The transcriptional landscape of the gastric mucosa in response to opposing nutritional states remains poorly defined. Here, we profiled gastric mucosal gene expression changes induced by diet-induced obesity (DIO) and c...The transcriptional landscape of the gastric mucosa in response to opposing nutritional states remains poorly defined. Here, we profiled gastric mucosal gene expression changes induced by diet-induced obesity (DIO) and calorie restriction (CR) in mice and investigated the physiological role of Decidual Protein Induced by Progesterone 1 (Depp1) using newly-generated Depp1-knockout (KO) mice. RNA sequencing revealed that DIO elicits a predominantly pro-inflammatory transcriptional program in the gastric mucosa, whereas CR upregulates genes involved in peptide transport and extracellular matrix organization while downregulating immunity-related pathways. Among CR-induced genes, Depp1 exhibited the strongest positive correlation with expression of gene encoding the gastric hormone ghrelin. qRT-PCR confirmed enrichment of Depp1 in gastric ghrelin cells and demonstrated CR-induced upregulation of Depp1 in additional tissues, including liver, kidney, and pancreas; notably, hepatic induction by CR was absent in ghrelin-KO mice. Despite this association, Depp1-KO mice displayed normal metabolic responses to CR, including preserved glucose homeostasis. In contrast, following 16 weeks of ad libitum high-fat diet feeding, male Depp1-KO mice exhibited greater weight gain, hyperphagia, increased fat and lean mass, and impaired glucose tolerance compared to wild-type littermates. These phenotypes were accompanied by selective hepatic gene expression changes affecting Pgc1a, Pck1, and Igf1. Collectively, these findings identify Depp1 as a CR-induced, ghrelin-associated gene that influences hepatic transcriptional responses yet is dispensable for short-term adaptation to CR, while also implicating Depp1 as a protective factor against metabolic dysfunction during DIO through mechanisms that remain to be defined.
Prostate cancer (PCa) represents a hormone-dependent malignancy where androgen receptor (AR) signaling plays a central role in disease initiation, progression, and therapeutic resistance. Recent advances have revealed th...Prostate cancer (PCa) represents a hormone-dependent malignancy where androgen receptor (AR) signaling plays a central role in disease initiation, progression, and therapeutic resistance. Recent advances have revealed that long non-coding RNAs (lncRNAs) constitute a critical regulatory layer in prostate cancer, with implications for endocrine signaling pathways. lncRNAs orchestrate complex gene regulatory networks through diverse molecular mechanisms including chromatin remodeling, AR splice variant regulation, competitive endogenous RNA networks, translational control, and metabolic reprogramming. In castration-resistant prostate cancer, dysregulated lncRNAs contribute to resistance against androgen deprivation therapy and next-generation AR antagonists such as enzalutamide. This review synthesizes current knowledge on lncRNA biology in PCa, emphasizing lncRNA relationships with AR signaling and endocrine resistance mechanisms. We discuss key lncRNAs that modulate AR activity, metabolic adaptation, and lineage plasticity. Additionally, we examine structure-function relationships that enable rational therapeutic design, lncRNA roles in bone metastasis and neuroendocrine differentiation, and lncRNA clinical utility as biomarkers for disease progression and treatment stratification. Therapeutic strategies include antisense oligonucleotides, small-molecule inhibitors of lncRNA-protein interaction disruptors, and combination approaches with DNA-damaging agents and AR inhibitors. Understanding lncRNA-mediated endocrine regulation provides insights into prostate cancer biology and offers avenues for overcoming therapeutic resistance in advanced disease.
Obesity has reached epidemic proportions globally, with its prevalence nearly tripling since 1975. It is now recognized as a chronic, relapsing disease associated with increased morbidity and mortality due to its strong...Obesity has reached epidemic proportions globally, with its prevalence nearly tripling since 1975. It is now recognized as a chronic, relapsing disease associated with increased morbidity and mortality due to its strong relationship with several cardio-renal-metabolic conditions. This narrative review aims to explore the major obesity-related complications - namely obstructive sleep apnea syndrome (OSAS), metabolic dysfunction-associated steatotic liver disease (MASLD), dyslipidemia, and chronic kidney disease (CKD) - highlighting their pathophysiological mechanisms, clinical consequences, and current therapeutic strategies. Obesity contributes to OSAS by increasing upper airway collapsibility and to MASLD through ectopic fat accumulation, insulin resistance, and inflammatory responses. Dyslipidemia in obesity is characterized by elevated triglycerides, small dense LDL particles, and low HDL-C, driven by chronic inflammation and insulin resistance. CKD progression, particularly obesity-related glomerulopathy (ORG), is also mediated by metabolic and hemodynamic derangements, including renin-angiotensin-aldosterone system activation and glomerular hyperfiltration. Therapeutic interventions such as lifestyle modification, pharmacological therapy - including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) - and bariatric surgery have shown efficacy not only in promoting weight loss but also in improving the clinical course of these obesity-related conditions. In particular, Very Low Energy Ketogenic Therapy (VLEKT) is emerging as a promising approach in improving metabolic parameters, hepatic steatosis, and cardiovascular risk factors. A comprehensive and multidisciplinary approach to obesity is essential, focusing not only on weight loss but also on mitigating associated complications. Effective management can significantly improve patients' quality of life and reduce the long-term burden of obesity on healthcare systems.
Endocrinology
· 2026 Jun · PMID 42360504
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In diabetic patients, hypoglycemia associated autonomic failure (HAAF) is a potentially lethal condition that results in attenuation of critical protective responses to low blood glucose, following repeated prior hypogly...In diabetic patients, hypoglycemia associated autonomic failure (HAAF) is a potentially lethal condition that results in attenuation of critical protective responses to low blood glucose, following repeated prior hypoglycemic episodes. The underlying mechanism(s) of HAAF is not fully understood. We previously demonstrated that activation of catecholamine (CA) neurons in the ventrolateral medulla (VLM) is both required and sufficient to elicit key protective responses to glucose deficit. Here we test the hypothesis that repeated selective activation of VLM CA neurons is sufficient to induce HAAF, even in the absence of glucose deficit. Using stereotaxic injections of an adeno-associated virus in female TH-Cre transgenic rats, we transfected rostral C1 CA neurons to express hM3D(Gq). In these rats, we found that a single clozapine-N-oxide (CNO) injection evoked robust hyperglycemia, with a magnitude and time course similar to those evoked by the glucoprivic agent, 2-deoxy-D-glucose (2DG). However, following repeated CNO injections in these same rats, the hyperglycemic response evoked by either CNO or 2DG were significantly attenuated. Moreover, plasma epinephrine levels, and Fos expression in VLM CA neurons and in the adrenal medulla, also were attenuated following repeated CNO injections. This constellation of effects is similar to those that define HAAF. Taken together our results suggest that repeated stimulation of VLM CA neurons mimics and could be a cause of the impairment of counterregulatory responses associated with pathogenesis of HAAF.
Endocrinology
· 2026 Jun · PMID 42343571
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The postnatal period of mouse development is critical for the maturation of many organs and fine tuning of hormonal feedback loops. These developmental transformations are necessary to allow the transition from a sucklin...The postnatal period of mouse development is critical for the maturation of many organs and fine tuning of hormonal feedback loops. These developmental transformations are necessary to allow the transition from a suckling pup to an independent life but they also determine the metabolic features of the adult. Thyroid hormones are key hormones that control these postnatal events. However, the impact of a short-term exposure to maternal hypothyroidism during the perinatal period on the metabolic outcome of the descendants was not clearly established. We used a new protocol to obtain animals exposed to maternal hypothyroidism only during gestation or only during their two first postnatal weeks. The developmental and the long-term consequences of these two short perinatal periods of hypothyroidism were assessed. Animals born from hypothyroid mothers did not show developmental delays. As adults they were undisguisable from the controls and could adequately face metabolic stresses such as exposure to a high fat diet or cold temperature. In contrast pups exposed to maternal hypothyroidism during lactation presented delayed growth and remained leaner than the controls. The expression of genes involved in different metabolic pathways in liver or brown adipose tissues were affected both during development and in adults. The adults were also more sensitive to diet induced obesity and to cold exposure. In conclusion in mice severe hypothyroidism in the pregnant dam is not detrimental for postnatal development or metabolic programing of the pups. In contrast postnatal hypothyroidism leads to developmental delays and long-lasting metabolic dysregulation in otherwise euthyroid animals.
Endocrinology
· 2026 Jun · PMID 42343567
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Luteinizing hormone (LH) and follicle-stimulating hormone (FSH), critical for reproduction, are heterodimers of a common α subunit and unique β subunits, that are limiting components in the mature hormone synthesis. GnRH...Luteinizing hormone (LH) and follicle-stimulating hormone (FSH), critical for reproduction, are heterodimers of a common α subunit and unique β subunits, that are limiting components in the mature hormone synthesis. GnRH from the hypothalamus regulates synthesis of LH and FSH β-subunits. Previous studies identified signaling pathways and transcription factors that mediate GnRH induction of β-subunits. However, these studies do not fully explain gonadotrope responsiveness to GnRH or mechanisms of how a single hormone can regulate two β-subunits differentially. We postulated additional transcription factors, coactivators or corepressors, that are awaiting identification. To provide novel candidates, we used discovery proteomics of protein complexes that associate with gonadotropin β promoters regions that contain GnRH-responsive elements, and protein complexes that interact with transcription factors that are activated by GnRH to induce gonadotropin β genes. Data are available via ProteomeXchange with identifier PXD075636. Using computational tools, such as Intervene and Tidyproteomics, we compare and contrast proteins in complexes to identify coactivators or corepressors that may be unique or in common for both gonadotropin β subunit transcriptional upregulation or repression, novel transcription factors, and proteins that may regulate both gonadotropin β gene expression, proteins specific to each promoter, and proteins that are recruited via interaction with intermediate GnRH-induced transcription factors. Our studies can serve as a resource to interrogate potential candidates in cell cultures and in vivo for their roles in gonadotropin β expression. Understanding the mechanisms whereby GnRH regulates gonadotropin hormone levels will provide insight into the physiology and pathophysiology of the reproductive system.
Nutrition shapes development, health and risk of disease over the life course and across generations. The predominant approaches to understanding these relationships have either been to consider the effects of single nut...Nutrition shapes development, health and risk of disease over the life course and across generations. The predominant approaches to understanding these relationships have either been to consider the effects of single nutrients, one at a time, or to consider associations with food types and dietary patterns. Although, to date, the single-nutrient approach has defined much of the scientific enquiry and public debate on the macronutrients - carbohydrate, fat and protein - there is an emerging appreciation that their proportions and quality matter more than their individual effects. Growing evidence demonstrates that macronutrient interactions operate at multiple biological levels, and research on dietary protein has proven a particularly productive entry point for characterizing these mixture effects. In this narrative Review, we begin by analysing key issues and introducing a framework for navigating the complexity of macronutrient mixtures (nutritional geometry), then consider the role of macronutrient proportions on food intake, systemic physiology, health and the risk of disease across the life course. Finally, we discuss how human nutritional biology has been subverted within the modern, industrialized food environment, contributing to the global burden of obesity and related diseases of unhealthy ageing.
BACKGROUND: Novel therapies targeting apolipoprotein C3 (apoC3) have recently emerged as promising treatment options for hypertriglyceridemia and have been evaluated in phase II and III randomized clinical trials. This s...BACKGROUND: Novel therapies targeting apolipoprotein C3 (apoC3) have recently emerged as promising treatment options for hypertriglyceridemia and have been evaluated in phase II and III randomized clinical trials. This study aimed to perform an updated meta-analysis to assess the effects of apoC3 inhibitors on triglyceride and apoC3 concentrations, as well as their impact on the risk of acute pancreatitis. METHODS: We conducted a meta-analysis of randomized, placebo-controlled trials evaluating apoC3-targeting therapies, including antisense oligonucleotides and small interfering RNA. Outcomes of interest included changes in triglyceride and apoC3 levels and the incidence of acute pancreatitis. The analysis was performed in accordance with PRISMA recommendations. RESULTS: Fourteen randomized trials comprising 3,422 participants met the inclusion criteria. Treatment with apoC3 inhibitors resulted in significant reductions in triglyceride levels compared with placebo (mean difference -58.7%; 95% CI -62.3 to -55.1; I=93.8%). Similarly, apoC3 concentrations were markedly decreased (mean difference -75.3%; 95% CI -80.3 to -70.3; I=94.7%). In addition, these therapies were associated with a significantly lower risk of acute pancreatitis (odds ratio 0.20; 95% CI 0.10 to 0.40; I=0%). CONCLUSIONS: ApoC3-targeting therapies significantly reduce triglyceride and apoC3 levels in patients with hypertriglyceridemia and are associated with a reduced incidence of acute pancreatitis, supporting their potential role as an effective therapeutic strategy in this high-risk population.
Hepatic nerves have an underexplored role in liver function. The global prevalence of liver disease has reached unprecedented levels, with over 1.6 billion individuals affected by metabolic dysfunction-associated steatot...Hepatic nerves have an underexplored role in liver function. The global prevalence of liver disease has reached unprecedented levels, with over 1.6 billion individuals affected by metabolic dysfunction-associated steatotic liver disease (MASLD). A comprehensive understanding of these liver disease mechanisms is essential for identifying the aetiologies of such conditions. Studies from the past 5 years suggest that hepatic nerves might influence the progression of MASLD to metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma. As MASLD advances, hepatic sympathetic activity increases while hepatic sympathetic innervation diminishes. Conversely, both parasympathetic and sympathetic innervation might contribute to hepatic fibrosis and liver dysfunction. This Review examines the function of hepatic neurons, their modulation by metabolic disease and the potential to target these mechanisms to develop novel treatments for liver diseases.
Iodine metabolism has a central role in thyroid physiology and thyroid cancer biology, shaping both tumour behaviour and therapeutic strategies. Within the past 20 years, advancements in molecular research and targeted t...Iodine metabolism has a central role in thyroid physiology and thyroid cancer biology, shaping both tumour behaviour and therapeutic strategies. Within the past 20 years, advancements in molecular research and targeted therapies have transformed the understanding of iodine metabolism in thyroid cancer and subsequently changed clinical management. In differentiated thyroid carcinomas, the ability of tumour cells to concentrate iodide provides the biological foundation of radioactive iodine treatment. However, loss of iodide-handling machinery function drives refractoriness in advanced disease, posing a major clinical challenge. Molecular genetics has now been integrated into routine clinical practice and genetically guided strategies to restore iodine uptake in previously non-avid lesions have emerged. This Review synthesizes these breakthroughs across molecular science, pathology, physics and clinical practice. We describe emerging predictive markers of radioiodine-refractory disease and summarize the current state of knowledge on iodide-handling mechanisms, their dysregulation in thyroid tumourigenesis and therapeutic advances made in the past 15 years aimed at redifferentiation. By bridging molecular insights with translational and clinical perspectives, we aim to highlight evolving paradigms that promise to refine patient stratification and improve outcomes in differentiated thyroid carcinoma.
Endocrinology
· 2026 May · PMID 42306870
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Prostate cancer development and progression depend on androgen receptor (AR) signaling. Therefore, androgen-deprivation therapy (ADT) and AR signaling inhibitors (ARSIs) are standard therapies for advanced or metastatic...Prostate cancer development and progression depend on androgen receptor (AR) signaling. Therefore, androgen-deprivation therapy (ADT) and AR signaling inhibitors (ARSIs) are standard therapies for advanced or metastatic disease. Although these treatments are initially effective, prostate cancer inevitably progresses to a lethal stage termed castration-resistant prostate cancer (CRPC). In the majority of patients, CRPC occurs via reactivation of AR signaling (CRPC-AR). However, lineage plasticity is a hallmark of cancer that drives AR-independent CRPC phenotypes in a subset of patients. One subtype of AR-negative CRPC is neuroendocrine prostate cancer (NEPC), which transforms from CRPC-AR by losing the characteristic AR-driven luminal epithelial identity and gaining neuroendocrine identity. Another AR-negative CRPC subtype lacks AR and neuroendocrine features and has therefore been classified as double-negative prostate cancer (DNPC). Chromatin modifications, alterations in three-dimensional (3D) genome structure, and expression of transcriptional regulators are crucial for controlling lineage states and modulating AR-dependent and AR-independent phenotypes in CRPC. Here, we highlight how high-resolution investigations of the 3D genome have revealed interdependence between chromatin architecture and transcriptional regulation, offering novel insights into the mechanisms of CRPC progression and context-specific targets for therapeutic intervention.
Dearing C, Lukinic E, McCartney C
… +2 more, Pace SA, Myers B
Endocrinology
· 2026 May · PMID 42299628
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Chronic stress increases risk for metabolic disorders, including diabetes mellitus. Additionally, projections from the infralimbic cortex (IL) to the rostral ventrolateral medulla (RVLM) regulate endocrine stress respons...Chronic stress increases risk for metabolic disorders, including diabetes mellitus. Additionally, projections from the infralimbic cortex (IL) to the rostral ventrolateral medulla (RVLM) regulate endocrine stress responses. However, the neurobiological basis for chronic stress effects on glucose homeostasis has not been identified. The current study tests the hypothesis that the IL-RVLM circuit is necessary to prevent glucose intolerance. Accordingly, male and female rats with Cre-dependent expression of tetanus toxin light chain (TeLC) to inhibit neurotransmitter release from RVLM-projecting IL neurons were subject to chronic variable stress (CVS) or remained as No CVS controls. Animals were then acutely challenged with an intraperitoneal glucose tolerance test (GTT). Endocrine metabolic function was evaluated during GTT via time courses of glucose, insulin, glucagon, and corticosterone. In No CVS females expressing TeLC, inhibition of IL-RVLM circuit signaling impaired glucose tolerance characterized by elevated glucose and decreased insulin sensitivity. Following chronic stress, females had impaired glucoregulation characterized by decreased glucose clearance and elevated corticosterone. When combined with TeLC, chronically stressed females showed shifts in the ratio of insulin to glucagon compared to CVS GFP females, suggesting circuit function impacts the pancreatic mechanisms mediating glucose homeostasis during chronic stress. In No CVS males, TeLC increased glucagon only. However, CVS TeLC males had impaired glucose tolerance, reduced insulin sensitivity, and decreased corticosterone. These data indicate that the IL-RVLM circuit mediates glucoregulation in a manner dependent on both sex and stress history. Collectively, the IL-RVLM circuit is necessary for the sex-specific maintenance of glucose homeostasis following chronic stress.
Wagenmaker ER, Gibson AG, Johnson MS
… +4 more, Choudhry AA, Provenzano NM, Dong B, Moenter SM
Endocrinology
· 2026 May · PMID 42290603
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Stress most often inhibits reproduction. Exposure to an acute layered psychosocial stress paradigm (ALPS) on proestrus disrupts the LH surge in 60% to 70% of adult female mice without interfering with the progression of...Stress most often inhibits reproduction. Exposure to an acute layered psychosocial stress paradigm (ALPS) on proestrus disrupts the LH surge in 60% to 70% of adult female mice without interfering with the progression of the estrous cycle. The present study aims to expand on these observations by investigating effects of ALPS exposure on ovulation and potential mechanisms involved in surge disruption. The most common response to ALPS exposure was disruption of the LH surge and blockade of ovulation; however, in some mice in which no LH surge was detected, ovulation did occur. Factors from the adrenal cortex and medulla, corticosterone and catecholamines (norepinephrine and epinephrine), respectively, are increased during stress; we thus tested whether these factors mediate the effects of stress on the LH surge and ovulation by applying ALPS in adrenalectomized (ADX) animals. ADX did not reverse the disruptions of the LH surge/ovulation after ALPS. Further studies aimed to investigate potential roles of individual adrenal factors in this response. We tested whether administering corticosterone, in the absence of stress, was sufficient to suppress the LH surge and ovulation. It was not. Finally, we tested whether blockade of β-adrenergic signaling during ALPS would rescue the LH surge and/or ovulation. Propranolol, a nonselective β-adrenergic receptor blocker, given 1 hour before ALPS failed to reverse the disruptive effects of stress. Together, these data confirm the effectiveness of ALPS in disrupting both the LH surge and ovulation. They further indicate that the adrenal gland is dispensable for these effects.
Adipose tissue has emerged as a dynamic endocrine organ that coordinates systemic energy balance and cardiometabolic health. This Review highlights the dual humoral and neuronal pathways through which adipose tissue regu...Adipose tissue has emerged as a dynamic endocrine organ that coordinates systemic energy balance and cardiometabolic health. This Review highlights the dual humoral and neuronal pathways through which adipose tissue regulates systemic metabolism. Humoral signals include peptide hormones, lipid mediators, metabolites, chemokines and exosomal microRNAs secreted by adipose depots. Neuronal circuits control adipose function rapidly and precisely: sympathetic efferents trigger lipolysis in white adipose tissue and thermogenesis in brown adipose tissue, whereas sensory afferents detect chemical, thermal and mechanical signals to adjust sympathetic activity. Nutritional and environmental stimuli (for example, diet, cold exposure and exercise), along with pathological states (for example, obesity, type 2 diabetes mellitus, lipodystrophy and ageing-associated disorders), dynamically modulate these endocrine and neural outputs. Methodological innovations, such as omics based on mass spectrometry or liquid chromatography-mass spectrometry, secretome labelling, adipose tissue organoid models and click chemistry, enable high-resolution characterization of adipose-derived signals and their targets. Finally, we discuss translational opportunities, including synthetic analogues of lipophilic hormones, and future therapeutic strategies that harness adipose communication networks.