Precision medicine tailors prevention, diagnosis and treatment of cardiometabolic diseases to individual genetic, environmental and lifestyle determinants, with the potential to fundamentally change healthcare. However,...Precision medicine tailors prevention, diagnosis and treatment of cardiometabolic diseases to individual genetic, environmental and lifestyle determinants, with the potential to fundamentally change healthcare. However, low-income and middle-income countries (LMICs) and small island developing states (SIDS) experience severe implementation barriers: inadequate healthcare infrastructure, prohibitive costs, under-representation in genomic datasets and additional SIDS-specific constraints. This Perspective advances three specific contributions beyond generic equity calls. First, it delineates distinct precision medicine pathways for larger LMICs versus SIDS, highlighting SIDS opportunities for regional consortia, shared sequencing and/or biobanking hubs and technological leapfrogging via mobile health platforms and digital phenotyping. Second, it emphasizes practical and high-impact entry points that are financially sustainable. Additionally, it advocates for integrating polygenic risk-based stratification into existing non-communicable disease care pathways rather than establishing separate specialist services. Third, it delineates a staged implementation framework that prioritizes ethical oversight and robust data governance, underscoring the importance of privacy safeguards, data sovereignty, equitable benefit sharing, community consent mechanisms and alignment with the Sustainable Development Goals to minimize associated risks of exploitation. Equitable partnerships between LMICs and high-income countries, expansion of diverse genomic data and community-driven innovation will ensure that precision tools effectively target metabolic phenotypes in LMICs and SIDS while advancing global health equity.
Zariñán T, Jardón-Valadez E, Gutiérrez-Sagal R
… +4 more, Ulloa-Pérez E, Nataraja S, Yu HN, Ulloa-Aguirre A
Endocrinology
· 2026 Apr · PMID 41988939
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Mutations in the follicle-stimulating hormone receptor (FSHR) may result in impaired plasma membrane expression due to misfolding and intracellular retention of the receptor, leading to disease. Rescue of misfolded recep...Mutations in the follicle-stimulating hormone receptor (FSHR) may result in impaired plasma membrane expression due to misfolding and intracellular retention of the receptor, leading to disease. Rescue of misfolded receptors may be achieved employing pharmacological chaperones (small molecules that specifically bind misfolded proteins, promoting their correct trafficking to their site of action). This study analyzed whether the small-molecule FSHR agonist CAN1405 rescued membrane expression and function of 13 mutant FSHRs leading to premature ovarian failure in women. FSHRs were expressed in HEK-293 cells, and membrane expression was assessed by immunoblotting before and after incubation with CAN1405. Three trafficking defective variants in the ectodomain of the FSHR (A189V, N191I, and D224V) and 3 others located in transmembrane domains (TMD) 3 and 4, and extracellular loop 2 (A462P, P504S, and P519T, respectively) failed to respond (or did it marginally) to CAN1405 by increasing their membrane expression. In contrast, in 7 variants located in the TMD2 (D408Y, A419T, and I423T), TMD6 (A575V, P587H, and F591S), and extracellular loop 3 (L597I), CAN1405 rescued membrane expression of the variants. Functional studies showed that after CAN1405 removal, rescued FSHRs responded to the orthosteric agonist in terms of cAMP-mediated signaling and ERK1/2 phosphorylation. Refined molecular dynamics simulations using the cryo-EM structure of the FSHR revealed key conformational changes and interactions within the TMDs provoked by CAN1405, highlighting potential allosteric binding sites critical for receptor activation. These findings offer a promising therapeutic strategy for treating mutation-provoked FSHR dysfunction and underscore the synergistic potential of computational biophysics in drug discovery.
Guarnieri G, Comeglio P, Filippi S
… +14 more, Cellai I, Acciai G, Bartolucci G, Pini A, Amedei A, Silvestri L, Garella R, Ragosta ME, Cipriani S, Marchiani S, Rastrelli G, Maggi M, Morelli A, Vignozzi L
Endocrinology
· 2026 May · PMID 41988766
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Metabolic syndrome (MetS), including obesity, dyslipidemia, hypertension, insulin resistance, and often testosterone (T) deficiency, is increasingly linked to impaired lung function, worsened by systemic inflammation. CO...Metabolic syndrome (MetS), including obesity, dyslipidemia, hypertension, insulin resistance, and often testosterone (T) deficiency, is increasingly linked to impaired lung function, worsened by systemic inflammation. COVID-19 highlighted the vulnerability of metabolically impaired patients to respiratory complications. Preclinical mechanistic studies remain limited. This study examined MetS effects on lung function and morphology, and the impact of T therapy in a high-fat diet (HFD)-induced MetS rabbit model. Male New Zealand White rabbits were assigned to: regular diet, HFD 6 weeks, HFD 12 weeks (HFD12W), HFD + T 12 weeks (HFD + T12W), and HFD + T last 6 weeks (HFD12W + T6W). Lung function was measured via airway opening pressure (PAO), and tissues analyzed for macrophages (RAM11), collagen (picrosirius red), and inflammatory/fibrotic gene expression. HFD induced MetS features, hypogonadism, increased PAO, reduced compliance, elevated fatty acids, and early macrophage remodeling. At 12 weeks, inflammation and fibrosis were prominent, with upregulation of IL1β, LOX1, RORγt, TLR2, COL1A1, COL3A1, and TGFβ1. T therapy increased plasma T, improved metabolic parameters, reduced PAO, and reversed inflammatory/fibrotic gene expression. Histology confirmed decreased macrophage clustering and fibrosis. PAO inversely correlated with T, with levels <3.76 nM predicting abnormal PAO with >80% sensitivity and specificity. MetS causes progressive lung injury via macrophage dysregulation, inflammation, and peribronchiolar fibrosis. T deficiency is central, as hormone administration improved lung function and histology. Immune-driven mechanisms, including Th2/Th17 cytokines and epithelial-mesenchymal transition markers, likely contribute. T's anti-inflammatory and antifibrotic effects may involve cAMP signaling. Clinically, assessing T and metabolic status is crucial, and T therapy may help mitigate lung consequences of MetS.
Vasomotor symptoms (VMS), including hot flushes and night sweats, affect approximately 70% of people experiencing menopause and have a notable effect on quality of life. Until the past few years, the underlying neuroendo...Vasomotor symptoms (VMS), including hot flushes and night sweats, affect approximately 70% of people experiencing menopause and have a notable effect on quality of life. Until the past few years, the underlying neuroendocrine mechanisms remained poorly understood, limiting therapeutic options beyond menopausal hormone therapy. The discovery that neurons expressing kisspeptin, neurokinin B and dynorphin (KNDy neurons) in the hypothalamic arcuate nucleus trigger VMS through modulation of neurons expressing neurokinin 3 receptor (NK3R) in the median preoptic area has revolutionized our understanding of VMS pathophysiology. During oestrogen withdrawal, hyperactivated KNDy neurons release excessive levels of neurokinin B, inappropriately triggering heat dissipation responses that are characteristic of hot flushes. This mechanistic insight has enabled the development of NK3R antagonists as the first non-hormonal therapeutic specifically targeting VMS neurobiology. These new treatments offer promise for populations in which hormone therapy is contraindicated. This Review synthesizes the current understanding of VMS neurobiological pathways, examines translational approaches from preclinical animal models to clinical studies, and discusses the evolution of treatments and mechanism-based interventions that might fundamentally transform the management of menopausal symptoms.
The thyroid gland develops in five main stages, each characterized by specific molecular and cellular processes that are highly conserved across invertebrates and vertebrate species. In vivo studies have elucidated the k...The thyroid gland develops in five main stages, each characterized by specific molecular and cellular processes that are highly conserved across invertebrates and vertebrate species. In vivo studies have elucidated the key molecular players orchestrating each stage of thyroid organogenesis and thyroid hormone biosynthesis, laying the groundwork for developing thyroid organoids in vitro. Thyroid organoids have been successfully derived from mouse and human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, as well as from fetal and adult thyroid tissues. Protocols using directed differentiation through chemical signalling modulators and/or by overexpression of pivotal thyroid transcription factors have yielded thyroid progenitors with varying levels of maturation, differing in timeline, purity and functional outcomes. However, only a few protocols have succeeded in producing thyroid organoids capable of recapitulating thyroid functionality both in vitro and in vivo. This Review explores the various thyroid organoid models currently available, their contributions to understanding thyroid developmental biology and their application in modelling thyroid diseases. We also discuss the current challenges to translating thyroid organoid technology from experimental frameworks into clinical applications, framing the question: could thyroid organoids offer a therapeutic avenue for hypothyroidism, particularly in cases of congenital, post-surgical and treatment-refractory conditions?
Aubert D, Wu S, Markossian S
… +4 more, Gauthier K, Teixeira M, Guyot R, Flamant F
Endocrinology
· 2026 May · PMID 41941594
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The transcription of the Hairless gene (Hr), which encodes a histone demethylase, is strongly induced by thyroid hormone (T3) in many cell types. This is mediated by heterodimers formed between T3 nuclear receptors and r...The transcription of the Hairless gene (Hr), which encodes a histone demethylase, is strongly induced by thyroid hormone (T3) in many cell types. This is mediated by heterodimers formed between T3 nuclear receptors and retinoid X receptors. These heterodimers are bound to specific DNA response elements present in regulatory sequences and activate transcription upon T3 binding. To address the significance of this regulation, we identified a single DNA response element upstream of the Hr transcription start site, which plays a key role in this regulation. A single nucleotide mutation in this DNA response element, which prevents the binding of heterodimers, was shown to prevent the activation of Hr by T3 signaling in mice. Analysis of gene expression in the heart and striatum of mice homozygous for this mutation highlights the influence of the Hairless cofactor on thyroid hormone signaling.
Endocrinology
· 2026 Apr · PMID 41926710
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Acute pharmacological administration of the endocrine hormone fibroblast growth factor 21 (FGF21) enhances insulin sensitivity. This acute insulin-sensitizing effect of FGF21 is mediated through direct signaling to brown...Acute pharmacological administration of the endocrine hormone fibroblast growth factor 21 (FGF21) enhances insulin sensitivity. This acute insulin-sensitizing effect of FGF21 is mediated through direct signaling to brown adipose tissues. Since skeletal muscle is an important site of insulin-stimulated glucose intake and shares a common progenitor cell with brown adipocytes, we examined whether the beneficial effects of FGF21 administration could be enhanced by making skeletal muscle a FGF21-responsive target tissue. This was accomplished by ectopically expressing the FGF21 co-receptor, β-klotho, in skeletal muscle. Here, we demonstrate that under normal conditions, FGF21 does not enhance insulin-stimulated glucose uptake in skeletal muscle. In addition, generation of FGF21 responsiveness and direct signaling to skeletal muscle also has no effect on FGF21-mediated increases in whole-body or skeletal muscle insulin sensitivity. Instead, FGF21 uniquely signals to brown adipocytes to enhance insulin-stimulated glucose uptake. Therefore, to identify how FGF21 signals to brown adipocytes to enhance insulin sensitivity, we performed comprehensive phospho-proteomics in brown adipocytes in response to FGF21 and/or insulin. Our results indicate that FGF21 administration increases the phosphorylation of several proteins involved in the trafficking of GLUT4 in primary brown adipocytes. These results provide new insights into how FGF21 enhances insulin sensitivity.
Endocrinology
· 2026 Apr · PMID 41926708
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Glucagon is a peptide hormone mainly secreted by the alpha cells of the pancreatic islets in response to nutritional stimuli. Traditionally recognized for its hyperglycemic function counteracting insulin action, it mainl...Glucagon is a peptide hormone mainly secreted by the alpha cells of the pancreatic islets in response to nutritional stimuli. Traditionally recognized for its hyperglycemic function counteracting insulin action, it mainly acts on the liver to affect glycogen, amino acid, lipid, and energy metabolism. Beyond its metabolic effects, glucagon also increases hepatocyte cell survival and reduces viral replication. Peptides with glucagon activity have recently emerged as a promising therapeutic candidate for obesity, type 2 diabetes, and associated liver disease, with several glucagon-based agents currently in phase 2/3 clinical trials. Despite this progression, and although discovered roughly the same time as insulin, how glucagon exerts its pleiotropic effects on metabolism and beyond remains relatively poorly understood. Knowledge of these signaling pathways could pave the way for further refinement of glucagon-based pharmacotherapy with more pronounced effects or reduced side effects. This review aims to address established literature and its limitations on glucagon signaling mechanisms and provides an update on the state of the art on glucagon signaling pathways to help in understanding the mechanisms behind glucagon action.
DI Marzio B, Gasparini G, Ambrosio A
… +13 more, Coin A, Filipponi L, Sartore G, Ferra E, Papa MV, Ravelli A, Ceolin C, DE Rui M, Zanforlini BM, Curreri C, Bertocco A, Devita M, Sergi G
BACKGROUND: Type 2 diabetes mellitus (T2DM) is frequently associated with cognitive decline in the older population. Although optimal glycemic control is known to be essential for disease management, the impact of hypogl...BACKGROUND: Type 2 diabetes mellitus (T2DM) is frequently associated with cognitive decline in the older population. Although optimal glycemic control is known to be essential for disease management, the impact of hypoglycemic agents on cognitive function remains poorly investigated. METHODS: This retrospective study included 93 geriatric outpatients with T2DM. Hypoglycemic treatments consisted of metformin, sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors, and insulin. Patient evaluations included glycated hemoglobin (HbA1c) measurements, Standardized Mini-Mental State Examination (MMSE), and Mini Nutritional Assessment (MNA). RESULTS: After one year of treatment, patients exhibited a significant reduction in HbA1c levels (from 8.06% [±1.19] to 7.19% [±0.84], P<0.001), improvement of MMSE scores (from 25.87 [±3.09] to 27.47 [±2.9], P<0.001). Regression analysis identified GLP-1RAs as the most effective agent in improving glycemic control (P<0.001) and cognitive function (P=0.016). Treatment with GLP-1RAs was associated with a reduction in MNA scores (P<0.001), though these remained above the malnutrition threshold. CONCLUSIONS: Our findings suggest that improved glycemic control may help slow cognitive decline in older patients with T2DM. Among the drug classes examined, GLP-1RAs showed the largest reductions in HbA1c and were linked to greater MMSE score gains.
Yamakawa M, Gajbhiye DS, Golan M
… +1 more, Kanda S
Endocrinology
· 2026 Apr · PMID 41913960
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Anterior pituitary hormone secretion is generally considered to be under the strong regulation of hypothalamic neuropeptides. In mammals, adrenocorticotropic hormone (ACTH), which plays a crucial role in the stress respo...Anterior pituitary hormone secretion is generally considered to be under the strong regulation of hypothalamic neuropeptides. In mammals, adrenocorticotropic hormone (ACTH), which plays a crucial role in the stress response, is secreted from corticotropes and is regulated primarily by corticotropin-releasing hormone (CRH). In teleosts, although the pharmacological effects of hypothalamic factors have been demonstrated, their relative importance in regulating ACTH release remains controversial. One reason for this is the lack of methods for evaluating ACTH release at cellular resolution. Using medaka as a model organism, we systematically examined the direct effects of hypothalamic peptides on ACTH cells by combining cell type-specific transcriptomics with Ca2+ imaging. We show that thyrotropin-releasing hormone (TRH) robustly elevates intracellular Ca2+ concentration ([Ca2+]ᵢ) in ACTH cells, surpassing the responses elicited by CRH or arginine vasotocin (AVT). TRH also strongly activates MSH cells, the other POMC-derived pituitary cell population, while CRH induces only a modest response. Furthermore, in situ hybridization chain reaction analyses revealed that TRH receptor (trhra) is expressed in MSH cells, supporting their direct responsiveness to TRH signaling, whereas TRH receptor expression in ACTH cells was below the detection limit, leaving open the possibility that their activation is mediated by indirect or low-abundance receptor pathways. These findings may suggest the existence of a novel TRH-driven regulatory pathway orchestrating both the stress axis and the pigmentation axis.
Cancers of the breast and prostate are one of the leading causes of cancer deaths in women and men, respectively. Although several treatment options have been developed to transform these cancers into manageable chronic...Cancers of the breast and prostate are one of the leading causes of cancer deaths in women and men, respectively. Although several treatment options have been developed to transform these cancers into manageable chronic diseases, they still contribute to over 70 000 deaths each year in the United States. Though majority of these cancers belong to slow growing differentiated subtypes, the cancers evolve over time due to treatment-related pressure into aggressive treatment-resistant types. A mechanism attributed to the transformation of hormonal and other cancers into aggressive treatment-refractory cancers is "lineage plasticity," a term used to describe a switch in the cell type or lineage. Evolving evidences suggest that the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway plays a key role in driving lineage plasticity. This review discusses the role of JAK-STAT signaling pathway in hormonal cancers' evolution into aggressive cancers and in treatment resistance, with focus on treatment-induced lineage plasticity.
Masoumparast M, Fiset JP, Nasri N
… +1 more, Silva MSB
Endocrinology
· 2026 Apr · PMID 41906631
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Socio-sexual behaviors, a key aspect of mammalian biology, are governed by evolutionarily conserved neuronal circuits that control partner preference, sexual attraction, and attachment. This mini-review summarizes recent...Socio-sexual behaviors, a key aspect of mammalian biology, are governed by evolutionarily conserved neuronal circuits that control partner preference, sexual attraction, and attachment. This mini-review summarizes recent advances in understanding neuroendocrine pathways involved in various levels of socio-sexual interactions, from mating preferences to forming long-term sexual partnerships. We first briefly examine how prenatal hormone exposure shapes brain structures that later influence partner choices, with a particular focus on mechanisms driven by sex steroid hormones in rodent models. We also highlight some of the latest evidence showing how multimodal sensory cues activate neural circuits and neuroendocrine responses to initiate sexual behaviors. Finally, we examine how molecularly defined neuronal populations differently impact sexual performance and socio-sexual attachment in a sex-dependent manner. Some of the evidence presented here might have been overlooked and warrants greater attention to improve guidance and discuss future directions for our field.
Morris PG, Liu X, Birt E
… +5 more, Vas S, Ruiz Cruz M, Schafer D, McQuillan HJ, Herbison AE
Endocrinology
· 2026 Apr · PMID 41906629
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Serotonin neurons are thought to exert a modulatory influence on the secretion of the gonadotropin hormones in mammals, but their mechanism of action remains unclear. We examined here the potential role of serotonin neur...Serotonin neurons are thought to exert a modulatory influence on the secretion of the gonadotropin hormones in mammals, but their mechanism of action remains unclear. We examined here the potential role of serotonin neurons in modulating the activity of the gonadotropin-releasing hormone (GnRH) pulse generator formed by the arcuate nucleus kisspeptin (ARNKISS) neurons. Acute brain slice electrophysiology revealed that ∼60% of ARNKISS neurons in diestrous female mice were activated by serotonin while less than 10% were inhibited. Pharmacological studies indicated that combinatorial patterns of 5-HT receptor subtype activation were likely responsible for the excitatory actions. The role of serotonin in ARNKISS neuron synchronization behavior was assessed using GCaMP imaging in acute brain slices from diestrous female and male mice. In both sexes, serotonin-evoked potent recurring bouts of synchronization activity amongst ARNKISS neurons. To evaluate the impact of serotonin in vivo, we used "fluidic" GCaMP fiber photometry in which serotonin was infused directly into the ARN while recording the ARNKISS neuron population activity in freely behaving diestrous female mice. In all cases, the infusion of serotonin evoked a robust ARNKISS neuron synchronization episode. These data demonstrate that serotonin exerts a direct, predominantly stimulatory action on ARNKISS neuron pulse generator through a variety of 5-HT receptors. Serotonergic inputs appear to provide a potent synchronizing influence on the ARNKISS neuron population and suggest considerable potential for 5-HT to control the frequency of pulsatile reproductive hormone secretion in mice and likely other mammals.