Acromegaly is a rare disease caused by growth hormone (GH) hypersecretion from a pituitary adenoma. Pegvisomant is the only approved GH receptor antagonist (GHRA) and is administered via daily subcutaneous injections, which limits real-world effectiveness. Here, we report the discovery and characterization of MAR002, a novel, half-life extended monoclonal antibody GHRA. MAR002 was identified by immunizing transgenic mice with the extracellular domain (ECD) of human and cynomolgus monkey GH receptor (GHR) and engineered with Fc modifications to limit effector function and extend serum half-life. MAR002 was benchmarked against pegvisomant in biophysical assays, cellular signaling inhibition studies, and a head-to-head pharmacokinetic/pharmacodynamic (PK/PD) study in cynomolgus monkeys. MAR002 exhibited higher binding affinity to GHR and >100-fold more potent inhibition of GH-induced GHR signaling than pegvisomant (human half-maximal inhibitory concentration [IC50] 1.05 nM vs 122 nM). Epitope binning demonstrated simultaneous binding of MAR002 and GH to GHR, consistent with an allosteric, non-competitive mechanism; notably, MAR002 inhibitory activity was maintained at supraphysiological GH concentrations, whereas pegvisomant activity was competitively reduced. In cynomolgus monkeys, a single 10 mg/kg intravenous (IV) dose of MAR002 sustained ≥50% IGF-1 suppression for 36 days compared with 15 days for an equimolar pegvisomant dose, with comparable maximal lowering (∼80%). These findings support clinical evaluation of MAR002 as a next-generation long-acting GHRA for acromegaly, with potential for reduced dosing frequency and more consistent suppression of the GH-IGF-1 axis.

Super-conserved Receptors Expressed in Brain (SREB) are a family of orphan G protein coupled receptors with three members in most vertebrates (GPR27 or SREB1, GPR85 or SREB2, and GPR173 or SREB3). They are associated with diverse physiological processes, ranging from glucose homeostasis to ovarian development. Despite a lack of confirmed ligands, our understanding of these receptors has increased based on interactions with putative SREB3 ligands such as phoenixin (PNX) and the development of synthetic SREB1 agonists (A8535 and PT-91). However, to date no studies have used these agonists in any complex vertebrate system. The objective of this study was to compare the in vitro transcriptomic responses to PNX-20, A8535, and PT-91 in the ovaries of three fishes with different SREB systems: 1) zebrafish (Danio rerio) that exhibit similar receptors to mammals, 2) mummichog (Fundulus heteroclitus) that lost a receptor but gained a fish-specific member, and 3) pufferfish (Dichotomyctere nigroviridis) that exhibit all four receptors. Agonist interactions with fish SREB1s were confirmed using in silico characterizations. Zebrafish exhibited the strongest transcriptome response, including agonist-induced changes in oxidative phosphorylation and cell adhesion pathways. Mummichog exhibited a less robust response, possibly related to receptor evolutionary divergence, while pufferfish exhibited an intermediate transcriptome response. Short-term agonist exposure did not alter ovarian steroid levels ((17)estradiol, 17-hydroxyprogesterone, cortisol, testosterone, or 11-ketotestosterone). Collectively, the data reveal previously unrecognized developmental, metabolic, neural, and vascular gene networks associated with SREB activation and suggest both receptor-specific signaling and functional overlap within this family.

Islet amyloid deposition derived from human islet amyloid polypeptide (hIAPP, amylin) is a hallmark of type 2 diabetes (T2D) and is tightly linked to progressive β-cell dysfunction and loss. It is now well established that the "toxic oligomer" hypothesis, in which soluble or intracellular hIAPP assemblies contribute to β-cell proteotoxicity and to the amplification of inflammatory stress, coexists with fibril associated and inflammation-driven mechanisms of toxicity. Regular physical activity (PA) is a cornerstone of T2D management and improves insulin sensitivity, glycemic control, ectopic lipid handling, and systemic inflammation, all of which could reduce β-cell secretory burden and the cellular milieu that favors hIAPP misfolding. However, direct demonstrations that PA delays or reduces islet amyloid formation remain scarce. This gap largely reflects methodological constrains in quantifying amyloid dynamics in humans and the absence of exercise studies with amyloid-specific endpoints. Herein, we synthesize mechanistic links by which exercise could influence hIAPP aggregation propensity (β-cell workload, glucolipotoxicity, endoplasmic reticulum stress, mitochondrial function, and inflammatory signaling) and highlight proteostasis pathways, particularly autophagy/lysosomal clearance, that are experimentally shown to defend β-cells against hIAPP oligomer toxicity. Overall, while direct evidence remains sparse, substantial mechanistic plausibility supports a link between PA and hIAPP amyloid biology. Future studies incorporating amyloid-specific outcomes are needed to determine whether exercise directly modifies amyloid formation, reduces oligomer burden, or primarily enhances β-cell resilience to proteotoxic stress.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder with developmental origins. While the etiology is unclear, current postulates include epigenetic programming. Cell-type-specific epigenetic changes by which prenatal androgen excess programs the neuroendocrine axis have not been defined. Using single-nucleus (sn) multiome sequencing (snRNAseq + snATACseq) of the mouse preoptic area, we profiled transcriptional and chromatin accessibility landscapes across 31 cell populations on postnatal day 18-22 in a prenatal androgenization (PNA) mouse model that produces neuroendocrine phenotypes that resemble hyperandrogenemic PCOS. Marker gene analysis identified 17 neuronal and 14 non-neuronal populations. We refined the GnRH neuron cluster to 41 neurons by manual curation. Cross-dataset comparisons were used to characterize the molecular transcriptional identity of these clusters. Gene set enrichment analysis of mRNA expression data revealed enrichment of protein synthesis and oxidative phosphorylation pathways and suppression of TNF/NF-κB signaling and steroid responsiveness across several clusters in PNA animals. Pseudobulk differential chromatin accessibility testing across ∼30,600 peaks identified 15 false discovery rate-significant differentially accessible regions, including two loci in GnRH neurons at genomic regions of unknown function, suggesting prenatal androgen exposure changes chromatin accessibility in this and other cell types. Chromosome accessibility at most sex steroid receptor genes was surprisingly present in GnRH neurons. Reduced Pgk1 promoter accessibility in multiple glial populations suggests PNA alters epigenetic regulation of glial energy metabolism. These findings support a model of developmental programming in which prenatal androgen exposure produces cell-type-specific changes that include but are not limited to epigenetic remodeling to generate the PNA phenotype.

Obesity prevalence has risen dramatically in recent decades, coincident with increasing human exposures to endocrine-disrupting chemicals (EDCs). Many EDCs act as "obesogens" by promoting adipogenesis and disrupting metabolism; however, little is known about their effects on neural circuits that regulate food reward and motivation. EDCs cause neurobiological and behavioral changes, implicating them in central energy balance regulation. In this experiment, we tested whether developmental exposure to the environmentally relevant EDC mixture NeuroMix (NMX) may have obesogenic-like effects in rats through central mechanisms. Using a dose-response approach, male and female rats were exposed perinatally to NMX (0, 0.1X, 1X, 10X doses) and assessed for adult high-fat food and sucrose preference, thyroid hormones, and transcriptomics in reward and hypothalamic nuclei. Females exposed to the 1X dose exhibited a nonmonotonic increase in fatty food preference and consumption accompanied by appreciable weight gain. Males showed reduced thyroid hormone levels at the highest 10X dose. NMX antagonized thyroid hormone receptor β in vitro, suggesting a potential molecular mechanism underlying the observed neuroendocrine effects. Transcriptomic analyses in 1X rats identified the nucleus accumbens (NAc) as a key neural substrate in both sexes, with spliceosomal complex eigengenes in the NAc acting as correlates of high fat food behaviors, and individual splicing factors emerging as possible neuromolecular mechanisms linking endocrine disruption to obesogenic eating. Together, this research demonstrates that environmentally relevant EDC mixtures exert sex- and dose-specific effects on food choice, thyroid hormones, and gene expression, highlighting neuromolecular reward mechanisms as potential contributors to environmentally mediated obesity risk.

At birth, blood glucose levels drop sharply before rising to normoglycemic adult levels. This is accompanied by functional maturation of pancreatic β-cells and the acquisition of glucose-responsive insulin secretion. Although transcriptional programs have been well characterized, the metabolic adjustments that enhance insulin secretion in neonatal β-cells remain poorly understood. Neonatal islets exhibit a high rate of basal insulin secretion, and elevating glucose to high concentrations produces little additional stimulation (unlike adult islets). This study aimed to elucidate how neonatal pancreatic β-cells become glucose-responsive, using an in vitro protocol involving culture of neonatal islets at low glucose to emulate systemic hypoglycemia. Low-glucose exposure markedly improved glucose responsiveness of neonatal islets by selectively lowering insulin secretion at low glucose concentrations. Unlike adult β-cells, neonatal β-cells were depolarized and generated spontaneous action potentials at low glucose, resulting in elevated [Ca2+]i and a blunted response to high glucose. These changes were reversed by brief (1-2 h) low-glucose culture, which was accompanied by increased KATP channel surface expression and activity. The effects of low-glucose incubation were mimicked by the AMPK agonist AICAR. These insights may inform strategies to restore glucose-regulated insulin secretion in type 2 diabetes.

As populations age worldwide, the incidence of fractures is increasing, leading to considerable disease burden and increased health-care costs. Bone mineral density (BMD), bone quality and muscle function are major contributors to fracture risk, with muscle function having a critical role in preventing falls. The gut microbiota is well established as a regulator of these parameters in rodents, with the immune system and short-chain fatty acids acting as key mediators of these effects. First-generation probiotic interventions have demonstrated modest effects on BMD in clinical trials. In humans, the association between the gut microbiota and muscle mass, muscle function and fracture risk seems to be more robust than the correlation between gut microbiota and BMD. Future research should prioritize the development of more targeted gut microbiota-based interventions, including second-generation probiotics, personalized dietary strategies, synbiotics, postbiotics and species-specific antibiotics with the potential to enhance both BMD and muscle function, thereby reducing risk of fractures.

Sleep is emerging as a key health topic in modern society. The prevalence of and focus on sleep-wake disorders is increasing, which has led to a large interest from the pharmaceutical industry to develop new treatments targeting sleep biology (that is, drugs that have the potential to mimic normal sleep-wake physiology). The orexin (also known as hypocretin) system is one of the key targets and regulators of sleep and wakefulness. In this Review, we will discuss the mechanisms by which loss of orexin signalling is involved in narcolepsy type 1 and whether loss and/or disruption of orexin signalling might have a role in other sleep disorders such as narcolepsy type 2, idiopathic hypersomnia and obstructive sleep apnoea. We will also describe current and emerging therapies for sleep disorders involving orexin, such as orexin receptor antagonists for insomnia and orexin receptor agonists for narcolepsy.

The hypothalamic neurons that coexpress kisspeptin, neurokinin B, and dynorphin (KNDy) play a crucial role in the control of gonadotropin-releasing hormone (GnRH) pulsatile release and, thereby, in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. However, the feedback mechanism of sex steroids on KNDy neurons is not fully understood. We selectively ablated KNDy neurons using intra-arcuate nucleus (ARC) injections of neurokinin-3 receptor agonist conjugated with saporin (NK3-SAP) to investigate their role in gonadotropin secretion in female rats under different feedback conditions. NK3-SAP rats bearing submaximal (75%) ablation of KNDy neurons displayed estrous cycle irregularity, an increased number of preovulatory follicles, and similar occurrence of corpora lutea. LH pulse frequency and amplitude, and basal LH and FSH levels were elevated in NK3-SAP rats on diestrus. Ovariectomy increased pulsatile LH secretion and basal LH and FSH levels, abolishing the differences between NK3-SAP and Blank-SAP. In estradiol (E2)-treated ovariectomized (OVX + E2) rats, NK3-SAP ablation of KNDy neurons increased the frequency of the LH pulses but not basal gonadotropin secretion. Thus, the submaximal loss of KNDy neurons potentiates pulsatile LH secretion and increases basal LH and FSH release during negative-feedback states, in which E2 is required for LH pulse modulation. Supporting a dynorphin role, treatment of OVX + E2 rats with kappa-opioid receptor agonist, nor-binaltorphimine, increased basal and surge LH secretion, associated with a higher c-Fos expression in KNDy and GnRH neurons. Our findings provide evidence that KNDy neurons play a role in limiting pulsatile and non-pulsatile gonadotropin secretion during negative feedback, possibly through a dynorphin output.

Osteogenesis imperfecta is a common genetic disorder of syndromic bone fragility manifesting in types with variable skeletal and extraskeletal severity. Over the past decades, the deforming types have almost exclusively received all scientific attention, leaving large knowledge gaps about the prevalent osteogenesis imperfecta type 1. However, studies within the past 5 years reveal serious unrecognized aspects of disease burden in this large patient population that contrast with osteogenesis imperfecta type 1's widely adopted classification as mild osteogenesis imperfecta. These patients present distinct clinical and molecular features, necessitating personalized clinical approaches and dedicated research. To our knowledge, this Review addresses this distinct patient group by recognizing the diverse facets of clinical burden, genetic landscape, bone pathophysiology, disease models and emerging treatment options. Owing to their later diagnosis, disease invisibility, increased mobility and uncharted clinical course compared with patients who have other types of osteogenesis imperfecta, these patients and their treating physicians face distinct healthcare and diagnostic challenges. In contrast to other patients with osteogenesis imperfecta with broader genetic causes, they are primarily characterized by molecular uniformity in the form of collagen type I deficiency. The scarcity of animal and cell models has also contributed to the lack of initiatives to explore osteogenesis imperfecta type 1. This Review aims to break this vicious cycle of osteogenesis imperfecta type 1 obscurity by defining knowledge gaps that future investigations of this disease should aim to address.

The endocrinology of equine pregnancy is unique, but many of its unusual phenomena closely resemble pregnancy in women. Placental estrone synthesis uses fetal adrenal androgen precursors in women, but from the fetal gonads in mares, peaking midway through the 11-month gestation. Unique to equine pregnancies, other estrogens like equilin, typified by an unsaturated B-ring sterol structure, are synthesized from 7-dehydrocholesterol (7-DHC), the immediate precursor to cholesterol, without cholesterol formation, peaking later in gestation. Currently, the spatial and temporal regulation underlying the redirection of 7-DHC from cholesterol to B-ring unsaturated steroid synthesis in equine fetal gonads remains unknown. Here, we investigate the developmental dynamics of the equine fetal gonads from the fourth to eleventh gestational month using RNA sequencing, immunofluorescence imaging, RNAScope, and gas chromatography-mass spectrometry. Our results suggest that placental estrone synthesis correlates with the expression of the last enzyme in the cholesterol synthesis pathway, 7-dehydrocholesterol reductase (DHCR7) in the fetal gonad, and its downregulation may drive the accumulation of 7-DHC and the synthesis of B-ring unsaturated steroids. B-ring unsaturated steroid secretion is the hallmark of Smith-Lemli-Opitz Syndrome in humans, resulting from mutations in the gene encoding DHCR7 in affected patients. This naturally occurring phenomenon in equine pregnancies may offer a unique comparative model for understanding the metabolic consequences of 7-DHC accumulation in these patients and a platform for drug development.

Obesity is a chronic, adiposity-based disease with increasing global prevalence and multiple, competing definitions. Traditionally, body mass index (BMI) has been the primary tool for diagnosis, although it does not completely reflect adipose tissue mass, distribution or associated organ dysfunction. In the past 2 years, major professional societies (including the European Association for the Study of Obesity (EASO), the Lancet Diabetes & Endocrinology Commission, the American College of Cardiology (ACC) and the American Association of Clinical Endocrinologists (AACE)) have advanced new diagnostic frameworks that move beyond BMI to incorporate multimodal assessment of adiposity and its clinical consequences. By integrating anthropometric precision with standardized complication assessment, these frameworks support earlier identification of risk, improved prognostication and more equitable, patient-centred obesity care. However, the way in which the new guidelines should be integrated into routine clinical care remains unclear. Here we synthesize current evidence across anthropometric measures of obesity and body composition imaging. We clarify the diagnostic performance, limitations and relevance of these measures across diverse populations. We compare areas of convergence and divergence among the new guidelines, particularly the shift towards defining clinical obesity on the basis of both excess adiposity and evidence of organ dysfunction or functional impairment.