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Tianwangbuxiandan decoction alleviates constipation and associated emotional disorders via regulating the brain-gut axis: Involving MAPK/ERK/JNK signaling pathways.
J Ethnopharmacol
Shaoliang Li, Pengning Wu, Yue Wang +3 more
Tianwang Buxin Dan (TWBXD) is a classical Chinese formula traditionally prescribed to "nourish Yin, calm the mind and relieve bowel stagnation" in disorders characterized by heart-kidney disharmony, insomnia, anxiety, and constipation. However, the mechanistic basis associating its gut-regulating and emotion-modulating effects along the gut-brain axis remains unclear.
Ethosomal Nanocarriers for Hydrophilic Peptide Encapsulation: Formulation Optimization, Stability, and In Vitro Release Performance.
Molecules
Yasemin Yağan Uzuner, Hakan Sevinç, Zeynep Kanlidere
Hydrolyzed collagen peptides (HCP) are widely used as bioactive ingredients in anti-aging and skin rejuvenation formulations due to their role in supporting skin hydration, elasticity, and extracellular matrix integrity. However, their high hydrophilicity limits effective incorporation into lipid-based systems, and restricts controlled release from formulations.
Acute L-Leucine Supplementation and Sprint Exercise Elicit Distinct Appetite and Inflammatory Responses in Persons with Overweight: A Randomized, Counterbalanced, and Crossover Design Study.
Nutrients
Elias de França, Ronaldo Vagner Thomatieli-Santos, Rita de Cássia Aquino +7 more
Our objective was to evaluate the acute effect of L-leucine supplementation and high-intensity sprint exercise on appetite-controlling neuropeptides and their association with the subjective perception of appetite (SPA), satiety (SPS), food intake, and inflammatory response in overweight participants.
Epigenetic Drivers of Pulmonary Hypertension: Environment Meets Genome.
Cureus
William N Whitley, Richard M Millis
Pulmonary hypertension (PH) is a progressive disease in which the pulmonary arteries thicken and narrow, raising pulmonary vascular resistance (PVR) and eventually straining the right ventricle. Known gene mutations explain only a minority of cases and often do not account for why the disease starts, worsens, or varies so widely between patients. Growing evidence suggests that epigenetic changes, chemical marks on DNA and its packaging that alter how genes are used without changing the DNA sequence, help explain this gap. These changes, including DNA methylation, histone modification, and non-coding RNAs, can be triggered by common exposures and disease states, and they can produce lasting shifts in vascular, immune, and metabolic pathways. This narrative review synthesizes current data showing how intrinsic stresses (mitochondrial dysfunction, oxidative stress, and cancer-like metabolic reprogramming) interact with extrinsic and often modifiable factors. Obesity, cigarette smoke, asbestos exposure, chronic hypoxia, and systemic inflammation drive PH through epigenetic reprogramming. We highlight major molecular hubs implicated across studies, including bone morphogenetic factor receptor 2 (BMPR2), NOTCH3, endothelin-1 (ET-1), transforming growth factor‑β (TGF-β), interleukin‑6 (IL-6), and CCL5, and we summarize emerging therapeutic approaches aimed at epigenetic regulators and microRNA networks. This narrative review was not conducted under Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and does not constitute a formal systematic review. The information in this review provides a practical framework for clinicians and researchers to improve risk assessments, to employ biomarkers, and to develop therapies that go beyond vasodilation to address upstream drivers of pulmonary arterial remodeling. This framework may also serve as a model for other difficult-to-treat diseases in which incomplete genetic explanations and limited attention to environmental exposures have slowed progress in prevention, early detection, and personalized treatment.
Effects of commercial genetic selection on gene expression in the developing neuroendocrine system of broilers.
Poult Sci
Panpradub Sinpru, Kristen Diehl, Laura E Ellestad +1 more
Selective breeding of broilers has significantly improved growth rates, muscle mass, and feed efficiency and may have influenced the neuroendocrine systems that regulate growth and metabolism. Embryonic development represents one-third of the life of a modern broiler. To assess the impact of genetic selection on the neuroendocrine regulation of growth and metabolism during embryonic development, we examined mRNA expression of growth-related genes in the hypothalamus and anterior pituitary of two chicken breeds: the modern Ross 708 broiler and the Athens Canadian Random Bred (ACRB) line, the oldest established strain for meat-type chickens. Hypothalami and pituitary glands were dissected from embryos at days 10, 12, 14, 16, and 18 of incubation (n = 4 for each combination of breed, age, and gender). Levels of mRNA for each target gene were quantified using reverse transcription-quantitative PCR. In the adrenocorticotropic axis, pituitary corticotropin-releasing hormone receptor 1 mRNA levels were influenced by the interaction of breed, age, and gender (P < 0.05). In the thyrotropic axis, pituitary thyroid-stimulating hormone β-subunit mRNA levels were affected by the interaction of breed, age, and gender (P < 0.05). In the somatotropic axis, mRNA levels of hypothalamic somatostatin were higher in ACRB than Ross, whereas overall pituitary growth hormone mRNA levels were greater in Ross than ACRB (P < 0.05). Pituitary growth hormone-releasing hormone receptor 2 and pituitary adenylate cyclase-activating polypeptide receptor 1 were influenced by the interaction between breed and age (P < 0.05). In the gonadotropic axis, hypothalamic gonadotropin-releasing hormone 1 and gonadotropin-inhibiting hormone were influenced by breed, age, and gender, while mRNA levels of pituitary follicle-stimulating hormone β-subunit were affected by the interaction between breed and age (P < 0.05). Hypothalamic agouti-related peptide, neuropeptide Y, and proopiomelanocortin mRNA levels were higher in ACRB than Ross in females (P < 0.05). These findings indicate that genetic selection of broilers has altered the adrenocorticotropic, somatotropic, thyrotropic, and gonadotropic axes, as well as hypothalamic control of appetite and metabolism during embryonic development.
A revised model of nuclear actin import: Importin 9 competes with cofilin, profilin, and RanGTP for actin binding.
J Biol Chem
Amanda J Keplinger, Prithi A Srinivasan, Sarah M Christensen +2 more
While predominantly studied in cytoplasmic contexts, actin plays critical roles in the nucleus, regulating genome accessibility, transcription, and DNA repair. Cell-based studies have contributed to a widely accepted model in which the import factor importin 9 (IPO9) acts in concert with the actin filament-severing protein cofilin to transport actin into the nucleus. The classical nuclear localization signal on cofilin is thought to anchor IPO9 to cofilin-bound actin monomers, driving the formation of an import-competent tripartite actin-cofilin-IPO9 complex. Contrary to this established model of actin import, we demonstrate that IPO9 directly binds to monomeric actin with midnanomolar affinity and, rather than promoting IPO9-actin complex formation, cofilin competitively inhibits the binding of IPO9 to actin. To define the mechanism of IPO9 binding, we subject monomeric actin to competitive IPO9 binding in the presence of well-established actin-binding molecules and find proteins that engage either the barbed face, profilin, or pointed face, DNase I, competitively limit IPO9-actin complex formation, whereas sterically less demanding binding partners, thymosin beta-4 and latrunculin B, do not. Consistent with these findings, we demonstrate that IPO9 modestly decreases the rate of actin filament assembly, a process that requires both actin faces, and that IPO9 exhibits minimal binding to actin filaments. Finally, we identify unexpected affinity between the nuclear import release factor RanGTP and monomeric actin; however, a tripartite IPO9-actin-RanGTP complex does not form. The competitive interactions observed between IPO9 and cytoplasmic actin-binding proteins suggest that dynamically coupled equilibria mediate the nuclear transport of actin monomers.
Effect of intracerebroventricular (ICV) injection of antimicrobial peptide expressed in the body-2 (LEAP-2) and its interaction with cannabinoid and ghrelin systems on food intake in broiler chickens.
Poult Sci
Ariana Rahmania, Morteza Zendehdel, Shahin Hassanpour
Liver-expressed antimicrobial peptide 2 (LEAP-2), initially identified as an antimicrobial peptide which endocannabinoid and ghrelin action may occur via changes in Leap2 expression. This study aimed to determine effect of ICV injection of LEAP2and its interaction with cannabinoid and ghrelin systems on food intake in broiler chickens. In the present study 4 experiments were conducted, each containing 4 experimental groups. In experiment 1, chicken injected with group 1 ICV injection of saline, group 2 with LEAP2 (0.75 nmol), group 3 with LEAP2 (1.5 nmol) and group 4 with LEAP2 (3 nmol). In experiment 2, chicken received ICV injections as group 1: saline, group 2: (D-Lys-3)-GHRP-6 (0.5 nmol), group 3: LEAP2 (3 nmol) and group 4 with co injection of the (D-Lys-3)-GHRP-6 + LEAP2. In experiment 3 chiken received ICV inejctions as: group 1: saline, group 2: SR141716A (6.25 µg), group 3: LEAP2 (3 nmol) and group 4 with co injection of the SR141716A + LEAP2. In experiment 4 chiken received ICV inejctions as: group 1: saline, group 2: AM630 (1.25 µg), group 3: LEAP2 (3 nmol) and group 4 with co injection of the AM630 + LEAP2. Immediately following the infusions, the broilers were returned to their respective boxes, where they were provided with pre-weighed meal and fresh water ad libitum. The cumulative meal consumption was subsequently measured at intervals of 30, 60, and 120 min post-administration. According to the results, ICV injection of the LEAP2 (1.5 and 3 nmol) significantly decreased food intake (P<0.05). Co-injection of the (D-Lys-3)-GHRP-6 + LEAP2 significantly decreased LEAP2-induced hypophagia (P<0.05). Co-injection of the (D-Lys-3)-GHRP-6 + LEAP2 significantly increased hypophagic effect of the LEAP2 (P<0.05). Co-injection of the SR141716A + LEAP2 significantly amplified LEAP2-induced hypophagia compared to control group (P<0.05). Co-injection of the AM630 + LEAP2 significantly amplified LEAP2-induced hypophagia compared to control group (P<0.05). These results suggested that LEAP2-induced hypophagia mediates via ghrelin and CB1 and CB2 receptors in neonatal chicken.
A Deep Learning Framework for Predicting Teprotumumab Treatment Response in Thyroid Eye Disease.
Ophthalmol Sci
Saul Langarica, Nahyoung Grace Lee, Adham M Alkhadrawi +4 more
To develop and evaluate a deep learning-based framework for quantifying thyroid eye disease (TED) severity before and after teprotumumab treatment, an insulin-like growth factor-1 receptor inhibitor, and to create a predictive model for forecasting individual patient responses to therapy.
Peripheral and CSF protein quantification in Parkinson's disease and multiple system atrophy-the nucleic acid-linked immuno-sandwich assay.
Brain Commun
Nirosen Vijiaratnam, Christine Girges, Arthur Mitchell +13 more
There are currently no validated peripheral biomarkers for the diagnosis, differentiation or progression of the neurodegenerative synucleinopathies, Parkinson's disease and multiple system atrophy. Diagnostic biomarkers that reflect the disease mechanisms or progression biomarkers that change with disease severity would be extremely valuable for assessing disease-modifying therapies. Our objective was to explore putative protein biomarkers of Parkinson's disease and multiple system atrophy, in relation to clinical disease severity, using the nucleic acid-linked immuno-sandwich assay central nervous system disease panel for biomarker quantification. We used the nucleic acid-linked immuno-sandwich assay CNS disease panel to test plasma from 161 Parkinson's disease patients collected at three time points (0, 48, 96 weeks) and serum from 43 multiple system atrophy patients at three time points (0, 24, 48 weeks) and compared results to paired plasma and serum samples collected from (n = 39) age-matched healthy control individuals at a single time point. We also tested paired CSF samples collected on two occasions, separated by 96 weeks from a subgroup of Parkinson's disease participants (n = 51) and after an interval of 48 weeks in a subgroup of multiple system atrophy participants (n = 23). All samples were taken contemporaneously with objective clinical assessments of disease severity. Biomarker comparisons were made across disease status and in relation to disease severity using linear modelling. Multiple proteins showed significantly different quantitative levels (false discovery rate-corrected P value < 0.05) between peripheral samples from Parkinson's disease and healthy controls and multiple system atrophy and healthy controls. For Parkinson's disease, we identified three key classes of proteins that showed significant differences between Parkinson's disease and controls: (i) amyloidogenic proteins, specifically, oligomeric alpha-synuclein was significantly higher in Parkinson's disease compared to controls. A number of other aggregating proteins also exhibited differences. (ii) Metabolic pathways, including the adipokine (chemokine-like protein TAFA-5), were associated with Parkinson's disease diagnosis, and (iii) inflammatory pathways (interleukin-7) were associated with Parkinson's disease diagnosis. Importantly, some of these same proteins were significantly associated with Parkinson's disease severity including oligomeric and phosphorylated forms of alpha-synuclein and insulin-like growth factor-1 receptor. We also confirmed as expected that neurofilament light levels strongly distinguish multiple system atrophy patients from healthy controls, while also demonstrating that serum inflammatory proteins (interleukin-6) as well as the phosphorylated alpha-synuclein ratio are strongly associated with multiple system atrophy severity. These results from the nucleic acid-linked immuno-sandwich assay multiplex platform provide additional insights into the complex pathogenetic mechanisms associated with alpha-synucleinopathy related neurodegeneration. Individual protein levels or the combination of multiple protein candidates may usefully serve as diagnostic biomarkers, or as biomarkers for disease progression in trials of potential disease-modifying interventions.
Injectable self-healing hydrogel loaded with a self-assembling LL-37 derivative for treating infected skin wounds.
Int J Pharm
Qi Ba, Jiaxin Yao, Hao Tian +10 more
Effective management of infected skin wounds remains a major clinical challenge, particularly as rising antibiotic resistance compromises conventional therapies. Antimicrobial peptides (AMPs) have emerged as promising alternatives, but their clinical translation is hindered by poor stability and potential toxicity. In this study, we report the rational design of a novel antimicrobial peptide, FR-20, a self-assembling derivative of the human cathelicidin LL-37, engineered for enhanced structural stability and antimicrobial efficacy. Using dynamic Schiff base cross-linking, we developed an injectable, self-healing chitosan hydrogel (CS/FR-20) loaded with FR-20. The hydrogel exhibited robust mechanical integrity, excellent injectability, and a porous microarchitecture, while maintaining strong cytocompatibility and hemocompatibility. CS/FR-20 demonstrated potent bactericidal activity against both Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA). In a murine full-thickness wound infection model, it effectively eradicated bacteria, reduced inflammation, accelerated tissue regeneration, and showed no detectable systemic toxicity. These findings establish CS/FR-20 as a versatile, biocompatible platform for treating infected wounds, offering a clinically translatable strategy to overcome antibiotic resistance and promote effective wound healing.
Investigation of Regulation and Binding Patterns of the Human Cathelicidin Peptide LL-37 in Complexation with Nucleic Acids, and its Impact on Neutrophil Extracellular Traps.
bioRxiv
Claudia Zielke, Behzad Rad, Josefine E Nielsen +6 more
The human cathelicidin host defense peptide LL-37 forms complexes with nucleic acids that can have either beneficial or detrimental health effects. We suggest that these differential impacts are directly connected to dsDNA binding by LL-37 and to complex formation between protomers. Here, we show using phage λ DNA that LL-37 binds non-specifically to dsDNA, condensing it, followed by complex formation between LL-37 peptides. We find that complex formation is concentration-dependent, with low LL-37 amounts yielding loosely aggregated DNA structures, while higher LL-37 concentrations lead to well-defined, disc-like structures of about 150 nm in diameter. The condensation of the nucleic acids, which causes a loss of the characteristic B-DNA features, results from interactions of the phosphodiester backbone with protonated amino acid side chains of the peptide at physiological pH, predominantly in A-T rich sequences of the nucleic acid. However, in our studies, electrostatic interactions did not appear to be the driving force for complexation, but rather we found the α-helical structure of the peptide with its amphipathic and hydrophobic surfaces to be essential. Further, we show that LL-37 also interacts with nucleic acids from neutrophil extracellular traps (NETs) in a concentration-dependent way, causing a reduction in NET aggregate area, which may offer new biophysical insights into diseases such as systemic lupus erythematosus (SLE), which involve slower-than-normal NET clearance. Our results indicate the key importance of LL-37 expression levels for regulation of the innate immune system for optimal human health, since the relative amounts of expressed LL-37 present to interact with extracellular DNA will determine the extent to which the DNA can be condensed, which in turn will affect the ability of the body to clear the NETs before they can cause inflammatory conditions.
Analysis of Antimicrobial Peptide Expression Under Acute and Chronic Alcohol Exposure: A Cross-Sectional Study and a Systematic Review of the Literature.
Int J Mol Sci
Maura Rojas-Pirela, Cristian Herrera-Flores, Pilar Costa-Alba +10 more
Alcohol exposure affects immune regulation and tissue homeostasis. Antimicrobial peptides (AMPs) are essential components of innate immunity, not only defending against pathogens but also modulating processes such as inflammation. However, their tissue-specific regulation in response to alcohol remains poorly characterized, particularly in humans after acute intoxication. We evaluated the expression of AMPs in the peripheral blood of patients with alcohol use disorder (AUD, n = 9), individuals with acute alcohol consumption (AAC, n = 9), and controls using quantitative polymerase chain reaction (qPCR). Additionally, we analyzed AMP expression in selected tissues of mice exposed to chronic ethanol feeding (National Institute on Alcohol Abuse and Alcoholism model for 5 days) and performed a systematic review of AMP regulation in alcohol-related disorders (2005-2025; n = 36 studies, reflecting a limited and heterogeneous body of available evidence). Human cathelicidin antimicrobial peptide (LL-37), lipopolysaccharide-binding protein (LBP), and bactericidal/permeability-increasing protein (BPI) were significantly upregulated in patients with AUD, whereas LL-37 and LBP were significantly upregulated in AAC. In the livers of ethanol-fed mice, LEP2, LCN2, and LBP levels were markedly increased, whereas LL-37 and LEP1 were downregulated. Duodenal tissue exhibited upregulation of DEFB1. In adipose tissue, DEFA2 was significantly increased in peripheral depots, whereas only LCN2 was upregulated in brain tissue. The systematic review demonstrated complex, heterogeneous, and organ-dependent AMP regulation and also highlighted the paucity of human data on AAC, a gap that our study partially addresses. Our results are consistent with the hypothesis that selected AMPs may serve as candidate markers of organ damage or microbial translocation and as possible therapeutic targets, a hypothesis that requires confirmation in larger, adequately powered studies.
Vitamin D in Infectious Diseases: A Narrative Review Focusing on COVID-19, Long COVID, and Influenza.
Nutrients
Olga Adriana Caliman-Sturdza, Roxana Elena Gheorghita, Iuliana Soldanescu +2 more
Vitamin D is a secosteroid hormone traditionally recognized for its role in bone and mineral metabolism, but it is increasingly understood to also function as an important immunomodulator influencing susceptibility to and outcomes of infectious diseases. This narrative review summarizes current evidence on the immunological, clinical, and preventive effects of vitamin D in the context of novel coronavirus disease (COVID-19), post-acute sequelae of SARS-CoV-2 infection (long COVID), and influenza. Mechanistically, vitamin D enhances innate immune defenses through the induction of antimicrobial peptides, including cathelicidin and defensins, and modulates adaptive immunity by suppressing maladaptive Th1/Th17 responses while promoting regulatory T-cell activity. Observational studies have frequently associated vitamin D deficiency with more severe COVID-19 outcomes; however, these associations may be influenced by confounding factors and reverse causality. Some meta-analyses suggest that vitamin D supplementation reduced rates of intensive care unit admission and ventilatory support, particularly among older adults and individuals with low baseline serum 25-hydroxyvitamin D concentrations. Emerging evidence also indicates that inadequate vitamin D status may be associated with an increased risk and symptom burden of long COVID, although causality has not been established. In the case of influenza, a limited number of randomized controlled trials (RCTs) and meta-analyses report a modest but statistically significant reduction in infection risk, especially with daily or weekly vitamin D supplementation in populations with low baseline vitamin D levels. Clinical guidelines consistently recommend maintaining adequate vitamin D status for general health but do not endorse high-dose vitamin D as a treatment for COVID-19 due to inconsistent trial findings. Overall, vitamin D should not be considered a standalone therapeutic agent; rather, maintaining sufficient vitamin D levels represents a low-risk, potentially beneficial strategy to support immune resilience against respiratory viral infections.
Heterogeneity of Treatment Effects of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss in Adults: A Systematic Review and Meta-Analysis.
JAMA Intern Med
G Caleb Alexander, Xuya Xiao, Sophie Dilek +6 more
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a novel class of therapeutics approved to treat chronic conditions such as cardiovascular disease, diabetes, and/or obesity. However, whether GLP-1 RAs' efficacy varies by age, sex, race and ethnicity, baseline body mass index (BMI), and baseline hemoglobin A1c (HbA1c) is unclear.
Effects of Glucagon-Like Peptide-1 Receptor Agonists (Mono and Combination Therapy) on Energy Expenditure: A Scoping Review.
Obes Rev
Flavio T Vieira, ZhiDi Deng, Manfred J Muller +6 more
Weight loss results in reduced energy expenditure (EE) due to body composition alterations (e.g., fat-free mass and fat mass losses) and mass-independent adaptations in EE (e.g., hormones). Glucagon-like peptide-1 receptor agonists (GLP-1RA) are indicated for obesity management; however, their effects on EE remain unclear.
In vitro metabolic profiling of weight-loss-inducing amylin receptor agonists in the context of preventive doping research.
J Pharm Biomed Anal
Hana Alhalabi, Lisa Borschel, Christelle Le Foll +3 more
Peptide hormone-based weight-loss therapeutics have gained increasing attention, driven amongst other reasons, by the clinical and commercial success of semaglutide. Their increasing accessibility raises concerns about their potential misuse in sports, especially in disciplines where weight management is decisive for athletic performance. Semaglutide has been included in the World Anti-Doping Agency's monitoring program since 2024. Given that amylin signalling is a key therapeutic target for next-generation weight-loss drugs, amylin receptor agonists such as pramlintide, cagrilintide and KBP-066 also warrant consideration as to metabolism and detection strategies in sports drug testing programs. This study aimed to characterize the metabolic profiles of pramlintide, cagrilintide and KBP-066, identify analytically suitable metabolites and develop and validate a LC-MS/MS-based detection approach. Comprehensive in vitro models, including human skin S9 fraction, kidney S9 fraction and biological fluids, were used to investigate metabolic pathways. HRMS/MS was employed to characterize metabolites and evaluate their suitability as analytical targets. For comparison, authentic post-administration rat samples were analysed for cagrilintide and respective biotransformation products. All three peptides underwent N-terminal and C-terminal degradation, yielding multiple stable metabolic products suitable as detection targets. Cagrilintide metabolites predicted from in vitro experiments were observed in authentic post administration rat plasma samples, confirming in vivo relevance. Finally, suitable preparation and detection methods were established and validated. This study provides the first systematic metabolic characterization of pramlintide, cagrilintide and KBP-066. The identified metabolites and LC-MS/MS detection approach offer a foundation for future monitoring of emerging weight-loss peptide hormone analogues in anti-doping contexts.
The story of amylin: from physiology to therapy.
Nat Metab
Anna Secher, Thomas A Lutz, Kirsten Raun
Amylin is a glucoregulatory peptide hormone discovered in 1986. Almost 20 years later, pramlintide, a human amylin analogue, emerged as the first amylin-based drug, approved as an adjunct treatment to insulin for type 1 diabetes (T1D) and type 2 diabetes (T2D). Despite its effects on multiple organ systems, the therapeutic potential of amylin has remained relatively underexplored until recently, when growing interest in amylin has prompted advancement of several amylin-based therapies towards clinical use. This Review contextualizes the evolving therapeutic potential of amylin, focusing on recent preclinical and clinical data, amylin receptor pharmacology and its broader biological effects. We discuss the potential and challenges of developing amylin-based treatments for cardiometabolic disease, including milestones in drug development of amylin, and its combination with additional molecules as part of the future landscape of therapies for patients with diabetes or obesity.
GLP-1 Release by Rare Sugar D-Allulose Ameliorates Sucrose-Induced Obesity and Glucose Intolerance in Ovariectomized Mice.
Int J Mol Sci
Kengo Iba, Miharu Kyo, Hirotaka Ishihara +5 more
Estrogen deficiency after menopause promotes visceral fat accumulation and insulin resistance, thereby increasing the risk of type 2 diabetes. Although hormone replacement therapy is partially effective, its use is limited by increased risks of cardiovascular disease and breast cancer, underscoring the need for safer preventive strategies. The rare sugar D-allulose has been reported to stimulate secretion of glucagon-like peptide-1 (GLP-1), a gut hormone, and improve obesity and glucose metabolism, suggesting its potential as a novel intervention for postmenopausal metabolic dysfunction. Here, we examined whether D-allulose improves obesity and glucose intolerance in a GLP-1-dependent manner under sucrose-fed conditions, using ovariectomized (OVX) female C57BL/6J mice as a model of menopause. OVX mice, but not sucrose-fed sham mice, developed exacerbated visceral obesity and glucose intolerance in response to dietary sucrose, despite similar total energy intake. Daily oral administration of D-allulose for two weeks significantly suppressed visceral fat accumulation, improved insulin resistance, and ameliorated glucose intolerance in sucrose-fed OVX mice. These beneficial effects were markedly attenuated in GLP-1 receptor knockout mice. Taken together, we found that sucrose intake after ovariectomy exacerbates visceral obesity and glucose intolerance, and that D-allulose effectively ameliorates these metabolic abnormalities. GLP-1-stimulating dietary components such as D-allulose may represent a safe and promising preventive strategy for metabolic dysfunction associated with menopause.
Nutritional Interventions in Type 1 Diabetes: Boosting Residual GLP-1 Responses-Is It an Option?
Nutrients
Maria Grammatiki, Xanthippi Tsekmekidou, Theocharis Koufakis +1 more
Type 1 diabetes (T1D) is characterized by autoimmune beta-cell destruction and lifelong insulin dependence, yet early-stage disease (Stages 1-2) retains residual beta-cell function that may still respond to incretin signaling. Incretin hormones-mainly glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-enhance postprandial insulin secretion and suppress glucagon, and GLP-1 also exhibits beta-cell protective effects in preclinical models. Although the incretin effect is markedly reduced in established T1D, intestinal GLP-1 secretion is largely preserved, creating a mechanistic rationale for strategies that increase endogenous GLP-1 during the "residual function" window. This narrative review summarizes dietary and lifestyle interventions that may enhance endogenous GLP-1 responses and discusses their potential role as adjuncts to insulin therapy, particularly when combined with emerging beta-cell-preserving immunomodulatory approaches that may prolong early disease stages. Mechanistically, high-fiber diets may increase GLP-1 via microbiota-derived short-chain fatty acids acting on L-cell receptors; low-glycemic index carbohydrates may favor distal nutrient delivery and a GLP-1-dominant incretin profile; and Mediterranean dietary patterns may promote GLP-1 secretion through unsaturated fatty acids, fiber, and polyphenols, including potential DPP-4-modulating effects. This narrative review examines nutrition and lifestyle interventions modulating residual incretins to elongate early T1D stages and enhance glycemic control as insulin adjuncts, per Nutrients' Special Issue. Available evidence is strongest in non-T1D populations, with limited T1D-specific trials, highlighting the need for stage-targeted studies incorporating GLP-1 dynamics, C-peptide, glycemic variability, and microbiome outcomes.
Functional characterisation of obesity-associated MRAP2 variants on MC4R and GHSR signalling.
Hum Mol Genet
Alejandra V Rodríguez Rondón, Karina Prins, Femke Volker +7 more
Melanocortin-2 receptor accessory protein-2 (MRAP2) modulates the activity of hypothalamic melanocortin-4 (MC4R) and growth hormone-secretagogue (GHSR) receptors, which suppress and promote appetite, respectively. We investigate whether obesity-associated variants of MRAP2 alter their ability to modulate MC4R and GHSR signalling as a possible mechanistic link to the development of obesity. Functional effects of five obesity-associated MRAP2 variants were analysed in HEK293 cells by co-expressing wild-type or variant MRAP2 with MC4R or GHSR. Endpoints included cell-surface and total expression, and ligand-induced second-messenger responses, β-arrestin-2 recruitment, and alternative G-protein activation. MRAP2 decreased basal MC4R cell-surface expression while GHSR cell-surface expression was not affected. In MC4R/MRAP2 expressing cells, maximal α-MSH-induced cAMP and β-arrestin-2 recruitment responses were increased. Similarly, ghrelin-induced Ca2+-mobilization in GHSR/MRAP2 expressing cells was increased, but β-arrestin-2 recruitment was suppressed. MRAP2 did not bias G-protein activation by either receptor, although previous reports show MRAP2 biases MC4R signalling towards Gαq/11. The variants did not significantly affect the ability of MRAP2 to modulate MC4R and GHSR signalling. Our results indicate that MRAP2 potentiates the ligand responsiveness of MC4R and GHSR, but has differential effects on β-arrestin-2 recruitment. The MRAP2 variants had no significant effects on the signalling endpoints tested. This suggests that, despite their association with obesity, the variants may be functionally benign, or that the absence of effects reflects limitations inherent to our cellular model. In addition, since MRAP2 can modulate multiple receptors and differentially modulate their signalling, we cannot rule out their influence on body weight regulation via other mechanisms.