization of glucose, its main energy substrate, and systemic diabetes is a significant risk factor for AD. In the course of biochemical and molecular investigations into this puzzling relationship, it has been shown that resistance to insulin action is a prominent feature of early stages of AD in the brain, thereby contributing to an energy failure state and a decline in synaptic function. In one AD-like cellular model, we found that β-amyloid (Aβ) accumulation inhibited insulin signaling and cell viability through an alteration of the PI3K/PDK-1/Akt signal pathway, an effect overcome by mTORC2 stimulation. A PDK-1 allosteric agonist, PS48, as well as newly synthesized analogs, were also found to reverse the metabolic defects caused by intracellular Aβ42 accumulation. In vivo, we previously showed that oral dosing of PS48 significantly improves learning and memory in APP/PS1 transgenic mice. Herein, we present evidence using unbiased immunohistological quantification and Western blot analyses demonstrating that ingested PS48 crosses into brain tissue where it targeted Akt and GSK3-β activities. Beneficial effects on neuronal number and Tau phosphorylation were found. Not unexpectedly, Aβ levels remained unchanged. These results support a path toward a future therapeutic trial of this untested strategy and agent in humans. Full article

Background/Objectives: Brain insulin resistance is a potential causal factor for dementia in Alzheimer’s disease (AD). Insulin-like growth factor-1 (IGF-1), a neurotrophin, plays a key role in central insulin signaling and neuroprotection. Intracerebrovenitricular (ICV) administration of streptozotocin (STZ) disrupts insulin signal transduction, leading to brain insulin resistance, which may mimic the early pathophysiological changes in sporadic AD (sAD). In this study, we investigated whether restoring insulin signaling through ICV injection of IGF-1 could ameliorate spatial memory deficits during sAD progression in a rat model induced by ICV STZ injection. Methods: Male Wistar rats (n = 40) were subjected to double ICV injections of STZ (0.75 mg/kg/ventricle, days 2 and 4) and IGF-1 (1 μg/single injection, days 1 and 3), and placed at the Morris water maze (MWM) at baseline, 7, 45 and 90 days after injections. Reference (days 1–3 and day 4 MWM)) and working (days 5–8 MWM) memory, microglia activation (CD68⁺ cells), and amyloid β (Aβ) deposition (immunohistochemistry) were measured. Results: We found that ICVIGF-1 administration protected working memory demonstrated as (1) reduced latency to reach the platform, and reduced swimming distance in trials 3 (p < 0.05) and 4 (p < 0.01) on days 45 and 90 post-injection and (2) a short-term (up to 45 days post-injection) enhancement of reference memory, manifested by a reduction in swimming distance and latency (p < 0.05). Furthermore, IGF-1 treatment reduced neuroinflammation in CA2 (p < 0.05) and Aβ deposition in CA1(p < 0.01) of the hippocampus. Conclusions: Central IGF-1 attenuates spatial memory deficits in the ICVSTZ-induced sAD model by reducing neuroinflammation and Aβ accumulation in the hippocampus. Full article

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and behavioral changes. It poses a significant global health challenge. AD is associated with the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain, along with chronic inflammation, dysfunctional neurons, and synapse loss. While the prevalence of AD continues to rise, the current FDA-approved drugs offer only limited effectiveness. Emerging evidence suggests that obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM) are also implicated in AD pathogenesis, with epidemiological studies and animal models confirming the impact of IR on Aβ accumulation, and high-fat diets also exacerbating Aβ accumulation. Since neuroinflammation activated by Aβ involves the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) pathway, the inhibition of NF-κB and NLRP3 inflammasome activation are potential therapeutic strategies in AD. Bioactive compounds, including polyphenols (resveratrol, epigallocatechin-3-gallate, curcumin, and quercetin), and omega-3 polyunsaturated fatty acids, show promising results in animal studies and clinical trials for reducing Aβ levels, improving cognition and modulating the signaling pathways implicated in AD. This review explores the interplay between obesity, IR, inflammation, and AD pathology, emphasizing the potential of dietary compounds and their role in reducing inflammation, oxidative stress, and cognitive decline, as viable strategies for AD prevention and treatment. By integrating epidemiological findings, observational studies, and clinical trials, this review aims to provide a comprehensive understating of how metabolic dysfunctions and bioactive compounds influence AD progression. Full article