The interaction of dietary nutrients with chemoreceptors in the gastrointestinal tract after a meal stimulates the secretion of gut hormones, which trigger the key processes of digestion and absorption, and also regulate energy intake and postprandial glycaemia. One of these receptors, first recognised for its capacity to gauge extracellular calcium (Ca2+), is the calcium-sensing receptor (CaSR). Subsequent to its cloning, the CaSR was found to sense not only Ca2+, but also L-amino acids (AAs) and, based on solved protein structures, distinct binding sites have been reported for Ca2+ ions and the aromatic AA, L-tryptophan (L-Trp). In the stomach and small intestine, the CaSR is expressed in enteroendocrine cells, and a substantial body of preclinical work has demonstrated that it mediates gut hormone secretion in response to L-Trp and another aromatic AA, L-phenylalanine (L-Phe), and that extracellular Ca2+ promotes these effects. In humans, intraluminal administration of L-Trp or L-Phe increases plasma levels of gut hormones, associated with reductions in both energy intake and the plasma glucose response to a subsequent meal. In addition, co-administration of Ca2+ enhances the effect of L-Trp to increase plasma levels of gut hormones (including cholecystokinin, glucagon-like peptide-1 and peptide YY) and reduce energy intake. These observations have implications for the development of novel nutrient-based management strategies for obesity and type 2 diabetes. This review considers preclinical and clinical evidence that CaSR activators, including extracellular Ca2+ as well as the aromatic AAs, L-Trp and L-Phe, stimulate gut hormones and lower both energy intake and postprandial glycaemia.

Vitamin D deficiency during pregnancy is associated with an increased risk of health issues in the offspring. Accordingly, recent Endocrine Society guidelines strongly support supplementation in pregnancy, also underlining that without consensus on optimal maternal vitamin D levels, routine screening is currently irrelevant. Knowledge of organ-specific effects of vitamin D and its association with maternal vitamin D status may aid in optimizing vitamin D supplementation. This systematic review outlines the proposed next-generation effects of vitamin D supplementation ≥400 IU/d and explores whether such effects are attributed to a specific maternal vitamin D level obtained during pregnancy. A systematic literature search was conducted in PubMed and Embase according to the PRISMA guidelines, focusing on health outcomes from 10 days postpartum and beyond. Of the 2383 screened articles, 38 were included. In 11 of 16 studies, vitamin D supplementation reduced respiratory tract infections in the first years of life. Growth or bone development benefits were observed in 6 of 12 studies. Positive effects on neurodevelopment and reduced autoimmune risk (diabetes-related antibodies) were noted, although further research is needed to determine the role of vitamin D. Very few studies have measured vitamin D concentrations, but even 1600 IU/d supplementation was associated with high frequency of infant vitamin D insufficiency. Current recommendations may not ensure sufficient vitamin D levels at birth, among others, increasing the risk of early-life infections. Further studies linking maternal and infant vitamin D levels to specific outcomes would aid in personalized nutritional advice during pregnancy and improve next-generation health.

The aim of this review is to describe the complex evolutionary processes that have integrated signaling cascades associated with 2 structurally and mechanistically dissimilar receptor families: G protein-coupled receptors (GPCRs) and membrane-spanning tyrosine kinase receptors (RTKs). Precision medicine, employing advanced personalized therapeutic strategies, requires better understanding of multiple mechanisms governing both normal and pathological cell regulation. The functional overlap of GPCRs and RTKs exhibits complex interactions. GPCRs canonically activate signaling through their interactions with G proteins; however, they can also initiate G protein-independent signaling through interactions with β-arrestin 1/2. In contrast to the GPCRs, RTK canonical signaling is initiated with ligand-dependent receptor kinase-mediated phosphorylation of specific intrinsic tyrosine substrates. This, in turn, activates multiple intracellular pathways. Despite these distinguishing characteristics, GPCRs and RTKs might have a common evolutionary origin. This shared ancestry potentially explains why GPCRs and RTKs can behave as functional RTK/GPCR hybrids by "borrowing" from each other's signaling toolbox. Intermingling of these cell surface receptors can result in noncanonical receptor transactivation/inactivation, trafficking, and signaling. Several mechanisms for heterogeneous receptor crosstalk have been proposed, including receptor protein/protein interactions and sharing docking, scaffolding, and downstream effectors. Recent identification of these signaling complexities has revealed unanticipated feedback loops and patterns of downstream target gene activation. In sum, recognizing these biological complexities should facilitate novel approaches to high-specificity therapeutic targeting.

The growth hormone (GH)/insulin-like growth factor I (IGF-I) endocrine system has a central role in metabolism and growth. The Somatomedin Hypothesis, postulated in the mid-1950s, claimed that the biological activities of pituitary GH are mediated by a liver-produced peptide termed somatomedin or IGF-I. In spite of the fact that this theory has been modified several times throughout the years to accommodate new developments in the field, it is still regarded as the main conceptual framework in the area of GH and IGF-I biology. Regardless of the unifying view that emanates from the Somatomedin Hypothesis, several opposing activities of GH and IGF-I have been described over the years. The present review addresses some of these metabolic activities, including diverging effects of these hormones on serum lipoprotein(a), sex hormone-binding globulin, insulin secretion, and adiponectin/leptin biology. In addition, we propose a number of potential mechanisms that can probably provide a cellular and biochemical basis for these divergent actions. Understanding the complex interactions between the GH and IGF-I signaling pathways might improve our understanding of basic molecular endocrine processes and result in potential clinical applications.

Climate change is a major threat to the world's population and is due to global warming from human activities that increase atmospheric greenhouse gas levels-burning fossil fuels, industry emissions, vehicular exhaust, and aerosol chlorofluorocarbons-that trap heat in the Earth's atmosphere and adversely impact air quality. Resulting higher global temperatures, extreme weather events, and rising sea levels lead to greater frequency of wildfires and floods, which, in turn, result in population displacements and threaten air and water quality, food and water security, economic and public health infrastructures, and societal safety. Climate change has direct and indirect impacts on human health and well-being across the globe, with disproportionate impact on vulnerable populations including women, pregnant persons, the developing fetus, children, older adults, indigenous peoples, persons with disabilities, preexisting and/or chronic medical conditions, and low income and communities of color. As consequences of climate change, global mortality and noncommunicable diseases are mounting because of lack of progress to reverse current trends. Climate change effects on reproductive processes and outcomes have received less attention globally, despite huge consequences for human development, fertility, and pregnancy outcomes. This review provides evidence for direct and indirect effects of climate change on human health with a focus on reproductive processes and outcomes based on experimental models and epidemiologic data, and strategies to mitigate harms. The goal is to increase awareness about climate effects on reproductive health among clinicians, researchers, the public, and policymakers, and to engage all stakeholders to change the current trajectory of harm.

The hypothalamus is the key regulator of human energy balance. Hypothalamic dysfunction leads to (morbid) hypothalamic obesity, but may have many more consequences such as hypopituitarism, adipsia, disruption of the circadian rhythm, decreased energy expenditure, low core body temperature, and behavioral changes. Many patients with hypothalamic dysfunction experience chronic fatigue, increased daytime sleepiness, headaches, inactivity, and mood disorders, all of which may contribute to the development of obesity. Adipsic arginine vasopressin deficiency, severe hypothermia, uncontrollable hyperphagia, and severe mood disorders may require 24/7 management. Signs and symptoms may be severe or mild. Severe hypothalamic dysfunction is usually readily diagnosed, but less severe hypothalamic dysfunction is much harder to recognize because, among other things, of its multifaceted presentation. Through raising awareness and by better categorization of the different clinical signs and symptoms of hypothalamic dysfunction within different domains, the underlying cause for fatigue and obesity observed in patients with hypothalamic dysfunction may be better understood, which in turn, will open new perspectives on successful management options. In this review, the state of the art for diagnostics and management of acquired hypothalamic dysfunction is summarized and a new management algorithm is suggested. The lessons learned from pediatric patients with acquired hypothalamic dysfunction, including hypothalamic obesity management through the different clinical domains, may also prove to be useful for patients with congenital or genetic forms of hypothalamic dysfunction resulting in fatigue and obesity, as well as for children with presumed "common" obesity.

Acromegaly is a chronic systemic disease associated with considerable morbidity due to its many complications, which lead to increased mortality rates. Adequate treatment is essential to reduce the development of long-term complications and to restore mortality rates to those of the general population. Three modalities of treatment are currently available (surgery, medical therapy, and radiotherapy). Surgery is considered the first-line treatment and achieves disease cure in approximately 50% of patients in reference centers. Three drug classes are currently available (somatostatin receptor ligands, dopamine agonists, and growth hormone receptor antagonists); however, disease control is not achieved in a considerable proportion of patients (∼40%). Despite substantial advances in medical therapy over the last few decades, the treatment burden is still high, and quality of life is not fully restored in many patients, even when biochemical control is achieved. Therefore, the development of medications with greater efficacy and/or easier and more convenient administration is an unmet need in the treatment of acromegaly. In addition, shifting from the current trial-and-error approach to a more precise treatment strategy guided by biomarkers predictive of the response to different medical therapies will optimize and improve patient outcomes. In this review, current treatments as well as new drugs in different phases of development are detailed, and the role of precision medicine in the treatment of acromegaly is discussed.

The adaptive starvation response allows us to survive periods of starvation-a characteristic of the environment in which humans evolved. We are now in an evolutionary transition from a global environment that was characterized by periods of famine to a world where obesity and caloric excess have become a new reality, but the mechanisms of fasting physiology remain relevant. First, many parts of the world are still plagued by famine with insufficient food resources and therefore the adaptive mechanisms required for survival during periods of decreased caloric intake are not simply relevant to our evolutionary past. Second, the obesity epidemic provides strong rationale for understanding the biology of fasting, as the same efficiencies that have evolved to allow us to survive periods of starvation also likely drive a genetic predisposition to obesity, and therefore some of the adaptive mechanisms may be maladaptive in the setting of food excess. A third compelling reason to explore the biology of fasting is that in model organisms, caloric restriction, without overt starvation, is an intervention that prolongs lifespan. The purpose of this review is to provide an overview of the biology of fasting. We will highlight potential mechanisms of benefit from fasting as well as examine data from model organisms and humans that indicate potential health risks of fasting, particularly related to bone fragility. Finally, we will review clinical studies to date that have investigated the effects of fasting on metabolic outcomes and suggest signals of benefit.

The human placenta serves as the predominant endocrine organ throughout pregnancy, assuming a central role in preserving endocrine homeostasis, facilitating maternal physiological adaptation, and safeguarding fetal well-being. Preeclampsia (PE), a multifaceted and systemic gestational complication, stands a primary contributor to maternal and perinatal morbidity and mortality. Defective placental development has been extensively acknowledged as the fundamental pathological foundation underlying this condition. Accumulating evidence has unveiled a disruption in the balance of steroid hormone production within placentas affected by early-onset PE (E-PE). Considerable endeavors have been undertaken to decipher the endocrine mechanisms driving E-PE. Recent investigations have illuminated a complex, multi-tiered regulatory system that governs placental steroidogenesis, encompassing epigenetic controls such as microRNAs (miRNAs) activity and metabolic flux-conjugated histone acetylation, post-translational modifications including O-linked β-N-acetylglucosamine (O-GlcNAc), as well as intricate endocrine feedback loops among steroids and other signaling molecules like melatonin. Notably, a growing body of evidence robustly supports a causal link between elevated placental testosterone (T0) synthesis and the onset of PE. Nevertheless, comprehensive studies exploring the endocrine pathophysiology of PE remain essential to illuminate novel therapeutic avenues for mitigating this adverse pregnancy outcome.

High-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (HG-NENs) comprise both highly proliferating well-differentiated NENs, called grade 3 NE tumors, NETs) and poorly differentiated NENs (also named NE carcinomas, NECs). The clinical management of these neoplasms poses unique challenges, and, while platinum plus etoposide is the first-line therapy in advanced setting of NECs, this is not the optimal regimen in G3 NETs in which other chemotherapy schemes, targeted agents and somatostatin analogues have shown to be active. However, overall response rates and clinical benefit are not satisfactory. Interestingly, HG-NENs may be a more suitable target for ICIs than low-grade NENs, because of their higher tumor mutational burden (TMB), increased PD-1 expression, probable increased PD-L1 expression and higher immune infiltration of tumor microenvironment. With these premises, few clinical trials have investigated the efficacy and safety of immune checkpoints inhibitors (ICIs) in HG GEP NENs. With our work we aimed to provide a comprehensive overview of the available literature data about ICIs' role in HG GEPNENs, by analyzing the critical points regarding study population, study design, study results, and potential useful biomarkers for selecting HG-GEP-NENs patients for ICI therapy.

The approvals of semaglutide and tirzepatide have set new benchmarks in the treatment of type 2 diabetes and obesity. Building on their success, novel GLP-1-based therapeutics are rapidly advancing. These next-generation agents engage not only GLP-1 receptors but also those for other gastro-entero-pancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, and peptide YY (PYY) to enhance energy uptake, storage, and expenditure through synergistic mechanisms. Both GIP receptor agonism and antagonism, particularly in combination with GLP-1 receptor agonism, have shown promise. Maridebart cafraglutide, combining GLP-1R agonism with GIPR antagonism, exemplifies this innovative approach. Glucagon co-agonists like survodutide and mazdutide have demonstrated significant weight loss and improved glycemic control. Amylin-based agents, including CagriSema (cagrilintide + semaglutide) and amycretin, enhance satiety and glycemic outcomes through complementary actions. Further innovation is seen in triple agonists such as retatrutide, which targets GIP, GLP-1, and glucagon receptors to amplify metabolic effects. Meanwhile, the emergence of orally active small-molecule GLP-1 receptor agonists like danuglipron and orforglipron, which are resistant to enzymatic degradation, marks a major advance in patient-friendly drug delivery. This review explores the mechanisms, clinical development, and therapeutic potential of these novel agents, excluding already approved drugs like liraglutide, semaglutide, and tirzepatide. We highlight how multi-receptor agonists and oral GLP-1-based therapies may reshape the future landscape of obesity and type 2 diabetes treatment by offering more effective and better-tolerated options.

Adults with adrenal cortisol insufficiency (ACI) often report cognitive dysfunction, especially in memory processing and executive function. Only a few studies have objectively compared cognitive function as the primary outcome between patients with ACI and controls, and these efforts have yielded inconsistent results. In this review, we examine the challenges facing researchers studying cognitive function in adult patients with ACI. We consider the effect of dysregulated cortisol on cognition in patients with ACI, and the inability of current guideline-recommended glucocorticoid treatment regimens to accurately reproduce circadian and ultradian cortisol secretion rhythms. Factors that contribute to inter- and intraindividual response are presented; the indirect effects of ACI comorbidities, complications, and symptoms on cognitive dysfunction are reviewed; and obstacles to employing neurocognitive testing are identified. Finally, we outline potential approaches to studying cognition in ACI using well-designed studies that account for the complexities and gaps in ACI research.

Glycerol and glycerol-3-phosphate are key metabolites at the intersection of carbohydrate, lipid and energy metabolism. Their production and usage are organismal and cell type specific. Glycerol has unique physicochemical properties enabling it to function as an osmolyte, protein structure stabilizer, antimicrobial and antifreeze agent, important to preservation of many biological functions. Glycerol and glycerol-3-phosphate are implicated in many physiological and disease processes relating to energy metabolism, thermoregulation, hydration, skin health, male fertility, aging, and cancer. Glycerol has countless applications in the food, pharmaceutical and cosmetics industries. It is used as a sweetener, preservative, thickening agent, humectant, osmolyte and cryoprotectant. It is widely used in skin and wound care products, laxatives, in cell and tissue preservation and in medicines for numerous conditions. Here, we review the multiple uses and functions of glycerol and glycerol-3-phosphate and associated transporters, enzymes and target genes in health, senescence and disease. We discuss the evidence that glycerol may be present at much higher levels in tissues and cells than in the blood. We bring particular focus to the newly identified glycerol shunt in the direct formation of glycerol independent of lipolysis and as a pathway allowing cells to adapt to various stresses. Relevant to chronic metabolic diseases, cancer and aging, glycerol and glycerol-3-phosphate presents important translational implications and thus warrants much more attention.

The thyroid is exposed to DNA damage induced by normal physiological processes (eg, oxidative stress resulting from thyroid hormone synthesis or mitochondrial respiration) or through environmental insults (eg, environmental pollutants, ionizing radiation exposure). Robust antioxidative stress defense and DNA repair mechanisms protect thyrocyte genome integrity, but defective or dysregulated DNA repair pathways have been implicated in thyroid pathology, including autoimmune thyroid disease and thyroid malignancy. In thyroid cancer, disturbed antioxidative stress defense, Mismatch Repair, Non-Homologous End-Joining, or DNA damage response pathways contribute to both the onset and progression of the disease. The insight into mechanisms governing thyrocyte genome integrity may help to gain better understanding of the pathology and suggest novel therapeutic regimens, urgently needed in treatment-refractory disease. In the current review, we provide comprehensive description of the exogenous and endogenous factors, as well as DNA repair mechanisms influencing thyrocyte genome integrity. Moreover, we pinpoint major research avenues that should be pursued in future research. This information will be valuable in directing new discoveries to better understand thyroid disease pathomechanisms, as well as aid development of novel diagnostic and therapeutic tools.

One of the major metabolic functions of glucocorticoids (GC) is to maintain circulating glucose levels during stress, as glucose is the preferred energy source for the brain. Because of their potent anti-inflammatory and immune modulatory activities, GC are frequently used to treat inflammatory and autoimmune diseases. Chronic GC exposure, which can be a result from long-term GC pharmacotherapy and prolonged stress, however, causes undesired adverse effects that include hyperglycemia and insulin resistance. These adverse effects limit the application of GC therapy. GC act through an intracellular GC receptor (GR), a transcriptional regulator, to modulate the transcriptional rate of specific genes to exert physiological responses. The liver is a major target tissue of GC to modulate glucose homeostasis. In this review, we discuss the mechanisms of GR-activated transcription of genes involved in glucose metabolism and how hepatic GR primary target genes participate in the regulation of insulin sensitivity and glucose homeostasis. Transcriptional coregulators involved in GR-regulated transcription of glucose metabolism genes and signaling pathways specifically activated upon chronic GC exposure to induce glucose disorders are introduced. Metabolic profiles of liver-specific GR knockout mice are also reviewed. Finally, individual-specific GC responses and mechanisms underlying these phenomena are discussed. Overall, more extensive studies of the mechanisms of GR-regulated hepatic glucose homeostasis not only will expand our knowledge of the regulation of metabolic homeostasis but are also critical for developing improved GC pharmacotherapy and novel approaches to tackle metabolic disorders by targeting GR.

Adipose tissue has emerged as a central regulator of human physiology, with its dysfunction driving the global rise in obesity-associated diseases, such as type 2 diabetes, cardiovascular and liver diseases, and several cancers. Once thought to be inert, adipocytes are now recognized as dynamic, responsive cells essential for energy homeostasis and interorgan communication, including the brain. Distinct adipose depots support specialized functions across development, sex, and aging. Technologies like single-cell RNA sequencing are unraveling depot-specific mechanisms, with the potential of identifying new therapeutic targets. This review highlights major scientific advancements leading to our current appreciation of the pivotal role of adipose tissue in health and disease. Many key discoveries in this field have been catalyzed by National Institutes of Health funding, particularly through the National Institute of Diabetes, Digestive and Kidney Diseases, now celebrating its 75th anniversary.

The multiple physiological effects of gut hormones in different metabolic tissues make them attractive therapeutic targets for the treatment of metabolic diseases. Currently, only GLP-1 receptor-based agonists and oral DPP-4 inhibitors are available on the market. Despite their positive clinical outcomes across a range of indications these treatments present several clinical challenges, including high costs, the need for peptide injections, and requirements for repeated administration. These limitations have driven research into improved GLP-1-based therapies, such as oral small-molecule agonists and novel drug delivery strategies based on emerging GLP-1 medicines. This article describes the challenges in clinical application and development of GLP-1-based pharmacotherapies. We review the development of oral small-molecule agonists and various drug delivery technologies, including ultralong-acting injectable technologies, continuous-acting implantable pumps, smart-acting electronic devices, nutrient-induced cell therapies, and noninvasive delivery systems. We discuss the current state of research, challenges to overcome, and opportunities to improve patient compliance and clinical outcomes. Additionally, we explore how endocrinological effects and patient-oriented needs can guide the development of advanced GLP-1 medicines.