Body and mind: how obesity triggers neuropsychiatric and neurodegenerative disorders

Frontiers in Psychiatry, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 7, 2025

Obesity has emerged as a significant health concern, particularly affecting young people worldwide.Its prevalence extends beyond Westernized countries and been projected to rise from 107.7 million obese children adolescents in 2015 254 by 2030 (1). This metabolic disorder poses severe consequences for healthcare systems globally, childhood obesity often persists into adulthood (2). Unlike other diseases, is pathological condition that renders individuals more susceptible various disorders, including syndrome, cardiovascular disease, nonalcoholic fatty liver cancer (3).Metabolic dysfunctions disrupt the structural functional of humans, central nervous system (CNS) (4). The hypothalamus, pivotal region situated between CNS periphery, serves control center energy homeostasis, body temperature, food intake, essential functions (5). Consuming diet high calories, carbohydrates lipids, triggers vicious cycle hyperactivation immune cells neuroinflammatory mediators within resulting widespread effects (6). Consequently, alterations this key brain led impairments all related neuronal circuits areas, mesolimbic dopamine (DA) system, hippocampus, nucleus accumbens, striatum, cortex, which are primarily associated with such cognition mood regulation.The gut microbiota plays role pathophysiology neuropsychiatric neurodegenerative context obesity. gut-brain axis mediates relationship (7). Obesity-induced peripheral influence function enhancing neuroinflammation, altering neurotransmitter synthesis, impairing insulin signaling These mechanisms have elevated risks depression, anxiety, cognitive decline, diseases (8). Specifically, Proteobacteria Cyanobacteria overrepresented patients (9,10). dysregulation metabolites these bacteria may contribute systemic inflammation oxidative damage, indirectly pathways relevant (11,12).Obesity disorders intricately interconnected, their share numerous characteristics (13). At level, obesity-related detrimental factors compromised integrity blood-brain barrier (BBB), prevents entry substances (14). BBB sophisticated highly specialized biological construct, characterized its selective permeability protective CNS. leads BBB, increased permeability, altered transport mechanisms, inflammatory responses Consistently, our findings indicate disruption induced high-fat (HFD) evidenced albumin extravasation hippocampus mice, represents critical mechanism pathogenesis (15). In condition, signals via gut-microbiotabrain can impact activity, both negatively positively metainflammation, levels pro-inflammatory mediators, activates astrogliosis microgliosis, leading neuroinflammation (16). microglia, resident CNS, (17). Under normal conditions, microglia maintain homeostasis regulating synaptic pruning clearing cellular debris. However, response chronic stress or inflammation, become activated release lead neurotoxicity (18). blocks machinery responsible neurogenesis, process renewal (19). Indeed, reduce neurogenesis suppressing stem cell proliferation, increasing apoptosis progenitor cells, decreasing survival newly developing neurons integration existing (20). Furthermore, long-term consumption Western-style HFD, low fiber content, substantial reduction short-chain acids, endogenous molecules notable anti-inflammatory neurogenesis-promoting properties (21). Our studies demonstrated HFD feeding depressive-and anxiety-like behavior intestinal dysbiosis, proliferation inflammatory-related microbes, alteration tryptophan metabolite pathway (22). production toxic tryptophan, quinolinic kynurenic acid, severally (23). neurobiological encompass reward circuitry, diminished serotonin (5-HT) DA levels, augmented hypothalamic-pituitary-adrenal (HPA) component body's (24). particular, known balance neurotransmitters regulation, 5-HT gammaaminobutyric acid (GABA). Elevated interleukin (IL)-6 tumor necrosis factor (TNF)-α serotonergic GABAergic systems, exacerbate symptoms (25). conditions serve etiological basis depressive anxiety phenotypes.Given growing intricate recent evidence also highlights shared mechanistic targets two conditions. For instance, peroxisome proliferator-activated receptor (PPAR)-α, whose lipid metabolism tissues well-established clinical therapy, recently recognized an tranquilizer caused dysmetabolism (26). PPAR-α widely distributed across amygdala, prefrontal thalamic nuclei, ventral tegmental area (VTA), basal ganglia (27). Moreover, research Jiang et al. (28) agonist WY14643 ameliorated depressive-like behaviors effect attributed activation Brain-Derived Neurotrophic Factor pathway.Neurodegenerative increasingly complex, bidirectional (29). Obesity, midlife, risk several Alzheimer's disease (AD), Parkinson's (PD), forms decline (30). correlation mediated combination metabolic, inflammatory, hormonal affect (31). resistance, changes (leptin adipokines), mitochondrial dysfunction, (32). Metainflammation, feature many dysmetabolism, impairs Neuroinflammation, turn, accelerates damage contributes progression. increases free radicals decreases antioxidant defenses, (33). process, coupled impaired function, damages structures, proteins, DNA, accelerating degeneration (34).Emerging underscores obesity, etiology AD, even if aging primary AD (35). Therefore, significantly correlates dysfunction (36). context, excessive weight processes derangements increase amyloid β (Aβ) accumulation (37). connection Aβ deposition; low-grade state, reactive oxygen species (38). (39). HFD-linked observed induce impair impacting (40).Notably, VTA, involved function.Different types HFDs alter potentially perceptions intake (41).Insulin influences transporter establishing outcomes (42). appears involve expression dopamine-degrading enzymes MAO-A MAO-B, reduces (43).Furthermore, microglial progression (44). interplay implies not only but through involving adipose tissue.While PD traditionally genetic environmental toxins, emerging indicates development (29).Specifically, suggested later life. mass index range at midlife exhibited higher likelihood years (45).Obesity linked worsening motor non-motor (46). It causing stiffness, flexibility, hindering physical already challenge PD. Additionally, older adults, be vascular health, worsen (47). during adipocytes cytokines TNF-α, IL-6, C-reactive protein (48).Lipid overnutrition subsequent metainflammation direct on brain, exacerbating player As it dopaminergic neurons, crucial (49). Since neurotoxic promote obesity-induced further activation, (50).At molecular regulate DA, contributing onset (51). Notably, leptin, produced adipocytes, regulation brain's (52). Research suggests leptin hallmark signal transduction, (53).The purpose opinion draw attention obesity-driven investigating how address "pandemic wellness." Identifying causal interrelationships comorbidities, although complex task, prevent counteract gluco-lipid dysmetabolism. scientific community made progress understanding pathogenic (Figure 1), there still much accomplish. contemplating possibly targeting due could innovative therapeutic strategies emphasizing necessity comprehensive approach takes account disorders.

Language: Английский

---

Shenling Baizhu San ameliorates non-alcoholic fatty liver disease in mice by modulating gut microbiota and metabolites

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: April 24, 2024

The prevalence of non-alcoholic fatty liver disease (NAFLD) and its related mortality is increasing at an unprecedented rate. Traditional Chinese medicine (TCM) has been shown to offer potential for early prevention treatment NAFLD. new mechanism "Shenling Baizhu San" (SLBZS) examined in this study the NAFLD preclinical level.

Language: Английский

---

The Probiotic Lactobacillus reuteri Preferentially Synthesizes Kynurenic Acid from Kynurenine

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3679 - 3679

Published: March 26, 2024

The gut–brain axis is increasingly understood to play a role in neuropsychiatric disorders. probiotic bacterium Lactobacillus (L.) reuteri and products of tryptophan degradation, specifically the neuroactive kynurenine pathway (KP) metabolite kynurenic acid (KYNA), have received special attention this context. We, therefore, assessed relevant features KP metabolism, namely, cellular uptake pivotal its conversion primary KYNA, 3-hydroxykynurenine anthranilic L. by incubating bacteria Hank’s Balanced Salt solution vitro. Kynurenine readily entered bacterial cells was preferentially converted which promptly released into extracellular milieu. De novo production KYNA increased linearly with increasing concentrations (up 1 mM) (107 109 CFU/mL) incubation time (1–3 h). neosynthesis blocked two selective inhibitors mammalian aminotransferase II (PF-048559989 BFF-122). In contrast mammals, however, not influenced other substrates large neutral amino transporter, affected presumed competitive enzyme (glutamine α-aminoadipate). Taken together, these results reveal substantive qualitative differences between metabolism.

Language: Английский

---

Therapeutic Potential of Palmitoylethanolamide in Gastrointestinal Disorders

Antioxidants, Journal Year: 2024, Volume and Issue: 13(5), P. 600 - 600

Published: May 14, 2024

Palmitoylethanolamide (PEA) is an endocannabinoid-like bioactive lipid mediator belonging to the family of N-acylethanolamines, most abundantly found in peanuts and egg yolk. When gastrointestinal (GI) effects PEA are discussed, it must be pointed out that affects intestinal motility but also modulates gut microbiota. This due anti-inflammatory, antioxidant, analgesic, antimicrobial, immunomodulatory features. Additionally, has shown beneficial several GI diseases, particularly irritable bowel syndrome inflammatory as various studies have shown, important emphasize its relative lack toxicity, even at high dosages. Unfortunately, there not enough endogenous treat disturbed homeostasis, though produced tract response stimuli, so exogenous intake mandatory achieve homeostasis. Intake could through animal and/or vegetable food, bearing mind a dosage needed therapeutic effect, compensated dietary supplements. There still open questions pending answered, further investigating PEA’s mechanisms action, especially humans, crucial implementing everyday clinical practice.

Language: Английский

---

The Effects of a Food Supplement, Based on Co-Micronized Palmitoylethanolamide (PEA)–Rutin and Hydroxytyrosol, in Metabolic Syndrome Patients: Preliminary Results

Nutrients, Journal Year: 2025, Volume and Issue: 17(3), P. 413 - 413

Published: Jan. 23, 2025

Background: Metabolic syndrome (MetS) patients have impaired hypothalamic regulatory functions involved in food intake and energy expenditure suffer from a state of meta-inflammation. Pre-clinical studies demonstrated that ultramicronized palmitoylethanolamide (PEA) acts both on the adipose tissue central nervous system, while hydroxytyrosol (HTyr) counteracts several types dysmetabolism. Objectives: The aim our randomized crossover double-blind placebo-controlled pilot study was to evaluate potential effects supplement (FS) containing co-micronized formulation PEA rutin along with HTyr, combined tailored calorie-controlled Mediterranean diet, MetS. Methods: Nineteen were enrolled block-randomized an eight-week MD together FS or placebo. After two-week washout period, treatments reversed. Data laboratory parameters those detected by capillary sampling, anthropometry, body composition analysis, ultrasound examination, blood pressure monitoring, 36-Item Short-Form Health Survey questionnaire, handgrip strength test, physical performance tests collected at each time point (protocol code R.S. 262.22, registered 20 December 2022). Results: At end study, supplemented showed significant reduction weight, mass index, fat mass, inflammation biomarkers (CRP ESR), compared placebo-supplemented patients. In contrast, fat-free phase angle, cell increased placebo Conclusions: Although preliminary, results clinical suggest PEA–rutin HTyr may be help against adiposopathy

Language: Английский

---

Aurantio‐Obtusin Regulates Gut Microbiota and Serum Metabolism to Alleviate High‐Fat Diet‐Induced Obesity‐Associated Non‐Alcoholic Fatty Liver Disease in Mice

Phytotherapy Research, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 14, 2025

ABSTRACT Non‐alcoholic fatty liver disease (NAFLD) is a progressive condition with limited effective treatments. This study investigated the therapeutic effects of Aurantio‐obtusin (AO), bioactive compound from Cassiae Semen , on obesity‐associated NAFLD. An obesity‐related NAFLD model was established in ApoE −/− mice fed high‐fat diet (HFD) for 24 weeks, AO administered during last 16 weeks. Mouse body weight, adipose tissue weights, serum lipid levels, hepatic steatosis, inflammatory damage, and colonic barrier integrity were evaluated. Gut microbial communities metabolic profiles analyzed using 16S rRNA sequencing untargeted metabolomics. Hepatic metabolism‐related gene expression assessed molecular biology techniques. treatment significantly ameliorated HFD‐induced adiposity, hyperlipidemia, symptoms. It preserved intestinal integrity, modulated gut composition by enriching beneficial taxa, improved profiles. favorably adjusted metabolism upregulating PPARα CPT1A while downregulating SREBP1, FASN, SCD1. Correlation analysis revealed significant associations among composition, metabolites, indicators. AO's benefits might be attributed to its ability modulate community profile, enhance function, regulate expression. presents promising agent NAFLD, warranting further investigation into potential clinical applications.

Language: Английский

---

Microbiota-indole-3-propionic acid-heart axis mediates the protection of leflunomide against αPD1-induced cardiotoxicity in mice

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 19, 2025

Anti-programmed death 1 (αPD1) immune checkpoint blockade is used in combination for cancer treatment but associated with cardiovascular toxicity. Leflunomide (Lef) can suppress the growth of several tumor and mitigate cardiac remodeling mice. However, role Lef αPD1-induced cardiotoxicity remains unclear. Here, we report that inhibits αPD1-related without compromising efficacy αPD1-mediated immunotherapy. changes community structure gut microbiota αPD1-treated melanoma-bearing Moreover, mice receiving transplants from Lef+αPD1-treated have better function compared to Mechanistically, analyze metabolomics identify indole-3-propionic acid (IPA), which protects dysfunction IPA directly bind aryl hydrocarbon receptor promote phosphoinositide 3-kinase expression, thus curtailing cardiomyocyte response injury. Our findings reveal mitigates toxicity through modulation microbiota-IPA-heart axis. The authors show leflunomide microbiota-indole-3-propionic acid-heart

Language: Английский

---

Symphony of the gut microbiota and endocannabinoidome: a molecular and functional perspective

Frontiers in Cellular and Infection Microbiology, Journal Year: 2025, Volume and Issue: 15

Published: March 26, 2025

This review examines the impact of interactions between gut microbiota and endocannabinoidome (eCBome) on health disease, highlighting their significance for physiological pathological processes. We identify key research gaps challenges to advance field. The discusses role dietary patterns physical activity in regulating these interactions. It also explores complex nature conditions such as inflammatory bowel disease (IBD), depression, anxiety, Alzheimer’s (AD), metabolic disorders. analysis evaluates contributions onset progression, molecular mechanisms signaling pathways involved. From this, we provide forward-looking perspectives future directions, advocating a more nuanced understanding microbiota–eCBome axis. anticipate that will integrate microbiota–endocannabinoidome into therapeutic strategies broad range diseases.

Language: Английский

---

The endocannabinoid and paracannabinoid systems in natural reward processes: possible pharmacological targets?

Physiology & Behavior, Journal Year: 2025, Volume and Issue: 296, P. 114929 - 114929

Published: April 22, 2025

Language: Английский

---

Role of Zhiqiao Chuanlian decoction in the treatment of food accumulation fever: Network pharmacology and animal experiments

Heliyon, Journal Year: 2024, Volume and Issue: 10(8), P. e29813 - e29813

Published: April 1, 2024

ObjectiveFood accumulation fever (FAF), a common clinical disease in children, is generally induced by the excessive intake of high-calorie or high-fat foods. Zhiqiao Chuanlian decoction (ZQCLD) classical traditional Chinese medicine (TCM) that may have therapeutic effects on FAF.MethodsNetwork pharmacological analyses ZQCLD and FAF were conducted. Animal experiments lasted for 14 days. Rats model, positive control, low-, medium-, high-dose groups fed diet. On days 11-14, group was given domperidone solution. The administered different concentrations ZQCLD. body temperature, gastric emptying rate, intestinal propulsion rate measured. Relevant indicators determined ELISA.ResultsThe main target proteins included IL-1β, C-C motif chemokine 2 (CCL2), prostaglandin G/H synthase (PTGS2), transcription factor AP-1 (JUN), haem oxygenase 1 (HMOX1), interferon-gamma (IFN-γ), peroxisome proliferator-activated receptor-gamma (PPAR-γ), inducible nitric oxide (NOS2/iNOS). Compared with those control group, weight, neuronal (NOS1/nNOS) levels significantly lower model whereas temperature endotoxin, interleukin-1β (IL-1β), PGE2, iNOS increased. In each treatment PGE2 returned to normal levels. rates low- medium-dose increased; higher medium- groups, endotoxin IL-1β lower; nNOS level lower.ConclusionsZQCLD treat regulating jejunal nNOS, serum hypothalamic

Language: Английский

---