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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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HDL resuscitates cells from ferroptosis

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.

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2-Methylbutyrylcarnitine (2MBC)

2-Methylbutyrylcarnitine (2MBC) is a short-branched-chain acylcarnitine involved in isoleucine catabolism. Increased circulating 2MBC has been used as a biomarker reflecting inherited defects in isoleucine degradation, particularly in short-branched-chain acyl-CoA dehydrogenase (SBCAD) deficiency. Recent evidence further identifies 2MBC as a gut microbiota-associated metabolite that can enter the circulation and elevate thrombotic risk.

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Androgen loss backfires: Brain gate for tumor immunity

Androgen deprivation is assumed to boost antitumor immunity—but Lee et al. overturn this logic in glioblastoma, showing that androgen loss activates a microglial inflammasome–hypothalamic–pituitary–adrenal axis cascade that elevates glucocorticoids and attenuates T cell function. The study reveals how organ context reverses endocrine control of tumor immunity.

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Decoding growth hormone actions on human growth plate stem cells

The epiphyseal growth plate is the key target of growth hormone (GH) therapy. Although growth plate stem cells are well defined in mice, their presence in humans was unclear. Using rare surgical specimens, the study by Chu et al. reveals conserved, GH-responsive stem cells in the human pubertal growth plate.

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Glucocorticoid resistance-induced inflammation drives cardiovascular–kidney–metabolic (CKM) syndrome pathophysiology

Prolonged activation of the hypothalamic–pituitary–adrenal axis results in excessive secretion of the glucocorticoid (GC) hormone cortisol, which contributes to weight gain, increased appetite, and inflammation. GCs are essential in regulating stress responses and suppressing immune functions. They bind to the GC receptor and influence gene expression through transcriptional mechanisms. Sustained elevation of GC levels may lead to GC resistance, thereby contributing to inflammation, adiposity, and insulin resistance, which negatively impact the hepatic, cardiovascular, and renal systems. This condition is referred to as cardiovascular–kidney–metabolic (CKM) syndrome. The notable pathologies associated with GC resistance and CKM syndrome are discussed, with particular emphasis on CKM staging and potential therapeutic strategies for individuals with cardiometabolic dysfunction.

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Hippo signalling in cellular and tissue-level metabolism across health and disease

Hippo signalling is increasingly recognised as an important regulator of metabolic adaptation rather than solely a pathway controlling organ size and growth. This review examines how nutrients, hormones, and energy stress regulate Hippo-Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) activity, and how Hippo signalling, in turn, rewires glucose, lipid, amino acid, and nucleotide metabolism. We highlight emerging concepts, including metabolite-specific checkpoints, tissue-specific Hippo functions across metabolic organs, and the context-dependent roles of Hippo signalling in obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease/steatohepatitis, cardiometabolic disease, and cancer. We also discuss how this bidirectional Hippo–metabolism axis is opening new therapeutic opportunities, while underscoring that effective translation will require cell-type- and disease-stage-specific targeting.

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From architecture to function: mechanisms shaping pancreatic islet morphogenesis

Islets of Langerhans are highly structured mini-organs containing hormone-producing cells of the pancreas that regulate glucose metabolism. Studies of…

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Mitochondria across the globe: diverse voices, shared energy

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Early-life gut fungi as modulators of metabolic development

Early life is a critical window during which microbes shape immune maturation, nutrient handling, and long-term metabolic health. Although fungi represent a minor proportion of the gut microbiome, emerging evidence suggests they exert a disproportionate influence. In this review, we synthesize current gut mycobiome knowledge during pregnancy and infancy, including ecological assembly, maternal and environmental sources, and links to early metabolic phenotypes. Recent studies on human cohorts and gnotobiotic mice demonstrate that specific fungal species can causally alter adiposity, adipose immune architecture, and bacterial function. We also highlight major knowledge gaps, including questions around true colonization, fungal activity, strain-level transmission, and the molecular basis of fungal–bacterial–host interactions. These findings position the early-life mycobiome as a promising frontier for discovery in metabolic development.

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Inborn errors of redox metabolism: an emerging nosology

Inborn errors of redox metabolism (IERM) are a growing yet poorly defined group of disorders, limiting understanding and treatment. We propose a dichotomous classification: primary IERM, involving genetic defects in redox pathways, and secondary IERM, where reactive oxygen species-mediated damage arises from other metabolic defects. This framework aims to guide future research.

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