The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is a comprehensive research program designed to elucidate the molecular pathways induced by exercise. As a continuation of 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.
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.
The HIF-2α inhibitor belzutifan was recently U.S. Food and Drug Administration (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 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.
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.
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.
