The prevalence of obesity is steadily increasing worldwide. Obesity profoundly alters the composition, structure, and function of adipose tissue (AT), the largest endocrine organ in the body. Adipose-derived mesenchymal stem cells (ASCs) are central to AT plasticity and become dysfunctional in obesity. In this review, we outline the molecular regulation of ASCs in self-renewal and differentiation, and their roles in regulating AT expansion, modulating immune and inflammatory response, and remodeling the extracellular matrix (ECM), positioning ASCs as decisive homeostatic regulators of AT. By integrating recent findings from cutting-edge studies and performing extensive bioinformatic analyses, we delineate ASC differentiation trajectories and propose a fundamentally revised view of ASCs with a heterogeneous hierarchy of functionally distinct subpopulations. Obesity impairs ASC subsets in their self-renewal and differentiation, driving fibro-inflammatory phenotypes that promote maladaptive immune response, ECM stiffening and fibrosis, and premature cellular senescence, acting as central hubs of obesity-associated tissue dysfunction. These alterations likely arise from reprogrammed ASC epigenomic landscapes and obesogenic niches characterized by an inflammatory milieu, toxic metabolites, and oxidative stress. Interestingly, substantial weight loss attenuates fibro-inflammatory stromal states and partially restores ASC pools, whereas fibrosis-associated transcriptional programs and niche memory persist, indicating incomplete reversal of obesity-induced stromal remodeling. Drawing on human, mouse, and experimental single-cell datasets, we provide mechanistic insights into the ASC-immune cell-ECM regulatory network, highlighting how obesity reshapes ASC identity, lineage trajectories, and niche signaling. Finally, we propose that therapeutic restoration of ASC plasticity may represent a promising strategy to reestablish AT homeostasis and limit the progression of metabolic disease.

Obesity is an alarmingly growing global epidemic strongly associated with type 2 diabetes, cardiovascular disease, metabolic syndrome, and chronic kidney disease. Metabolic dysfunction-associated steatotic liver disease (MASLD) is considered an important contributor within this interconnected spectrum, representing a new component of the broader cardio-kidney-metabolic (CKM) syndrome, now more aptly labelled as the cardio-kidney-liver-metabolic (CKLM) syndrome. This narrative review synthesizes evidence from epidemiological studies, clinical trials, and ongoing scientific research to explore the multifaceted associations, complex interplay and shared pathophysiological mechanisms among these disorders. The clinical implications of this interplay are substantial, underscoring the need for a holistic approach encompassing early detection, comprehensive risk assessment, and multi-targeted interventions. Therapeutic strategies discussed include lifestyle modification, anti-diabetic, anti-obesity, lipid-lowering agents, and bariatric surgery. Given MASLD's potential role in the CKLM spectrum, future research should deepen the understanding of shared mechanisms and develop integrated clinical management strategies to improve outcomes and reduce their global burden.

Congenital pituitary hormone deficiency (CH) is a rare disorder that usually involves deficient production of growth hormone (GH) and other pituitary hormones. Many cases are syndromic, affecting other aspects of craniofacial development and sometimes other organs. There are many genes implicated in congenital pituitary hormone deficiency, and some of them also cause more severe disorders like septo-optic dysplasia (SOD) and holoprosencephaly (HPE). It is not clear why mutations in the same gene can cause such variable clinical features. In addition, the molecular etiology of many cases is not identified with current genetic testing approaches. To realize the promise of the human genome project, more genetic causes need to be identified, and the basis for variable clinical presentations needs to be better understood. In this review we provide information about the overlapping genetic causes of this spectrum of disorders in humans, discuss the influence of genetic background and environment on presentations, and highlight animal models that expand our understanding of how genetic and environmental factors can synergize to generate diverse phenotypes. Evidence for genetic and environmental contributions to this spectrum of disorders is strong.

The textbook view of the regulation of calcium homeostasis centers on parathyroid hormone, calcitriol, and calcitonin. While this paradigm has long dominated the field, it represents only part of a broader evolutionary and physiological landscape. This article focuses on Stanniocalcin 1 (STC1), a calciotropic hormone originally discovered in bony fish. Since its discovery in the 1970s, our understanding of STC1 has evolved from a "fish-specific" hormone to a member of a multifunctional glycoprotein family with deep roots in metazoan evolution. Recent studies in zebrafish show that STC1 inhibits calcium uptake through two mechanisms: it reduces TRPV6-dependent calcium influx and limits the proliferation of calcium-transporting ionocytes. Mechanistically, STC1 suppresses local insulin-like growth factor (IGF) signaling by binding pappalysin-family IGF-binding protein (IGFBP) proteases, thereby modulating IGFBP processing and downstream IGF activity. This STC1-Pappalysin-IGFBP-IGF axis has recently been positioned as a central node in an organ-brain communication pathway that links calcium uptake to brain function and animal behavior. In humans and other mammals, STC1 is expressed in many tissues locally and exerts local actions in a paracrine fashion. Dysregulation of STC1 expression has been associated with chronic kidney diseases and multiple cancer types. Recent studies have uncovered a novel role for STC1 in tumor immune evasion as a phagocytosis checkpoint and a "don't eat me" signal. This review integrates recent findings on the multifunctional roles of STC1 in regulating calcium homeostasis, IGF signaling, and cancer immunity, and to highlight the therapeutic potential of targeting STC1 in kidney diseases and cancer immunotherapy.

Cardiovascular-kidney-metabolic (CKM) syndrome represents an intricate and interdependent nexus among metabolic risk factors, such as diabetes and obesity, chronic kidney disease (CKD), and cardiovascular disease (CVD), collectively exerting a profound impact on global morbidity and mortality. The rising prevalence of type 2 diabetes (T2D) underscores the urgent need for therapeutic strategies that transcend glycemic control to target the intricate pathophysiology underlying these conditions. This review examines the expanding role of novel antidiabetic drug classes, including sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dual or triple-incretin agonists, across the CKM continuum. These agents have demonstrated significant benefits in reducing major adverse cardiovascular events (MACEs), attenuating CKD progression, and enhancing metabolic health, independent of their glucose-lowering properties. Across the CKM continuum, we prioritize weight-centric incretin therapy (GLP-1RAs or dual incretins) in stage 0-1 (obesity/prediabetes), SGLT2 inhibitors first for albuminuric CKD and/or heart failure risk in stage 2 (with early addition of GLP-1RAs when CVD/obesity predominates), and layered combination therapy in stage 3, typically SGLT2 inhibitor + GLP-1RA/dual incretin (± finerenone for persistent albuminuria), to maximize cardiovascular and kidney protection. By synthesizing evidence from pivotal clinical trials, evaluating emerging combination therapies, and delineating the evolving treatment paradigm, this review aims to provide a comprehensive perspective on how these antidiabetic therapies influence CKM syndrome management. As research advances, an integrated, multifaceted approach to diabetes care leveraging these agents may lead to substantial improvements in cardiovascular, kidney, and metabolic outcomes.

Endocrine tissues must continuously adjust their structure and function in response to circadian cues, metabolic state, and physiological stress. Within these dynamic systems, stem cells contribute not only to tissue maintenance and repair but also to functional plasticity. The hypothalamic-pituitary-adrenal (HPA) axis exemplifies this integration of local stem cell regulation with systemic endocrine control. In this Review, we highlight the shared regulatory principles and tissue-specific adaptations of stem cell populations across the hypothalamus, anterior pituitary and adrenal gland. We discuss tanycytes as hypothalamic stem cells, SOX2+ stem cells as key regulators of pituitary plasticity, and multipotent and lineage-restricted progenitors that sustain adrenal cortical and medullary renewal. Across HPA axis organs, conserved signaling pathways and multiple modes of cell-cell communication, including paracrine and feedback mechanisms, coordinate stem cell behavior with endocrine output. Importantly, we present growing evidence that endocrine stem cells influence organ function beyond direct cell replacement, shaping tissue responsiveness, and adaptation to physiological demand. Disruption of these processes contributes to endocrine dysfunction and tumorigenesis. Integrating insights from genetic models, human single-cell and spatial atlases, we outline how viewing the HPA axis as an integrated stem cell system provides a framework for understanding endocrine plasticity and identifies emerging opportunities and challenges for regenerative and therapeutic strategies.

Sex steroid hormones, such as estrogen, progesterone, and testosterone, are primarily known as critical regulators of reproductive function in both males and females. However, increasing evidence indicates that fluctuating levels of sex hormones also affect non-reproductive organs, including tissues in the musculoskeletal system. Observations from muscle and bone literature support a model in which hormonal state modulates exercise-induced mechanotransduction and downstream extracellular matrix (ECM) remodeling. However, soft connective tissues - cartilage, meniscus, tendon, ligament, intervertebral disc - are often overlooked, despite being the primary sites of career-ending sports injuries and chronic degeneration. This review focuses on these tissues, aiming to examine how sex hormones and other sex-specific molecules critically regulate the process of exercise adaptation at the tissue level. We first outline sex steroid biosynthesis, bioavailability, and receptor mechanisms and then examine how steroids intersect with mechanosensing and mechanotransduction. Looking further downstream, we then assess how hormonal state regulates ECM turnover and functional adaptations. We propose novel connections and mechanisms by which sex hormones and other sex-specific molecules determine load-induced responses via specific mechanotransduction pathways and through ECM remodeling. We conclude by outlining open questions and experimental needs that would aid in establishing causal relationships between sex hormones and exercise responses in soft musculoskeletal tissues.

DAX-1 (NR0B1) is a pivotal regulator of mammalian reproductive and endocrine development. Discovered as a gene whose dosage imbalance can reverse sex in XY individuals, DAX-1 is now recognized as a key component of the network controlling gonadal formation and function. Despite decades of research, the molecular mechanisms of its function in gonad development and function remain only partially understood. We combine genetic, developmental, molecular and biochemical perspectives to present how DAX-1 regulates gene expression from early sex determination and gonadal differentiation to the maintenance of steroidogenic homeostasis in adrenal and gonadal tissues. Recent advances have reshaped our view of DAX-1 beyond its classical role as a transcriptional repressor. Evidence shows that it functions within dynamic transcriptional networks, interacting with regulators such as SF-1 (NR5A1), SOX9 and other nuclear receptors to fine-tune gene expression in a context-dependent manner. Genomic, structural, and proteomic studies reveal that DAX-1 participates in complexes integrating developmental and hormonal cues, coordinating differentiation and steroidogenesis. Moreover, its emerging roles in RNA-associated gene regulation broaden its functions beyond canonical nuclear receptor signaling. We revisit DAX-1 contribution to sex determination and differentiation from an evolutionary and mechanistic viewpoint, emphasizing its interactions with the SRY-SOX9 axis and its dosage-sensitive influence on gonadal fate. The developmental and clinical consequences of DAX-1 mutations and copy number variations manifest as a spectrum of human phenotypes, from adrenal hypoplasia congenita to differences/disorders of sex development (DSD), highlighting its essential role in maintaining endocrine balance.

Appetite regulation is a complex yet vital concept, with several pathways conserved throughout evolution that are still to be fully understood. Appetite, or the drive to search for and consume food, is driven by the integration of different food and environmental cues, as well as internal state. It is dynamically managed by intricate systems that can be broadly categorized into homeostatic (driven by physiological energy needs) and hedonic feeding (driven by pleasure and reward). This review compiles and analyzes recently described and unconventional mechanisms of appetite control in mammals, detailing their underlying molecular pathways and neural circuit integration, and implications for drug discovery. The hypothalamus plays a vital role in this, serving as the main hub for appetite control, integrating peripheral hormonal and neural signals to maintain energy balance and where several pathways converge. Beyond the established hypothalamic Arcuate Nucleus (ARC) circuit, key regulators examined include neuropeptides like Orexin A, Oxyntomodulin, PACAP, and Galanin, alongside key receptor systems such as the Melanocortin-3 receptor (MC3R), the Endocannabinoid (ECS) and the Endorphin Systems. We also explore the roles of the NUCB2/nesfatin-1 pathway and amino acid transporters (SLCs). These examinations resulted in a blurred vision of the distinction between homeostatic and hedonic regulation, with pathways converging on the hypothalamus as well as the mesolimbic reward system. Understanding this interconnected regulatory network is vital for improving therapies for disorders such as obesity, anorexia nervosa, and binge-eating disorder. This comprehensive knowledge paves the way for the development of targeted, precision medicine, or the implementation of multi-target compounds.

Endometriosis affects approximately 10% of reproductive-aged women worldwide and is a leading cause of chronic pelvic pain. Despite its high prevalence and substantial socioeconomic burden, the mechanisms underlying endometriosis-associated pain remain incompletely understood, resulting in delayed diagnosis and limited therapeutic durability. Notably, pain severity frequently shows poor correlation with lesion burden, indicating that endometriosis-associated pain extends beyond the presence of endometriotic lesions alone. Accumulating evidence supports a model in which endometriosis-associated pain arises from the convergence of endocrine dysregulation, immune activation, aberrant neuroangiogenesis, and maladaptive neural plasticity, with estrogen dominance and progesterone resistance serving as central upstream drivers of pain biology. Estrogen-dependent inflammation and progesterone resistance establish a permissive microenvironment that promotes immune dysfunction, neurotrophic signaling, and nociceptor sensitization. These peripheral processes drive sustained afferent input to the central nervous system, leading to peripheral, central, and cross-organ sensitization that can perpetuate pain independently of lesion activity. In this review, we synthesize current evidence across the clinical spectrum of pain, mechanistic pathways, and therapeutic approaches in endometriosis. We integrate insights from inflammatory and immune pathways, neuroimmune crosstalk, hormonal regulation, and sensitization processes, emphasizing progesterone resistance and estrogen-mediated signaling as central modulators. Advances from preclinical models and emerging multi-omics technologies are highlighted to define pain signatures that transcend lesion-based classification. Finally, we discuss emerging therapeutic strategies targeting neuroimmune and endocrine pathways and propose a precision medicine framework that incorporates mechanistic biomarkers, translational models, and pain-specific clinical endpoints to improve stratification, reduce ineffective interventions, and achieve individualized pain relief for women with endometriosis.

Sepsis, a life-threatening syndrome caused by dysregulated host responses to infection, remains a major global health challenge with high mortality and no specific therapy. Profound disturbances in immune and metabolic homeostasis, two tightly interconnected processes regulated by nuclear receptors (NRs), are central to sepsis pathophysiology. Although NRs are well-studied in inflammatory and metabolic disorders, their roles in sepsis have been underappreciated. Emerging evidence shows that systemic inflammation suppresses multiple NRs, contributing to immune dysfunction, metabolic failure, and poor outcomes. Targeting pivotal NRs, such as hepatocyte nuclear factor 4α, retinoid X receptor, and the glucocorticoid receptor, could restore NR activity and re-establish immune-metabolic balances. This review highlights NR dysfunction in sepsis and explores biomarker and opportunities for improved patient outcomes.

Primary aldosteronism (PA) is the most common endocrine cause of high blood pressure, affecting more than 1 in 10 people with hypertension. Once considered rare, it has become a public health priority because undiagnosed PA confers significantly higher risks of stroke, myocardial infarction, heart failure, chronic kidney disease, and impaired quality of life. As a result, international guidelines now recommend routine screening for PA in all adults with hypertension. Despite this progress, diagnostic challenges remain. Conventional screening with plasma aldosterone, renin, and the aldosterone-to-renin ratio suffers from intra-individual variability and interference by medications, diet, posture, amongst other factors. Even when PA is diagnosed, distinguishing lateralizing from non-lateralizing adrenal disease is difficult. The current gold-standard test, adrenal vein sampling, is invasive, technically demanding, confined to specialized centers, and often yields inconclusive results. Emerging biomarker research offers new opportunities. Novel steroidomic-based approaches, such as steroid profiling, show promise for both diagnosis and subtyping. Circulating and urinary proteomic and metabolomic signatures are beginning to reveal molecular fingerprints of PA and its subtypes, while transcriptomic studies of adrenal tissue, circulating cells, and extracellular vesicles, along with circulating microRNAs, provide insights into pathophysiology and candidate diagnostic markers. Markers of end-organ damage are also emerging as complementary indicators of disease burden and treatment response. This review synthesizes current molecular and clinical biomarker research in PA, with an emphasis on their diagnostic, subtyping, and prognostic potential. By integrating traditional hormone assays with advances in multi-dimensional biomarker discovery, we highlight possibilities that may transform the diagnosis and management of PA.

The prepartum surge in plasma glucocorticoids is a critical signal for fetal organ maturation, facilitating the transition from fetal reliance on the placenta for functions including respiration, nutrition, and waste removal to newborn use of their own physiological systems. The fetal glucocorticoid surge is conserved across mammalian species, but mechanisms driving the surge differ. Preterm birth interrupts fetal maturation because babies are born before the rise in endogenous glucocorticoids occurs, placing the newborn at greater risk of morbidity and mortality. In particular, lung immaturity increases risk of short-term and long-term respiratory disease. Antenatal corticosteroids (ACS) are routinely administered to women at risk of preterm birth to mimic the missed maturational signal of elevated glucocorticoids. Consequently, ACS improve neonatal survival and respiratory outcomes. Clinical guidelines universally recommend ACS use, but recommended regimens, gestational age limits, and use in settings of pre-existing maternal conditions vary. Importantly, preterm infants have variable responsiveness to ACS treatment, and do not benefit equally. While male fetal sex and fetal growth restriction may be associated with lower ACS responsiveness, there is limited understanding of underlying factors. Emerging evidence points to differential glucocorticoid receptor isoform expression and elevated pre-treatment plasma cortisol concentrations as potential contributors to variable ACS response. Improved insight into underlying mechanisms is crucial for identifying responsive subgroups and optimising ACS treatment beyond the current one-size-fits-all approach to enhance health outcomes for preterm infants.

The islet of Langerhans (or pancreatic islet) is a unique endocrine organ that secretes multiple hormones that in turn orchestrate energy metabolism in humans. As in other metabolic organs, growth factor(s) regulate functional islet mass to maintain whole-body glucose homeostasis. Over the past decades, a large body of evidence has pointed to insulin and insulin-like growth factors (IGFs) as playing central roles in modulating diverse aspects of islet cell biology and a dysregulated insulin/IGF pathway has come to be recognized as a pathophysiological hallmark of type 2 diabetes (T2D). Several recent reports, especially focused on β-cells, highlight emerging aspects of insulin/IGF signaling, including a role for RNA modifications, transcriptional regulation by nuclear insulin and IGF-1 receptors, and the discovery of an insulin inhibitory receptor, inceptor. In this review, we summarize the functional roles of insulin/IGF signaling in regulating islet cell biology, the short- and long-term effects of insulin therapy in humans, and discuss potential strategies to maximize the beneficial effects of insulin action in islets to counter diabetes.

Childhood obesity is a complex disorder which results from the combined contribution of genetics, the environment, and development, which is programmed and coordinated by epigenetic mechanisms. Of them, DNA methylation has emerged as an important molecular interface between environmental inputs and changes in gene expression. In this review, we provide an overview of the role of DNA methylation in childhood obesity during the key developmental stages, from prenatal life and childhood to adolescence. We also highlight the available evidence from candidate genes and genome-wide association studies implicating critical loci involved in energy homeostasis and adipogenesis, where DNA methylation is altered. Further, we also provide an overview of how maternal obesity, nutritional status, and bariatric surgery shape offspring's methylation profiles and contribute to the increased risk of programming obesity across generations. Although aberrant methylation patterns are consistently associated with altered metabolic phenotypes, disentangling causality remains a significant challenge. Herein, we highlight emerging approaches, such as rigorous longitudinal cohorts, epigenetic Mendelian randomisation, and CRISPR-based epigenome editing, that are beginning to provide the analytical clarity needed to move beyond association. Finally, we examine the potential of DNA methylation signatures to inform early risk stratification and prevention possibilities. Although yet to be clinically validated, whole-genome methylation profiling is increasingly integrated with systems biology and multi-omics frameworks, making the identification of robust, clinically actionable markers more promising. A more precise understanding of how epigenetic processes shape susceptibility to childhood obesity could ultimately support strategies capable of altering lifelong metabolic trajectories.