Itaconate

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.

dlvr.it

Decoding the CRH system from clinical failures to therapeutic translation

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.

dlvr.it

Butyrate

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.

dlvr.it

Nitric oxide

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.

dlvr.it

Mitochondria as central regulators of cancer progression and antitumor immunity

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.

dlvr.it

Neural regulation and manipulation of pancreatic β cells

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.

dlvr.it

Glucocorticoids

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.

dlvr.it

Exercise metabolism: MoTrPAC-ing the liver in endurance exercise

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.

dlvr.it

Rethinking neurovascular coupling in white matter

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.

dlvr.it

Material-bound energy export as a metabolic fate

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.

dlvr.it

Reappraisal of GLP-1 receptor agonists in older adults

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.

dlvr.it

Obesity’s immune memory: an epigenetic barrier to recovery

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.

dlvr.it

Calcitonin

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.

dlvr.it

Is glutamate an adipose redox signal that regulates lipolysis?

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.

dlvr.it

Broadcasting live: a genetic proximity labelling mouse model to map cell-specific secretomes

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.

dlvr.it

FGF21

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.

dlvr.it

The local–systemic axis of the skeletal muscle secretome

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.

dlvr.it

Glucose metabolism meets mechanobiology

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.

dlvr.it

Calculated free testosterone: rightful heir to the free thyroxine index?

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.

dlvr.it

A multistakeholder call for belzutifan biomarker data in advanced pheochromocytoma and paraganglioma

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.

dlvr.it

Exercise-evoked immunometabolic niches coordinate context-dependent muscle metabolism

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.

dlvr.it

Kisspeptin

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.

dlvr.it

Nordic track: NIH dysfunction and my Helsinki recruitment

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.

dlvr.it

Mitochondria setting the stage for ferroptosis

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.

dlvr.it

Mitochondria produce lactate to vent redox pressure

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.

dlvr.it

Beyond fat storage: neuronal lipid droplets regulate whole-body metabolism

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.

dlvr.it