Obesity is a growing global health challenge associated with major cardiometabolic complications. While bariatric surgery remains the most effective treatment for severe obesity, recent advances in incretin-based pharmacotherapy, multi-receptor agonists, and endoscopic bariatric procedures have substantially expanded therapeutic options. Beyond mechanical restriction, these interventions exert their effects through complex hormonal and neurophysiological mechanisms involving gut-brain signaling, gastric motility, and enteroendocrine adaptations. Gut-derived hormones, including ghrelin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), amylin, and leptin, play a central role in the regulation of hunger, satiation, and satiety by integrating nutrient sensing, vagal afferent signaling, and central hypothalamic pathways. Surgical procedures such as laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass induce profound and durable hormonal remodeling, whereas endoscopic sleeve gastroplasty primarily modulates gastric physiology with more modest and heterogeneous endocrine effects. Intragastric balloons induce a transient delay in gastric emptying and achieve moderate short-term weight loss, although their metabolic and weight-loss effects appear limited in durability. In parallel, GLP-1 receptor agonists and emerging multi-agonist therapies reproduce several post-bariatric hormonal adaptations and achieve clinically meaningful weight loss. In this review, we summarize current knowledge on digestive hormone physiology and provide an updated overview of the hormonal mechanisms underlying pharmacologic, endoscopic, and surgical bariatric interventions, highlighting their respective roles within a continuum of obesity treatment strategies.

Human development begins with the fusion of sperm and oocyte, yet the maternal genome plays a far more active and essential role than traditionally appreciated. This review critically examines the influence of maternal genetic integrity on embryogenesis and offspring health, emphasizing that the maternal genome is not merely a passive donor of half the DNA, but a vital architect of early life. We explore the role of maternal effect genes (MEGs) in orchestrating early zygotic development, detailing their functions in epigenetic regulation, mitochondrial dynamics, DNA repair, and cell division. A curated reference of MEGs, spanning mouse models and human pathogenic variants, is presented to support future research and clinical diagnostics. Beyond early embryonic development, maternal genetic integrity has lasting implications for offspring well-being. Errors in DNA replication and repair machinery within the maternal germline can lead to de novo variants (DNVs)-spontaneous germline variants that can be passed on to the offspring and impact their health at different ages. We highlight an underappreciated contribution of maternally derived DNVs to a growing list of sporadic disorders and present the first comprehensive catalogue of associated diseases. We further examine DNVs compatible with multigenerational transmission, investigating how maternal age and mutational processes-such as recombination errors and epigenetic drift-influence both disease risk and evolutionary outcomes. By integrating insights from developmental biology, genomics, and reproductive medicine, this review reframes the maternal genome as a dynamic and fragile foundation upon which life depends-offering new directions for understanding fertility, sporadic disease, and intergenerational health.

Immune checkpoint molecules (ICMs) are a class of surface proteins predominantly expressed on immune cells that play a key role in maintaining immune homeostasis by regulating the functions of T cells and other immune cells. Beyond their established immunoregulatory roles, emerging evidence indicates that ICMs are also involved in metabolic regulation. Within the tumor microenvironment (TME), tumour-derived ICMs have been shown to modulate glucose, amino acid, and lipid metabolism in infiltrating T cells, thereby influencing their metabolic reprogramming and functional states. Certain ICMs expressed on immune cells may directly regulate systemic metabolism through cell-intrinsic, immune-independent mechanisms. Moreover, specific ICMs are constitutively expressed in key metabolic tissues, such as pancreatic islets, liver, and adipose tissue, where they are thought to contribute to the maintenance of systemic metabolic homeostasis. Clinically, host metabolic status can affect the efficacy of immune checkpoint inhibitor (ICI) therapies. Conversely, ICI treatment can lead to metabolism-related adverse effects, such as ICI-associated diabetes (ICI-DM), which may extend beyond classic autoimmune insulin-dependent diabetes. Accumulating evidence suggests that ICMs can exert direct regulatory roles in metabolism independent of their canonical immune functions. Elucidating how ICMs regulate metabolism could, on the one hand, improve ICI therapy by maintaining metabolic homeostasis and preventing T cell exhaustion, and on the other hand, facilitate the development of novel therapeutic strategies for metabolic diseases that simultaneously target metabolic and inflammatory pathways. This review synthesises current knowledge on the metabolic roles and regulatory mechanisms of ICMs.

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.