The living record of
peptide science.

Positron emission tomography to assess drug occupancy at peripheral and central incretin receptors.

EBioMedicine

Amina Khalil, Irina Velikyan, Mengfei Xiong +3 more

Incretin mimetics, especially dual/triple agonists, are effective for type 2 diabetes and obesity, though mechanisms remain unclear. This study applied PET using [68Ga]Ga-DO3A-Exendin-4 and [68Ga]S02-GIP-T4 to assess GLP-1R and GIPR occupancy of SAR441255 (a GLP-1R, GIPR, and GCGR agonist) and tirzepatide in pig pancreas and CNS.

Aging and Thymosin Alpha-1.

Int J Mol Sci

Maria A Simonova, Igor Ivanov, Natalia S Shoshina +9 more

Aging is characterized by immune decline, mainly due to thymic involution-the age-related shrinkage of the thymus gland. This leads to reduced T-cell production, chronic inflammation, and increased susceptibility to age-related diseases. Thymosin alpha-1 (Tα1), a peptide hormone produced by the thymus, exhibits potent immunomodulatory, anti-inflammatory, and antioxidant properties. It helps restore immune function by stimulating T-cell differentiation, enhancing thymic output, and modulating dendritic cell and macrophage activity. Preclinical and clinical studies show that Tα1 can improve vaccine response in the elderly and mitigate immunosenescence. The hybrid drug Refnot (a fusion of tumor necrosis factor alpha (TNFα) and Tα1) combines Tα1's immunomodulation with TNF's antitumor activity but has reduced toxicity. It represents a promising therapeutic approach to counteract age-related immune dysfunction and inflammation, potentially by slowing the aging process. Further research is needed to validate its long-term efficacy and safety in geriatrics.

Persistent renin-angiotensin system and inflammatory dysregulation following COVID-19 impairs ischemic stroke recovery.

Exp Mol Pathol

Amy May Lin Quek, Ooiean Teng, Ju-Hea Park +3 more

Previous studies indicate that stroke recovery is worse in patients with prior COVID-19, suggesting persistent biological perturbations. We investigated lingering renin-angiotensin system (RAS) and inflammatory alterations after COVID-19 to uncover mechanisms driving impaired ischemic stroke recovery. We conducted a prospective observational cohort study comparing clinical and molecular profiles of ischemic stroke patients with and without recent COVID-19 infection to age-matched healthy controls. Plasma angiotensin-(1-7), angiotensin II, and soluble ACE2 were quantified, high-throughput proteomic profiling was performed using the Olink® Explore platform, and RNA sequencing was conducted to identify molecular mechanisms related to COVID-19-associated stroke and stroke outcomes (90-day modified Rankin Scale (mRS)). A total of 189 participants (38 COVID-19-associated stroke, 77 non-COVID-19 stroke, and 74 healthy controls) were enrolled. COVID-19-associated stroke patients exhibited significantly higher proportions of cryptogenic strokes (21.1 % vs 10.4 %), earlier hospital presentation (mean 185 vs 310 min), greater use of endovascular thrombectomy (97.4 % vs. 52.6 %), yet poorer functional outcomes (mRS ≥3) at 3 months (73 % vs. 47 %, all p < 0.05). Both stroke groups showed elevated angiotensin-(1-7) levels compared to controls, but angiotensin II levels were notably higher only in non-COVID-19 stroke patients. Proteomic analysis revealed sustained elevation of interferon-gamma (IFN-γ) signaling in COVID-19-associated stroke patients. Reduced AKT3 levels emerged as a significant predictor of poor outcomes, independent of renin-angiotensin biomarkers (adjusted OR 0.40; 95 % CI 0.16-0.94). Stroke patients with low AKT3 levels and poor outcomes exhibited significant upregulation of ribosomal proteins (RPS15, RPS4X, RPS7, RPS18, RPSA, RPS27A, RPS13, RPS23), reflecting heightened translational stress. Persistent RAS and inflammatory dysregulation following COVID-19 may contribute to worse stroke recovery. Future studies should validate and investigate the therapeutic implications of these findings.

Haemostasis and beyond: The expanding role of desmopressin in intensive care.

World J Crit Care Med

Saketh Vinjamuri, Ekta Tiwari, Sahil Kataria +1 more

Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic analogue of arginine vasopressin, the body's natural antidiuretic hormone. It acts selectively on V2 receptors, promoting renal water reabsorption and stimulating the release of von Willebrand factor (vWF) and factor VIII, while exerting minimal vasoconstrictive effects through V1 receptors. Developed in the late 1960s and introduced clinically in the early 1970s for the management of central diabetes insipidus, desmopressin was engineered to provide a longer duration of action and reduced cardiovascular side effects compared to native vasopressin. Its haemostatic potential was later recognized when it was observed to enhance endogenous levels of vWF and factor VIII, leading to its incorporation into the treatment of mild haemophilia A and von Willebrand disease (vWD). This unique combination of antidiuretic and prohemostatic properties has broadened its therapeutic role across various clinical settings. In critical care, desmopressin has emerged as a potentially valuable agent in managing complex scenarios such as uremic platelet dysfunction, trauma-associated coagulopathy, intracranial hemorrhage, vWD, and central diabetes insipidus. However, despite its mechanistic appeal and broad pharmacologic utility, the full scope of desmopressin's applications in the intensive care unit (ICU) remains underrecognized. This review aims to provide a comprehensive examination of desmopressin's pharmacological characteristics, evidence-based indications in critically ill patients, therapeutic efficacy, safety profile, and practical considerations for dosing in the ICU setting.

Chronic Stress Segregates Mice into Distinct Behavioral Phenotypes Based on Glucocorticoid Sensitivity.

Int J Mol Sci

Polina Ritter, Rasha Salman, Yuliya Ryabushkina +1 more

Chronic stress alters hypothalamic-pituitary-adrenal (HPA) axis function, affecting corticosterone regulation and adaptive responses. Understanding individual variability in stress adaptation requires identifying distinct HPA axis response patterns. Here, we assessed HPA axis sensitivity in male C57BL6 mice exposed to 30 days of chronic social defeat stress (CSDS). Negative feedback integrity was evaluated using the dexamethasone suppression test (DST), with corticosterone measured after saline or low-dose dexamethasone administration at days 10 and 30. Behavioral testing (open field, elevated plus maze, social interaction test, partition, social defeat, forced swimming test, sucrose preference test) and qPCR analysis of HPA-axis-related genes in the hypothalamus (Crh, Crhr1, Crhbp, Fkbp5, Nr3c1), pituitary (Pomc, Crhr1, Nr3c1, Nr3c2), and adrenal glands (Cyp11a1, Cyp11b1, Hsd11b1, Mc2r, Star, Fkbp5, Nr3c1) were performed. K-means cluster analysis identified three distinct response profiles differing in baseline and dexamethasone-suppressed corticosterone levels. Clusters also exhibited differences in behavioral phenotypes and HPA axis gene expression. Cluster 1 showed low basal corticosterone and an abnormal dexamethasone suppression response, without significant Crh or Crhbp dysregulation in the hypothalamus. Cluster 2 exhibited elevated basal corticosterone, a blunted dexamethasone response, anhedonia, and reduced immobility in the forced swim test; increased Crh and reduced Fkbp5 suggested enhanced glucocorticoid receptor sensitivity and sustained hypercortisolemia. Cluster 3, characterized by normal basal corticosterone and normal dexamethasone response, displayed upregulation of Crh and Crhbp, consistent with balanced and potentially adaptive HPA axis regulation under chronic stress. These results demonstrate that corticosterone response heterogeneity reflects distinct adaptive trajectories under chronic stress. Identifying behavioral and molecular markers of these strategies may advance understanding of stress vulnerability and resilience mechanisms, with implications for stress-related disorders.

Structural and mechanistic divergence in LL-37, HNP-1, and Magainin-2: An integrated computational and biophysical analysis.

Curr Res Struct Biol

Sinethemba H Yakobi, Uchechukwu U Nwodo

Escalating antimicrobial resistance necessitates the development of alternative therapeutics that circumvent conventional enzymatic and efflux-based defence systems. Antimicrobial peptides (AMPs) represent a compelling class of innate immune effectors, however, their clinical translation is hindered by incomplete mechanistic understanding of how structural organization and conformational dynamics shape antimicrobial function. In this study, we performed an integrated comparative analysis of three mechanistically representative AMPs-LL-37, HNP-1, and magainin-2-to resolve how maturation pathways, fold topology, amphipathic architecture, and dynamic target engagement govern antimicrobial action. Consensus secondary-structure prediction, AlphaFold2/PEP-FOLD modelling, and physicochemical profiling revealed three distinct structural signatures. LL-37 exhibited a flexible disorder-to-helix transition enabling adaptive, curvature-driven membrane dissolution, HNP-1 adopted a rigid cysteine-stabilized β-sheet that promotes lipid clustering and entropic inhibition of membrane-associated enzymes, and magainin-2 formed a stable amphipathic α-helix optimized for toroidal pore initiation. Machine-learning classification corroborated strong antimicrobial likelihood for HNP-1 and magainin-2, with LL-37 displaying context-dependent activation. Protein-peptide docking and normal-mode elastic network modelling further demonstrated the possibility of LL-37 allosterically dampening conformational cycling of the MexB efflux pump, HNP-1 restricting catalytic-loop mobility in LpxC, and magainin-2 enhancing correlated β-barrel breathing in OprF to promote pore formation. These findings delineate three mechanistically distinct antimicrobial strategies-adaptive membrane dissolution, rigid pore-stacking inhibition, and dynamic pore initiation-linked directly to peptide structural organization. This framework provides a rational basis for mechanism-guided AMP optimization and the engineering of next-generation membrane-active therapeutics with reduced resistance susceptibility.

Consumption of Unprocessed and Ultraprocessed Foods in Adolescents with Obesity: Associations with Neuroendocrine Mediators of Appetite Regulation and Binge Eating Symptoms.

Nutrients

Patrícia Sousa Neres, Aline de Piano Ganen, Raquel Munhoz da Silveira Campos +4 more

Background/Objectives: Obesity is a multifactorial disease associated with increased consumption of ultraprocessed foods and reduced intake of unprocessed foods. Binge eating, one of the most prevalent eating disorders among adolescents, is closely linked to obesity. Food intake is regulated by both the hedonic system, responsible for reward responses, and the physiological system, which controls hunger and satiety through hormones, such as ghrelin and leptin. The present study aimed to investigate associations between the intake of unprocessed and ultraprocessed foods, neuroendocrine mediators of appetite regulation, and binge eating in adolescents with obesity. Methods: This cross-sectional study included 96 adolescents with obesity who were recruited in São Paulo, Brazil, between 2010 and 2012. Anthropometric and body composition assessments were performed. Binge eating symptoms were evaluated using the binge eating scale (BES), and dietary intake was assessed with a validated Food Frequency Questionnaire, with items classified according to the Nova system. Frequency data were converted into annual consumption scores. Serum levels of ghrelin, leptin, neuropeptide Y (NPY), agouti-related peptide (AgRP), melanin-concentrating hormone (MCH), and alpha-melanocyte-stimulating hormone (α-MSH) were analyzed. Results: Lower consumption of unprocessed foods was associated with higher ghrelin concentrations (p = 0.023), accompanied by a greater percentage of body fat (p = 0.047) and a reduced percentage of lean mass (p = 0.047) compared with adolescents in the second tertile. AgRP was a positive predictor of annual consumption score of ultraprocessed food (β = 0.30; p = 0.04), independent of age, body fat, and binge eating symptoms. Conclusions: In conclusion, lower intake of unprocessed foods was associated with alterations in orexigenic and anorexigenic mediators, suggesting that dietary patterns in adolescents with obesity may influence the neuroendocrine mediators of appetite regulation.

Organokine-Mediated Crosstalk: A Systems Biology Perspective on the Pathogenesis of MASLD-A Narrative Review.

Int J Mol Sci

Sandra Maria Barbalho, Lucas Fornari Laurindo, Vitor Engracia Valenti +3 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic condition with a complex pathophysiology involving multiple organs. Organokines, including hepatokines, myokines, cardiokines, renokines, osteokines, and adipokines, play central roles in lipid metabolism, glucose homeostasis, inflammation, and fibrosis. Dysregulation of these signaling molecules contributes to the progression of MASLD and its systemic complications. This review examines the role of organokine-mediated crosstalk between the liver and peripheral organs (e.g., muscle, heart, kidneys, bone, and adipose tissue) in the pathogenesis of MASLD. Key molecules, such as myostatin, FGF-21, IL-6, and adiponectin, influence insulin sensitivity, lipid metabolism, and inflammation. Some organokines have protective effects (e.g., FGF-21, irisin, and klotho), while others, such as myostatin and fetuin-A, exacerbate insulin resistance and fibrosis. These findings suggest that targeting organokines could provide potential biomarkers and therapeutic strategies for MASLD. Future research should focus on elucidating the molecular mechanisms and assessing the role of organokines in the prevention and treatment of MASLD.

Aviptadil Therapy in Acute Respiratory Distress Syndrome Patients: A Systematic Review and Meta-analysis.

Indian J Crit Care Med

Ashritha A Udupa, Pratibha Todur, Souvik Chaudhuri +8 more

Acute respiratory distress syndrome (ARDS) is a life-threatening condition with a high mortality rate despite advances in supportive care. Aviptadil, a synthetic analogue of vasoactive intestinal peptide (VIP), exhibits anti-inflammatory potential and cytoprotective effects that may improve pulmonary function. However, its role in improving survival among ARDS patients remains uncertain. This systematic review and meta-analysis aimed to evaluate the effectiveness of aviptadil in improving survival and oxygenation outcomes in ARDS.

CNP inhibits T3 - induced hypertrophic growth in H9c2 cells: Impact of HDAC inhibitor.

Arch Biochem Biophys

Gopinath Nagaraj, Elangovan Vellaichamy

C-type natriuretic peptide (CNP) is a multifaceted paracrine factor that regulates vital physiological functions of the cardiovascular system. The present study was designed to investigate the anti-hypertrophic activity of CNP in the presence and absence of HDAC inhibitor Suberoylanilide hydroxamic acid (SAHA) in T3-induced H9c2 cells. The H9c2 cells were treated with T3 (10 nM) for 48 hours to induce hypertrophic growth. T3 alone-treated cells exhibited an increase in cell size (p < 0.001) as compared with control H9c2 cells. CNP treatment effectively reverted the increased cell size by 61 %, and also altered the expression of hypertrophic marker genes. Interestingly, a significantly enhanced anti-hypertrophic activity was noticed in CNP co-treatment with SAHA, and also a more significant decrease in the expression of hypertrophic marker genes (α-sk, and α-MHC) was also observed. Moreover, CNP treatment with SAHA effectively reversed the T3-induced changes in the expression of Npr1 and Npr2 genes in H9c2 cells. In addition, CNP co-treated with SAHA reversed the T3-induced abnormal calcium influx by normalizing of CaMKII and SERCA2a. The findings of the present study clearly show that CNP co-treatment with SAHA significantly enhances the CNP-mediated anti-hypertrophic activity, probably by restoring Npr1 and Npr2 gene expression and calcium influx. Taken together, we conclude that CNP in combination with SAHA represents a novel therapeutic approach for the treatment and management of cardiac hypertrophy and heart failure.

Natriuretic Peptides as Multisystem Regulators: From Clinical Biomarkers to Therapeutic Targets in Cardio-immunology.

Cardiovasc Drugs Ther

Jathniel Panneflek, Mahmoud Barbarawi, Yasitha Kakarlapudi +3 more

Natriuretic peptides (NPs) ANP, BNP, and CNP extend beyond biomarkers of wall stress to regulators of cardiovascular, renal, metabolic, and immune pathways via cGMP-PKG signaling. We synthesize mechanistic and translational evidence, highlight NP "resistance," and appraise therapeutic strategies that augment NP signaling.

Webb-Dattani syndrome in a 17-year-old girl.

Endocrinol Diabetes Metab Case Rep

Jamilah Saleh Alyami, Wael Mohammad Almistehi, Khalid Ibrahim Alkanhal

Webb-Dattani syndrome (WEDAS) is an extremely rare autosomal recessive disorder caused by pathogenic variants in the ARNT2 gene. It is characterized by a triad of congenital hypopituitarism, structural brain abnormalities, and multisystem developmental defects. We report the case of a 17-year-old girl with WEDAS who presented with global developmental delay, panhypopituitarism, and arginine vasopressin (AVP) deficiency, formerly known as central diabetes insipidus with adipsia, visual impairment, renal anomalies, and spastic quadriplegia. Her endocrine profile revealed deficiencies in ACTH, TSH, and ADH, and gonadotropins, with a possible growth hormone deficiency. Management included hormone replacement with hydrocortisone, levothyroxine, and desmopressin, as well as fluid regulation and supportive care. Despite multiple hospitalizations due to complications including hypernatremia and infections, the patient survived into adolescence - the longest reported survival in this condition to date - before passing away at age 17. This case expands the known clinical phenotype of WEDAS, emphasizing the importance of early recognition, genetic testing, and a multidisciplinary approach to care for affected individuals, particularly in consanguineous populations where the syndrome may be underdiagnosed.

Hypothalamic regulation of obesity: Revealing the therapeutic potential of a novel anti-obesity peptide.

Vascul Pharmacol

Yi Ning Choo, Ram Narayanan, Vetriselvan Subramaniyan

Obesity is a chronic, complex condition defined by excessive fat buildup due to an imbalance between caloric consumption and energy expenditure. The significant global rise in prevalence of obesity is associated with numerous comorbidities, such as cardiovascular disease, type 2 diabetes, and non-alcoholic fatty liver disease. Conventional management approaches, including diet, exercise, pharmacotherapy, and bariatric surgery, may demonstrate restricted long-term effectiveness owing to inadequate adherence and physiological adjustments. Recent advancements in neuroscience underscore the hypothalamus as a pivotal regulator of energy balance via essential nuclei, including the arcuate nucleus (ARC), paraventricular nucleus (PVN), lateral hypothalamic area (LHA), and ventromedial nucleus (VMN). This review examines the therapeutic potential of a new anti-obesity peptide that targets hypothalamic signalling pathways. Preclinical and clinical evidence endorses the utilization of glucagon-like peptide-1 receptor (GLP-1R) agonists and novel multi-receptor drugs such as AMG 133, which integrate GLP-1R activation with glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonism. These therapies exhibit improved weight reduction and metabolic enhancement. Moreover, the integration of hypothalamic peptide therapy with lifestyle modifications or post-bariatric care provides synergistic advantages. Notwithstanding favorable results, peptide therapy encounters obstacles such as administration methods, sustained effectiveness, and expense. Overcoming these obstacles is crucial for the effective implementation of peptide-based treatments in sustained clinical obesity control.

A multi-tissue integration of immunocytes and inflammaging biomarkers predicts biological age through LASSO-optimized modeling.

Biogerontology

Jiawei Yang, Haichen Zhang, Qiong Zhang +8 more

Immunosenescence, a recognized hallmark of aging, is characterized by imbalances in immunocyte populations and a state of chronic inflammation. However, the tissue-specific dynamics of these changes and their potential as predictive biomarkers for aging remain poorly characterized. In this study, we established a multi-tissue immunological signature as a robust predictor of biological age by integrating immunocyte and cytokine profiling. Using Sprague-Dawley (SD) rats from five age groups (1-12 months), we systematically quantified 45 immunocyte subsets across peripheral blood, mesenteric lymph nodes, thymus, and spleen using flow cytometry, and profiled 22 serum cytokines/chemokines via Flexible Multi-Analyte Profiling (xMAP). Firstly, classic age-dependent shifts were observed across our rat samples, including progressive thymic involution and depletion of peripheral T-cells. Cytokine levels exhibited age-related chronic inflammation progression, marked by elevated IL-1α, granulocyte colony-stimulating factor (G-CSF), and TNF-α. To integrate these multidimensional datasets into a predictive aging metric, we employed Least Absolute Shrinkage and Selection Operator (LASSO) regression, selecting 22 biomarkers through regularization (λ = 0.111). The integrated model combining cellular and cytokine data demonstrated superior performance (training R2 = 0.957, validation R2 = 0.887), outperforming single-modality models based on immunocytes or cytokines. Notably, splenic parameters dominated the aging signature, contributing seven biomarkers representing 60% of model weight-particularly Th-cell expansion and Tc-cell depletion. Peripheral blood Th-cell proportion emerged as another key predictor. Our findings position the spleen as a critical aging hub and identify peripheral/splenic Th-cell modulation as promising therapeutic targets for age-related immune dysfunction, revealing novel mechanistic insights into aging-associated immune remodeling.

Letter to the Editor - Qualitative evidence submitted by patients to NICE: need for more quality or unrealistic and unfair requirements?

J Comp Eff Res

Rocco Falchetto, Jasmin Barman-Aksözen

Giant Sellar Meningocele: Intact Pituitary Function and New-onset Arginine Vasopressin Deficiency After Surgery.

JCEM Case Rep

Oscar Josué Gómez-Romero, Baldomero González-Virla, Guadalupe Vargas-Ortega +3 more

Sellar and sphenoidal meningoceles are rare entities that can lead to neurological, ophthalmological, and endocrine complications. We report the case of a 28-year-old man with a giant sellar meningocele who presented with chronic headache and bitemporal hemianopsia but with preserved pituitary function at diagnosis. Magnetic resonance imaging revealed a large defect of the sellar floor with herniation of meninges and displacement of the optic chiasm and pituitary gland. The patient underwent endoscopic transsphenoidal repair. Within 24 hours, he developed arginine vasopressin (AVP) deficiency requiring long-term desmopressin therapy, which persisted beyond 6 months, fulfilling the criteria for permanent AVP deficiency. No other pituitary hormone deficits were observed. Visual field impairment did not improve after surgery, although further deterioration was prevented. This case underscores that adult sellar meningoceles can present with intact anterior pituitary function but still carry a risk of isolated permanent AVP deficiency after surgical repair. To our knowledge, this is among the largest adult sellar meningoceles reported with preserved anterior pituitary function at presentation and subsequent permanent isolated AVP deficiency, emphasizing the need for careful perioperative counseling and long-term endocrine follow-up.

Insulinoma Unmasked By Tirzepatide: A Rare Case of Postprandial Hypoglycemia In a Nondiabetic Patient.

JCEM Case Rep

Michael Polisky, Dina Kamel, Jeong-Hee Ku

A 63-year-old woman with obesity presented with severe postprandial hypoglycemia that worsened after starting tirzepatide for weight loss. Further evaluation led to the diagnosis of insulinoma. This case suggests that the use of tirzepatide can provoke severe hypoglycemia episodes in patients with insulinoma and highlights the importance of including insulinoma as a differential diagnosis for hypoglycemia in patients taking incretin-based therapy.

GLP-1 receptor agonists on WHO-EML 2025 list: major breakthrough bounded by persistent challenge.

J Diabetes Metab Disord

Kanimozhi Mani

The World Health Organisation (WHO) periodically updates its Model List of Essential Medicines (EML) and Essential Medicines for Children (EMLc) to address evolving global health priorities. The 24th EML and 10th EMLc, released on 5th September 2025, mark a major milestone by expanding access to twenty new medicines for diabetes, cancer, cystic fibrosis, haemophilia, psoriasis, and blood disorders. Notably, the inclusion of glucagon-like peptide-1 (GLP-1) receptor agonists-semaglutide, liraglutide, dulaglutide-and the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, tirzepatide, represents a paradigm shift in the management of type 2 diabetes mellitus (T2DM) and obesity. These agents have demonstrated significant benefits in lowering blood glucose levels, reducing cardiovascular and renal complications, and promoting weight loss in T2DM patients with established cardiovascular disease (CVD), chronic kidney disease (CKD), or obesity. This move aims to bridge the longstanding treatment gap in low- and middle-income countries (LMICs), where high drug costs have limited access to such therapies. Their recognition as essential medicines enables prioritisation of limited resources, facilitates equitable pricing, and supports the development of generics and biosimilars post-patent expiry. This inclusion aligns with Sustainable Development Goal 3.4, which aims to reduce premature mortality from non-communicable diseases (NCDs) by 1/3 by 2030. However, challenges persist, including financial constraints, limited healthcare infrastructure, and risks of irrational use, particularly for obesity alone. Effective implementation through national policies, training, and rational prescribing frameworks is essential to translating this global milestone into tangible public health benefits and to reducing the growing burden of diabetes and obesity worldwide.

High-fat diet-induced obesity accelerates puberty in male rats through SMIM20/phoenixin upregulation.

Front Endocrinol (Lausanne)

Tao Xie, Wei Qin, Dan Zeng +5 more

Controversy exists regarding the relationship between obesity and pubertal onset in boys, and the underlying mechanisms remain unclear.

rbfox1 LoF mutants show disrupted bdnf/trkb2 and crhb/nr3c2 expression and increased cortisol levels during development coupled with signs of allostatic overload in adulthood.

Transl Psychiatry

Adele Leggieri, Judit García-González, Saeedeh Hosseinian +7 more

Mutations in the RBFOX1 gene are associated with psychiatric disorders but how RBFOX1 influences psychiatric disorder vulnerability remains unclear. Recent studies showed that RBFOX proteins mediate the alternative splicing of PAC1, a critical HPA axis activator. Further, RBFOX1 dysfunction is linked to dysregulation of BDNF/TRKB, a pathway promoting neuroplasticity, neuronal survival and stress resilience. Hence, RBFOX1 dysfunction may increase psychiatric disorder vulnerability via HPA axis dysregulation, leading to disrupted development and allostatic overload. To test this hypothesis, we generated a zebrafish rbfox1 loss of function (LoF) line and examined behavioural and molecular effects during development. We found that rbfox1 LoF mutants exhibited hyperactivity, impulsivity and heightened arousal, alongside alterations in proliferation - traits associated with neurodevelopmental and stress-related disorders. In adults, loss of rbfox1 function led to decreased fertility and survival, consistent with allostatic overload. At the molecular level, at larval stages rbfox1 mutants showed increased cortisol levels and disrupted expression of key stress-related genes (bdnf, trkb2, pac1a-hop, crhb, nr3c2). Pharmacological intervention targeting TRKB restored crhb and nr3c2 gene expression and hyperactive and hyperarousal behaviours. In adults, dysregulation of crhb, nr3c2 and bdnf/trkb2 genes was only seen following acute stress exposure. Our findings reveal a fundamental role for RBFOX1 in integrating stress responses through its regulation of BDNF/TRKB and neuroendocrine signalling.