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.

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 activity may contribute to chronic kidney disease, heart failure, and metabolic dysfunction.

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.

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.

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.

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.