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 biosen...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...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) up...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.
Trends Endocrinol Metab
· 2026 Jun · PMID 42248738
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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 C...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.
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 t...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.
Trends Endocrinol Metab
· 2026 Jun · PMID 42242931
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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...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.
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 stres...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.
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 sugge...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.
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 redo...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.
Metabolic dysfunction-associated steatotic liver disease (MASLD) shows substantial sex-related differences, often attributed to sex hormones. However, this purely hormone-centric view may be oversimplistic. Studies compa...Metabolic dysfunction-associated steatotic liver disease (MASLD) shows substantial sex-related differences, often attributed to sex hormones. However, this purely hormone-centric view may be oversimplistic. Studies comparing Turner syndrome (TS, 45X) and Klinefelter syndrome (KS, 47XXY) to euploid controls indicate that variations in X-chromosome dosage are closely associated with cardiometabolic burden and increased MASLD risk, even before puberty and irrespective of sex hormone levels. Transcriptomic studies further reveal genome-wide, dosage-sensitive regulatory effects of X-chromosome quantity. This opinion article argues that X-chromosome dosage is an active biological variable capable of reprogramming cardiometabolic and hepatic pathways. By highlighting TS and KS as models of liver disease, we suggest a framework to stimulate further research and improve our understanding of sex-specific heterogeneity in MASLD.
Beyond its classical role in gating reward processes, dopamine (DA) also contributes to the orchestration of feeding and energy balance. This review synthesizes and discusses recent advances in understanding how dopamine...Beyond its classical role in gating reward processes, dopamine (DA) also contributes to the orchestration of feeding and energy balance. This review synthesizes and discusses recent advances in understanding how dopaminergic and dopaminoceptive circuits integrate hedonic and homeostatic signals across mesocorticolimbic and hypothalamic networks. We examine how these distributed ensembles encode nutrient status, motivation, and peripheral cues, and how cell type-specific receptor signaling shapes their functional outputs. Conceptualizing DA circuits as integrated networks, rather than segregated pathways, provides a unifying framework for understanding feeding behavior in both physiological and pathological states, including metabolic and eating disorders. This perspective may inform targeted strategies to modulate specific dopaminergic nodes within the feeding network.
Trends Endocrinol Metab
· 2026 May · PMID 42156257
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Because vitamin D (VitD) plays a key role in calcium balance, the body has evolved homeostatic mechanisms to maintain 1α,25-dihydroxyvitamin D levels within a physiological range. Historically, measurements of total 25-h...Because vitamin D (VitD) plays a key role in calcium balance, the body has evolved homeostatic mechanisms to maintain 1α,25-dihydroxyvitamin D levels within a physiological range. Historically, measurements of total 25-hydroxyvitamin D [25(OH)D] have provided assessments of VitD status. However, this approach has important limitations because it measures 25(OH)D bound to vitamin D-binding protein (DBP), while it is free 25(OH)D that is biologically relevant. This opinion article discusses precision diagnostic approaches to minimize the confounding effects of interindividual variation in DBP levels. Ratios of VitD metabolites [25(OH)D, 1,25-dihydroxyVitD, and 24,25-dihydroxyVitD] provide DBP-independent indices of VitD status. This precision diagnostic approach could have an especially favorable impact on patients with several clinical conditions, for example, malabsorption, impaired activation of VitD, or estrogen-induced increases in DBP.
Islets of Langerhans are highly structured mini-organs containing hormone-producing cells of the pancreas that regulate glucose metabolism. Studies of endocrine cell differentiation and clustering into immature proto-isl...Islets of Langerhans are highly structured mini-organs containing hormone-producing cells of the pancreas that regulate glucose metabolism. Studies of endocrine cell differentiation and clustering into immature proto-islets, as well as remodeling into mature islets, are beginning to clarify the critical timepoints and mechanisms governing islet formation across species. In this review, we compare the mechanistic features of the current models of islet morphogenesis, linking them to established intrinsic and extrinsic signals. These signals coordinate endocrine cell differentiation, migration, and clustering to form a distinct 3D islet architecture, while their disruption leads to islet dysfunction. Understanding 3D islet morphogenesis will enable the generation of mature stem cell-derived islets for regenerative therapies and help identify druggable pathways to restore islet function in diabetes.
Many diverse signals regulate feeding behavior. In Nature Metabolism, Xiao et al. describe the discovery of a new appetite-suppressant metabolite found in pythons, which is also conserved in humans. This research broaden...Many diverse signals regulate feeding behavior. In Nature Metabolism, Xiao et al. describe the discovery of a new appetite-suppressant metabolite found in pythons, which is also conserved in humans. This research broadens our understanding of postprandial physiology and raises new questions related to metabolic pathology and therapy.
In a recent Cell study, Zuo et al. identified pyruvylation as a previously unrecognized post-translational modification (PTM) mechanism that suppresses type I interferon signaling and antiviral immunity through pyruvate-...In a recent Cell study, Zuo et al. identified pyruvylation as a previously unrecognized post-translational modification (PTM) mechanism that suppresses type I interferon signaling and antiviral immunity through pyruvate-mediated pyruvylation of the signal transducer and activator of transcription 1 protein. This expands the repertoire of metabolite-controlled PTMs and highlights pyruvylation as a promising antiviral therapeutic approach.
Metabolic dysfunction-associated steatohepatitis is traditionally viewed as a hepatocyte-autonomous metabolic disorder. A recent study by Xi et al. identifies a soluble glycoprotein nonmetastatic melanoma protein B ectod...Metabolic dysfunction-associated steatohepatitis is traditionally viewed as a hepatocyte-autonomous metabolic disorder. A recent study by Xi et al. identifies a soluble glycoprotein nonmetastatic melanoma protein B ectodomain that activates the pseudokinase receptor tyrosine kinase to drive ERK-dependent lipogenesis, revealing an extracellular mechanism that instructs hepatic metabolism and highlighting a potential therapeutic target.