Endocrine reviews最新文献

{"title":"The Microbiome-Metabolokine-Adipokine Axis in Insulin Resistance: Adaptive and Maladaptive FGF21-GDF15 Signaling.","authors":"P K Mustakin, Mansyur Arief, K Nurrahmi, Liong Boy Kurniawan, Ihza Makarim Amirul Reswara","doi":"10.1210/endrev/bnag038","DOIUrl":"https://doi.org/10.1210/endrev/bnag038","url":null,"abstract":"<p><p>Insulin resistance emerges from disturbances in interorgan metabolic communication in which nutrient exposure, microbial metabolism, and host endocrine responses interact across multiple metabolic compartments. This state-of-the-art review proposes a revised Microbiome-Metabolokine-Adipokine (MMA) Axis as a focused framework linking gut microbial metabolic signals with enteroendocrine, hepatic, and adipose responses and the stress-responsive metabolokines fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). Microbiome-derived and microbiome-modified signals, including short-chain fatty acids, bile acids, branched-chain amino acid-related metabolites, tryptophan-derived metabolites, and microbial inflammatory products, can influence intestinal receptor signaling, incretin secretion, hepatic nutrient sensing, adipose lipid buffering, and systemic insulin sensitivity. Within this network, FGF21 and GDF15 are positioned as distinct but complementary adaptive endocrine signals rather than components of a fixed sequential pathway: FGF21 predominantly coordinates responses to nutrient and metabolic stress, whereas GDF15 communicates broader cellular stress through GFRAL-RET-dependent regulation of nutrient intake and energy balance. Importantly, persistent elevation of either metabolokine during insulin-resistant states should not automatically be interpreted as endocrine resistance or maladaptation. We instead propose that progression toward insulin resistance reflects a context-dependent mismatch between increasing metabolic stress and the capacity of integrated endocrine responses to maintain metabolic flexibility and substrate homeostasis. Current evidence strongly supports individual microbiome-metabolite, enteroendocrine, hepatic, adipose, FGF21, and GDF15 signaling modules, but a direct causal microbiome-FGF21-GDF15 sequence has not been established in humans. The revised MMA Axis therefore provides a testable framework for defining how microbiome-derived metabolic signals interface with host endocrine adaptation during the development of insulin resistance.</p>","PeriodicalId":11544,"journal":{"name":"Endocrine reviews","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Menopause-driven metabolomic shifts: unraveling cardiovascular disease risk in women","authors":"Cristina Molina-López,Marta Rojas-Torres,Angela Rubio,Inés Pineda-Torra","doi":"10.1210/endrev/bnag036","DOIUrl":"https://doi.org/10.1210/endrev/bnag036","url":null,"abstract":"Abstract Menopause marks the end of a woman's reproductive life, and the transition to this stage is accompanied by profound physiological and metabolic changes. These include alterations in lipoproteins and various metabolites, such as lipids, fatty acids, and amino acids, resulting in a more atherogenic profile and, in some cases, an increased risk in cardiovascular disease (CVD). CVD remains the leading cause of death among women, and lipid profiles change substantially in postmenopause, representing a key sex-specific risk factor. Thus, elucidating the metabolic pathways affected during menopause is crucial to reducing the burden of menopause-related conditions. However, the underlying molecular mechanisms of this increased metabolic burden remain incompletely understood. Recent advances in metabolomic technologies, including mass spectrometry (MS), nuclear magnetic resonance (NMR), and computational tools, have greatly improved our ability to characterize these metabolic shifts. This review summarizes current knowledge on the metabolic changes associated with menopause and their implications for CVD development.","PeriodicalId":11544,"journal":{"name":"Endocrine reviews","volume":"45 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149089125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucocorticoids in pregnancy: a master-switch for fetal maturation.","authors":"Yoshi Tan, Michael J Stark, Vicki L Clifton, Michael D Wiese, Janna L Morrison, Kathryn L Gatford","doi":"10.1210/endrev/bnag015","DOIUrl":"10.1210/endrev/bnag015","url":null,"abstract":"<p><p>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 such as 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 preexisting 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 pretreatment plasma cortisol concentrations as potential contributors to variable ACS response. Improved insight into underlying mechanisms is crucial for identifying responsive subgroups and optimizing ACS treatment beyond the current one-size-fits-all approach to enhance health outcomes for preterm infants.</p>","PeriodicalId":11544,"journal":{"name":"Endocrine reviews","volume":" ","pages":"666-701"},"PeriodicalIF":23.9,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13577750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin/IGF signaling in islet biology and its therapeutic implications.","authors":"Hyunki Kim, Rohit N Kulkarni","doi":"10.1210/endrev/bnag014","DOIUrl":"10.1210/endrev/bnag014","url":null,"abstract":"<p><p>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. 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 propose potential strategies to maximize the beneficial effects of insulin action in islets to counter diabetes.</p>","PeriodicalId":11544,"journal":{"name":"Endocrine reviews","volume":" ","pages":"637-665"},"PeriodicalIF":23.9,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147971342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"Screening for Endocrine Hypertension: An Endocrine Society Scientific Statement\".","authors":"","doi":"10.1210/endrev/bnag031","DOIUrl":"10.1210/endrev/bnag031","url":null,"abstract":"","PeriodicalId":11544,"journal":{"name":"Endocrine reviews","volume":" ","pages":"704"},"PeriodicalIF":23.9,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetics and childhood obesity: DNA methylation coordinates environment and gene regulation.","authors":"Suneesh Kaimala, Melvin Khee-Shing Leow, Suraiya Anjum Ansari, Bright Starling Emerald","doi":"10.1210/endrev/bnag013","DOIUrl":"10.1210/endrev/bnag013","url":null,"abstract":"<p><p>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 randomization, 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.</p>","PeriodicalId":11544,"journal":{"name":"Endocrine reviews","volume":" ","pages":"608-636"},"PeriodicalIF":23.9,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13577769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Sentinel Hormone GDF-15, Glucocorticoid Homeostasis and Adrenal Disorders.","authors":"Ilaria Bonaventura, Isabel Weigand, Andrea M Isidori, Matthias Kroiss, Martin Reincke","doi":"10.1210/endrev/bnag035","DOIUrl":"https://doi.org/10.1210/endrev/bnag035","url":null,"abstract":"<p><p>Growth and differentiation factor 15 (GDF-15) is a stress-responsive hormone secreted by various cell types in response to cellular stress. To regulate ingestive behaviour, suppress food intake, and induce nausea and vomiting during cellular stress, GDF-15 signals via a brainstem-restricted receptor, GFRAL. Elevated circulating GDF-15 levels serve as a biomarker of cellular stress and are increased in a wide range of diseases. GDF-15 has recently been established as a causal factor in cancer cachexia and GDF15-GFRAL antagonism is being pursued as a therapeutic strategy. Recent studies have highlighted a dynamic interplay between GDF-15 and the hypothalamus-pituitary-adrenal (HPA) axis, suggesting that GDF-15 acts as a sentinel hormone in stress responses. Here, we review the canonical role of GDF-15 in stress-related conditions and its potential impact on circadian regulation and HPA axis dysregulation. The review explores the potential activation of the HPA axis by GDF-15 and discuss the hypothesis that downstream glucocorticoid signalling may contribute to some of the cardiovascular, metabolic, immune, and musculoskeletal changes reported for GDF-15. Additionally, the review discusses the potential role of GDF-15 in adrenal insufficiency and its treatment and in adrenocortical carcinoma. In summary, this review aims to elucidate the role of GDF-15 in glucocorticoid homeostasis and adrenal disease in the context of the stress response.</p>","PeriodicalId":11544,"journal":{"name":"Endocrine reviews","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obesity science, research gaps, and opportunities in the new era of obesity medicines: an Endocrine Society scientific statement.","authors":"Ania M Jastreboff, Jamy D Ard, Kevin D Hall, Lee M Kaplan, Harlan M Krumholz, Michelle Van Name, Donna H Ryan, Daniel J Drucker","doi":"10.1210/endrev/bnag025","DOIUrl":"https://doi.org/10.1210/endrev/bnag025","url":null,"abstract":"<p><p>The medical management of obesity has been transformed by the introduction of obesity medicines (OMs), based on the actions of glucagon-like peptide-1 and other nutrient-stimulated hormones, enabling the achievement of unprecedented weight reduction through pharmacotherapy. Here we review our current understanding of key issues surrounding obesity treatment, weight reduction, and improving health for people living with obesity. Key gaps in our knowledge of fundamental aspects of energy homeostasis are identified with a focus on their translational importance for improving outcomes. We discuss the utility of weight and health metrics, heterogeneity in achievement of clinical outcomes, individualization of treatment targets and goals, strengths and limitations of clinical trial, observational and real-world data (RWD), opportunities for improving the joint use of lifestyle management and OMs, gaps in our understanding of the long-term safety and side effects of current and emerging medicines, and the potential negative effects of losing weight. Collectively, while not intended as guidance for treatment, this document highlights the considerable progress and new research opportunities for interrogating basic and clinical science with the goal of translating advances in endocrine science into optimized outcomes for a broad range of individuals along the continuum of the weight journey.</p>","PeriodicalId":11544,"journal":{"name":"Endocrine reviews","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding Adrenal Cellular Heterogeneity in Primary Aldosteronism by Single-Cell Analysis.","authors":"Amnani Aminuddin, Elena Aisha Azizan, Sam O'Toole, Morris J Brown","doi":"10.1210/endrev/bnag034","DOIUrl":"https://doi.org/10.1210/endrev/bnag034","url":null,"abstract":"<p><p>Primary aldosteronism (PA), characterised by autonomous aldosterone excess, accounts for a substantial proportion of patients with hypertension, particularly those with resistant disease. Current clinical management is largely guided by a binary classification into unilateral and bilateral PA; however, accumulating clinical, pathological, and molecular evidence indicates that this framework inadequately captures the underlying biological heterogeneity. Variable surgical outcomes, biochemical recurrence following adrenalectomy, and refined aldosterone synthase (CYP11B2)-based histopathological classifications highlight PA as a disease spectrum driven by disrupted adrenal zonation, cellular plasticity, and diverse aldosterone-driving somatic mutations. Despite major advances in defining the molecular basis of PA over the past decade, most insights have been derived from bulk genetic analyses of surgically excised tissue, limiting resolution of cellular heterogeneity and disease evolution. In this review, we integrate current understanding of PA pathophysiology with recent advances in single-cell and spatial technologies that have transformed adrenal research. We outline key methodological approaches enabling high-resolution interrogation of adrenal development, tumour heterogeneity, and the adrenal microenvironment. Finally, we discuss the translational implications of single-cell insights for PA, including improved patient stratification, identification of pre-operative biomarkers, and the development of mechanism-based, genotype-informed therapies beyond conventional mineralocorticoid receptor antagonism. Collectively, these advances support a paradigm shift from lateralisation-based management toward precision approaches targeting the cellular and molecular drivers of aldosterone excess.</p>","PeriodicalId":11544,"journal":{"name":"Endocrine reviews","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The evolution of new approaches to the treatment of congenital adrenal hyperplasia.","authors":"Deborah P Merke, Richard J Auchus","doi":"10.1210/endrev/bnag033","DOIUrl":"https://doi.org/10.1210/endrev/bnag033","url":null,"abstract":"<p><p>Conventional management of classic congenital adrenal hyperplasia (CAH) relies on glucocorticoid (GC) therapy, both to replace the cortisol deficiency and to reduce the production of upstream cortisol precursors and subsequent metabolites. To attenuate the disinhibited hypothalamic-pituitary-adrenal (HPA) axis under endogenous cortisol deficiency, GCs are often administered at supraphysiological doses and at non-physiological timings, particularly to blunt the HPA axis activation in the early morning before awakening. Long-term studies of adults with CAH show increased risk of co-morbidities, which are often associated with chronic excessive GC exposures. To maintain disease control and to mitigate the adverse effects of conventional therapy, alternative approaches have been trialed. Circadian delivery of hydrocortisone with modified-release preparations or continuous subcutaneous infusion achieves better control at the same or lower daily dose than hydrocortisone tablets. GC-sparing therapies, the first being the corticotropin-releasing factor type 1 receptor antagonist crinecerfont, offer a block-and-replace approach, with near-physiologic dosing of GCs and a second agent to reduce precursor accumulation. The melanocortin type 2 (ACTH) receptor antagonist atumelnant and the anti-ACTH antibody asedebart are in trials. This article reviews the historical background, genetics, pharmacology, and data supporting the use of alternative strategies, as well as the practical implications and limitations of these approaches in routine patient care. A new era of CAH management has arrived, and we provide a perspective on the path forward using new tools to address the remaining unsolved challenges.</p>","PeriodicalId":11544,"journal":{"name":"Endocrine reviews","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}