Hyocholic acid (HCA), a newly identified human primary bile acid, regulates glucose and lipid metabolism and maintains immunometabolic homeostasis. This forum article highlights HCA and its derivatives as key mediators of inter-organ crosstalk across the lifespan, underscoring their potential to advance diagnostics and therapeutics for immunometabolic disorders.

Caloric restriction and weight loss reduce resting metabolic rate (RMR) beyond what is explained by the loss of fat-free mass, a phenomenon known as adaptive thermogenesis (ATRMR). Here, we frame ATRMR conceptually as the result of shifts in energy budgets within the body. Given the brain’s central role as both a key regulator of energy intake and a major energy consumer within the body, we hypothesize that ATRMR represents one component of the weight-loss-associated reduction in energy expenditure and may reflect a redistribution of energy from the body to the brain, consistent with the hypothesis that adequate cerebral energy supply is preferentially maintained.

Valine is catabolized by branched-chain amino acid aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKDH) to yield isobutyryl-CoA, which is catabolized via enzymes, including acyl-CoA dehydrogenase family member 8 (ACAD8) and short-chain enoyl-CoA hydratase 1 (ECHS1), and ultimately enters the tricarboxylic acid (TCA) cycle. Isobutyrylcarnitine buffers isobutyryl-CoA, which is mediated by carnitine O-acetyltransferase (CrAT). Isobutyrylcarnitine can also be exported across the mitochondrial membranes via the carnitine-acylcarnitine translocase (CACT) and secreted into the extracellular space through organic cation transporter 1 (OCT1).

In the central nervous system (CNS), extracellular ATP (eATP) is released by neurons and glial cells. Once in the extracellular space, eATP activates purinoceptors before being hydrolyzed to adenosine, establishing a signaling axis that regulates neuronal and glial activity through ionotropic P2X, metabotropic P2Y, and adenosine receptors (ARs). Under pathological conditions, eATP accumulates through additional release mechanisms and feed-forward amplification, involving connexin hemichannels, pannexins, and the P2×7 purinoceptors (P2×7R).

Heart failure (HF) is a leading cause of hospitalizations and deaths worldwide. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have been shown to improve HF outcomes despite no evidence of cardiac SGLT2 expression. This forum highlights some proposed mechanisms of SGLT2i efficacy, limitations of these studies, and potential future directions.

Adipose tissue does more than store energy and release hormones: distinct depots continuously communicate metabolic state to the brain. Existing signal-centered models do not fully explain leptin resistance, weight regain, or metabolic heterogeneity among individuals with similar adiposity. We propose the AdipoCode, a framework in which adipose depots convey their state through combined hormonal, metabolic, inflammatory, extracellular vesicle, and neural signals. We hypothesize that dysfunction can arise through inaccurate peripheral representation (encoding), altered signal delivery (transmission), inappropriate central responses (decoding), or maladaptive brain-to-adipose feedback. The AdipoCode is intended as a testable framework rather than an established biological code, and it suggests that durable therapy may require restoring communication across multiple stages rather than replacing a single signal.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of antioxidant signaling. Xirouchaki et al. show that NRF2 activation in skeletal muscle regulates metabolic homeostasis and healthy aging. Complementary evolutionary adaptations enhancing NRF2 signaling in horses underscore its role in muscle function and metabolism.

Certain immune and metabolic phenotypes persist in the host long after the original trigger has faded. These phenotypes are maintained by persistent epigenetic and metabolic changes and are increasingly recognised as key determinants of human disease. Obesity, a growing epidemic that affects one in eight people worldwide, provides an ideal terrain to test this hypothesis: it can imprint a long-term memory in adipose tissue and immune cells, making weight loss challenging and sustaining vulnerability to relapse and long-term health risks. We propose that lipid metabolism and signalling may play a central role in establishing and maintaining this memory. We discuss emerging literature defining obesity memory and its molecular basis. Because the field remains in its infancy, we highlight open questions for future studies.

Oxysterols are generally viewed as individual signaling molecules regulating lipid homeostasis, immunity, development, and disease. However, many primary oxysterols are metabolic hubs that undergo iterative enzymatic transformations, generating secondary and higher-order metabolites with distinct biological activities. We propose the oxysterolome to describe this interconnected network of oxygenated sterols and their metabolic descendants. Through receptor diversification, functional divergence, and the emergence of novel biological activities, iterative metabolism expands the informational and functional diversity of cholesterol-derived signaling. Deciphering the oxysterolome will require moving from the study of individual metabolites toward reconstruction of interconnected metabolic networks, providing new perspectives for understanding endocrine regulation, aging, immunity, and disease.

Ferro-aging links age-associated iron dyshomeostasis to chronic lipid peroxidation and progressive functional decline across human and nonhuman primate tissues. Vitamin C extends beyond its antioxidant activity by directly inhibiting ACSL4, limiting polyunsaturated fatty acid incorporation into membrane phospholipids and thereby reducing lipid peroxidation and ferro-aging-associated phenotypes.

Metabolic adaptation is often framed as differential gene expression, yet nutrient state also remodels which transcript isoforms from a gene contribute to physiology. This review presents isoform usage as an organizing principle of endocrine and metabolic regulation: a layer that connects nutrient sensing to transcript architecture, protein function, tissue specialization, and disease vulnerability. We synthesize evidence that fasting, feeding, insulin, and metabolite availability reshape isoform outputs across metabolic organs independently of total mRNA abundance. We then integrate functional examples, nutrient-responsive RNA-processing mechanisms, human genetic and disease data, and emerging RNA-targeted interventions. These findings suggest that metabolic disease reflects not only dysregulated gene expression but also failure to maintain the appropriate isoform state required for adaptive physiology.

The European Society of Endocrinology (ESE) awards celebrate members who have excelled in their field, contributing to the advancement of endocrine science. Of the nine awards in this program, six are ESE jury-voted awards that gave the winners the opportunity to present their lectures at the annual European Congress of Endocrinology (ECE) 2026, held in Prague, Czech Republic, on 9–12 May 2026. In this TrendsTalk article, we had the pleasure of interviewing three of the ESE 2026 awardees, who share with the readers of Trends in Endocrinology & Metabolism what the award means to them professionally and personally, and how their experiences, opportunities, and challenges have shaped their development as outstanding researchers in the field of endocrinology.

Subjects with diabetes have an increased risk of dementia, Parkinson’s disease, and stroke. In the central nervous system, there is increased inflammation, blood–brain barrier permeability, amyloid-β and α-synuclein deposition, and decreased neuronal synaptogenesis and survival. The role of hexokinases in controlling glucose metabolism therein is often overlooked. We propose that hexokinase-2 dysfunction-driven glycolytic overload is critically involved. This increases glycolytic intermediates in astrocytes, microglial cells, microvessel endothelial cells, and pericytes, stimulating mitochondrial dysfunction, protein O-linked β-N-acetylglucosaminylation, protein kinase C phosphorylation, and methylglyoxal-induced unfolded protein response and NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome activation. Therapeutic prevention is achieved through activation of transcription factor nuclear factor erythroid 2-related factor 2, increasing the expression of glucose-6-phosphate (G6P) dehydrogenase, glyoxalase 1, and antioxidant enzymes. This diverts excess G6P to the pentose phosphate pathway, methylglyoxal to the glyoxalase pathway, and counters oxidative stress, respectively.

Ammonium is a toxic product of amino acid degradation and protein turnover that is incorporated into arginine and detoxified via the urea cycle. Recent work has expanded the role of ammonium detoxification and the urea cycle toward broader metabolic functions. This review examines how ammonium and urea cycle-related metabolites function beyond nitrogen disposal and work as bioactive regulators across the cardiovascular, renal, and metabolic disease spectrum. We discuss how interorgan coordination among the gut, liver, kidney, heart, and immune system links arginine metabolism, ammonium detoxification, and metabolic signaling. Evidence suggests that ammonium can influence mitochondrial function, inflammatory tone, and tissue remodeling. The review considers how noncanonical urea cycle may contribute to chronic kidney disease, heart failure, and metabolic dysfunction.

There are two distinct biological forms of somatostatin (SST), SST-14 and SST-28, which are encoded through separate genes. SST signals through five known G protein-coupled receptors (SSTR1–5), all of which function to inhibit adenylate cyclase. The two isoforms display differing binding affinities for SSTR1–5. SST and its receptors are broadly expressed throughout the body, with all five receptors expressed in the brain, where SST’s inhibitory effects are known to influence cortical circuits.

People with HIV (PWH) are now effectively treated with antiretroviral therapy, including integrase strand transfer inhibitors (INSTIs) and nucleoside reverse transcriptase inhibitors (NRTIs). In the context of the global obesity epidemic, cardiometabolic complications, including type 2 diabetes, are increasingly common in PWH. In this article, we address the potential diabetogenic role of some current antiretrovirals. Beyond classical risk factors, INSTIs could promote diabetes through weight gain and drug-specific effects. They can also, rarely, induce severe acute ketosis-prone hyperglycemia. Because INSTIs and some NRTIs could alter insulin and lipid levels, standard indices of insulin resistance may be unreliable. Diabetes management generally follows recommendations for the general population, with the use of glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors to reduce glycated hemoglobin A1c, weight, and cardiometabolic risk.

Restoring NAD+ to physiological levels shows promise for countering brain aging and neurodegeneration, backed by preclinical and growing clinical evidence. Key challenges remain: measurement validity, brain delivery, optimal dosing, and trial design. This forum examines current evidence, addresses ongoing controversies, and outlines priorities for future research and translation.

Itaconate is a Krebs cycle-derived metabolite generated by aconitate decarboxylase (ACOD1) from aconitate. Originally identified for its antimicrobial activity, itaconate is now recognised as an important link between metabolism and inflammation. Itaconate accumulates in myeloid cells following stimulation via Toll-like receptors and type I interferons, where it modulates inflammatory signalling pathways.

The corticotropin-releasing hormone (CRH) system orchestrates stress adaptation, integrating neuroendocrine, autonomic, immune, and behavioural responses to internal and external challenges. For over 2 decades, CRH receptor type 1 (CRH-R1) has been pursued as a therapeutic target for neuropsychiatric disorders. Despite compelling biological rationale and extensive preclinical validation, most CRH-R1 antagonist programmes have failed in depression, anxiety, post-traumatic stress disorder, and alcohol use disorder. In contrast, CRH-R1 antagonism has demonstrated clinical proof-of-concept in congenital adrenal hyperplasia, and CRH receptor type 2 agonism is attracting growing translational interest in cardiovascular and metabolic diseases. This review reassesses CRH-system therapeutics, extracting generalisable lessons from both failure and success and outlining a roadmap for future drug development.

Butyrate (C4:0) is a short-chain fatty acid produced by the gut microbiota through the anaerobic fermentation of dietary fiber and, to a lesser extent, proteins, amino acids, and other metabolites. Butyrate also acts on the microbiota itself, modulating bacterial gene expression and community composition. It is absorbed by intestinal epithelial cells (IECs) via Monocarboxylate transporter 1 (MCT1)/Solute carrier family 16 member 1 (SLC16A1), Sodium-coupled monocarboxylate transporter 1 (SMCT1)/Solute carrier family 5 (SLC5A8), and passive diffusion.

Nitric oxide (NO) is a short-lived signaling free radical produced from L-arginine and oxygen by nitric oxide synthase (NOS) enzymes or regenerated from dietary nitrate/nitrite pools. Depending on its localization, concentration, and environment, NO plays a variety of roles. At low nM levels, it regulates vasodilation, angiogenesis, and vascularization, and participates in neuronal signaling; at higher levels, it supports host defense and can be self-damaging.

Mitochondria coordinate metabolic and signaling pathways that influence cancer progression across multiple stages of the disease. Beyond supporting tumor growth, mitochondria contribute to metastatic dissemination and shape interactions between tumor and immune cells through diverse outputs, including metabolite production, redox regulation, and mitochondrial genome dynamics. In this review, we discuss how mitochondrial functions sustain cancer cell proliferation, regulate pathways that facilitate metastatic progression, and influence antitumor immunity. We further highlight emerging roles for mitochondrial DNA variation, intercellular mitochondrial transfer, and mitochondrial dysfunction in immune cell exhaustion and senescence. Finally, we discuss how these advances are revealing therapeutic opportunities to target mitochondrial pathways and enhance the efficacy of current cancer immunotherapies.

Pancreatic β cells are regulated by integrative neural signals beyond simple autonomic efferent control. Emerging evidence highlights the critical roles of afferent nerve signals and the gut–liver–brain–pancreas network in regulating β cells. Harnessing these intrinsic neural pathways may offer innovative therapeutic strategies for restoring β cell function and mass.

Glucocorticoids (GCs) are secreted by the adrenal cortex following activation of the hypothalamic–pituitary–adrenal (HPA) axis by external stressors via GC receptor (GR)-mediated mechanisms. Physiologically, GCs regulate organ metabolism, immune function, and energy homeostasis. However, chronic or excessive GCs impair mood regulation, cardiovascular tone, insulin sensitivity, lipid handling, and muscle and bone strength. The physiological and pathophysiological effects are mediated through nongenomic and genomic mechanisms.

The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is a comprehensive research program designed to elucidate the molecular pathways induced by exercise that improve health. As a continuation of the MoTrPAC studies, Kelty et al. report dynamic and sex-dimorphic molecular responses in rats through which endurance exercise regulates liver metabolism to maintain tissue homeostasis.

Neurovascular coupling (NVC) is associated with activity-dependent functional hyperemia in gray matter. White matter may operate under distinct vascular–metabolic principles. We propose that white matter operates through a reserve-based form of NVC in which local energetic reserves help sustain energy homeostasis despite transient mismatches between metabolic demand and vascular supply.

Basal metabolism is classically described in terms of oxidative energy expenditure. Here, we propose material-bound energy export as a complementary metabolic fate of biosynthetic products. This framework distinguishes substrate oxidation from irreversible material export and provides a new physiological perspective on substrate partitioning, energy balance, and metabolic regulation.

Glucagon-like peptide-1 receptor agonists are transforming cardiometabolic care, yet their expanding use in older adults raises an overlooked question: can cardiovascular and renal protection come at the expense of muscle mass, nutritional resilience, and independence? We propose a geriatric-informed prescribing framework that redefines treatment success beyond weight loss.

Obesity leaves a lasting epigenetic imprint on adaptive immunity. A recent work by Niven et al. demonstrates that obesity-associated DNA methylation in CD4+ T lymphocytes persists after weight loss, sustaining inflammatory memory and delaying immune recovery. These findings suggest that treatment of obesity may require the restoration of immune homeostasis.

Calcitonin, a regulator of bone homeostasis, can be used in the treatment of Paget’s disease and postmenopausal osteoporosis. Calcitonin is diagnostically useful in the identification of medullary thyroid carcinoma and is also elevated in other carcinomas for example, those of the prostate, lung, colon, breast, and pancreas). Procalcitonin levels are raised in sepsis caused by bacteria and fungi and may be diagnostically useful for detecting infections.

Uncontrolled adipose lipolysis is a defining feature of insulin resistance and metabolic disease. Although insulin potently suppresses lipolysis, the mechanisms that override antilipolytic control in insulin resistance remain poorly defined. Building on recent advances in metabolic tracing, redox biology, and adipose-neuronal crosstalk, we propose that adipocyte metabolism actively regulates lipolysis. We outline a model whereby redox imbalance within adipocytes promotes the diversion of glucose-derived carbon towards glutamate synthesis. This, in turn, may activate sympathetic drive within white adipose tissue, derepressing lipolysis even under fed conditions. This could reposition ‘selective insulin resistance’ as a consequence of metabolic rewiring rather than solely due to defective insulin signalling. This suggests that future studies should explore adipose redox balance and neurometabolic signalling as avenues for treating metabolic disease.

Secreted proteins regulate a range of physiological functions and pathologies; however, identifying these in vivo has been technically challenging. The article by Plucińska et al. introduces a genetically encoded proximity labelling mouse model, enabling the capture of cell-specific secretomes in plasma and tissue in response to physiological stressors.

Fibroblast growth factor 21 (FGF21) is a stress-inducible hepatokine produced and secreted primarily by the liver in response to metabolic stress. FGF21 acts on adipose tissue and the central nervous system to orchestrate energy and nutrient homeostasis. In the pancreas, FGF21 preserves glycemic control. Most other tissues respond to FGF21 indirectly through adiponectin (APN) and neurogenic pathways. ACE2: Angiotensin converting enzyme 2.

Exercise stimulates the release of bioactive factors, termed exerkines, that contribute to local and systemic adaptation. Circulating exerkines are often interpreted as direct readouts of muscle secretion, overlooking regulatory processes within tissues that shape their production, transformation, and release. Using skeletal muscle and endurance exercise as a model system, we define a local–systemic secretome axis shaped by spatial organization, stimulus-specific programs, temporal dynamics, extracellular processing, and paracrine circuitry. By integrating evidence from recent transcriptomics, proteomics, interstitial fluid, and extracellular vesicle studies, we outline how these processes govern signal propagation from muscle to circulation and inform the interpretation of circulating exerkines as biomarkers and therapeutic targets.

Tissue stiffening is widespread in pathology. A new study by Vite et al. reveals a mechanistic link between tissue stiffness and impaired glucose uptake in cardiac muscle cells. The study bridges glucose metabolism and mechanobiology and suggests tissue stiffness may contribute to metabolic inflexibility and insulin resistance in heart failure.

Diagnosis of male hypogonadism relies on combining clinical features and total testosterone (T) measurement. Yet, androgen assessment stands at a familiar crossroads, reminiscent of the thyroxine (T4) era, when total T4 gave way to the free T4 index and ultimately free T4. Although calculated free T (cFT) is strongly linked to androgen-sensitive outcomes, a few critics contest its validity. Paradoxically, their vague recommendations to ‘interpret total testosterone in relation to sex hormone-binding globulin (SHBG)’ provide little practical guidance. They further advocate omitting cFT from the diagnostic workup of male hypogonadism, despite its ability to systematically correct for SHBG, thereby forfeiting a rational, evidence-based approach. We propose a pragmatic framework for diagnosing male hypogonadism and a research agenda to further validate cFT as a robust, clinically accessible tool.

The HIF-2α inhibitor belzutifan was recently FDA-approved for advanced pheochromocytoma/paraganglioma. This multistakeholder article calls for clinical-trial genomic correlates and outcome data to clarify efficacy across these molecularly heterogeneous neuroendocrine tumors.

Exercise improves metabolic health; yet paradoxically, many exercise-responsive myokines and immune mediators are also implicated in chronic inflammation and metabolic dysfunction. In this opinion article, we propose that these immune responses are organized within spatially defined immunometabolic niches. Endothelial-associated neutrophils act as early coordinating cells that integrate muscle-derived and vascular signals, initiate local immune remodeling, and are associated with neutrophil extracellular trap formation. Metabolic outcomes arise from coordinated intercellular interactions rather than individual mediators, even in the absence of overt muscle injury. We further suggest that postexercise insulin sensitization emerges as a spatially regulated property of these niches. This perspective provides a conceptual framework in which inflammatory signals, including interleukin-1, exert context-dependent beneficial effects on metabolism and muscle function.

Kisspeptins, encoded by KISS1, are neuropeptides that act via KISS1R (or GPR54) in hypothalamic and peripheral tissues. Kisspeptin neurons integrate sex steroids, metabolic, and environmental cues to control GnRH secretion, which governs pubertal onset. The sex-specific organization of kisspeptin circuits contributes to dimorphic reproductive hormone secretion and the timing of fertility.

National Institutes of Health aims to prioritize groundbreaking work that challenges existing views with rigor and reproducibility, and shows potential for translation. Increasingly, however, reviewers penalize applicants for novelty, critique of dogma, and for having work translated, while program officers are now guided to refuse review of proposals on forbidden topics. These practices have the potential to substantively degrade U.S. biomedical progress and played a role in my laboratory’s move to Europe.

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Recent advances challenge the view of ferroptosis as a predominantly cytosolic process and instead position mitochondria as central regulators of ferroptosis by coordinating iron metabolism, lipid composition, and redox homoeostasis. This review discusses ferroptosis from a mitochondrial perspective and examines its potential relevance to primary mitochondrial diseases, where defects in oxidative phosphorylation profoundly remodel cellular metabolism and redox homoeostasis. The review highlights emerging roles for mitochondrial iron–sulfur cluster biogenesis, coenzyme Q metabolism and trafficking, mitochondrial lipid remodelling, and stress-response signalling in shaping ferroptotic vulnerability. Finally, we discuss current evidence linking ferroptosis to mitochondrial pathology and the therapeutic opportunities arising from targeting ferroptosis pathways in mitochondrial disease.

Conventionally viewed as a waste product or a cytosolic pyruvate source, recent findings suggest that lactate may also directly contribute to mitochondrial oxidative metabolism. Using an intramitochondrial lactate biosensor, Rauseo et al. instead find that energized mitochondria are producers of lactate, which buffers mitochondrial redox to mitigate reactive oxygen species production.

Lipid droplets are dynamic organelles long thought to form in neurons only during disease. However, a study by Manceau et al. discovered that lipid droplets are not only present in healthy neurons but also regulate whole-body metabolism when formed in hunger-responsive neurons in the brain.

Cells undergo ferroptosis when membrane antioxidant defenses are inhibited, while lipophilic antioxidants can rescue cells from such insults. O’Loughlin et al. show that mTORC1-regulated high-density lipoprotein (HDL) uptake from the culture medium protects cells from ferroptosis.