Trends in Endocrinology and Metabolism

Tanycytes: bloodhounds of the metabolic brain Constant monitoring and fine-tuning of internal body status to maintain energy homeostasis despite changing physiological needs and environmental conditions are essential brain functions. Hypothalamic tanycytes – specialized ependymoglial cells at the interface between the blood and the brain – play crucial roles in this regulation through mechanisms as diverse as sensing and responding to circulating nutrients and metabolic hormones, gating their access or shuttling them into the brain, modulating hypothalamic neuronal function and neuroendocrine communication with peripheral organs, and generating new regulatory neurons. We summarize these mechanisms and emphasize striking recent discoveries that extend beyond energy balance to reproduction and even cognitive aging. These highlight the need for a deeper understanding of the physiological and pathological roles of these unique cells.

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MASLD in childhood as a multisystem health challenge beyond the liver The rising prevalence of childhood obesity and type 2 diabetes has made metabolic dysfunction-associated steatotic liver disease (MASLD) an urgent pediatric health concern. Beyond its well-known hepatic and cardiometabolic burden, emerging evidence also links MASLD to impaired bone health, growth deficits, sleep disturbances, and neurobehavioral issues including depression and anxiety. These extrahepatic complications significantly affect long-term health and psychosocial risks. Progression to steatohepatitis and fibrosis may also increase the lifetime risk of hepatic and extrahepatic cancers. Greater clinical awareness and further research into its mechanisms and comorbidities are urgently needed; moreover, early detection and coordinated, multidisciplinary care will be essential to improve patient outcomes. We explore the multifaceted long-term health impact of MASLD as a childhood-onset multisystem disorder.

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Adrenalectomy is underused: a call to reduce mortality Adrenal tumors driving hormone excess, like primary aldosteronism, Cushing syndrome, and pheochromocytoma, claim thousands of lives yearly; yet, adrenalectomy remains underused despite its lifesaving potential. Ideal surgical rates in the USA, UK, and Sweden could prevent tens of thousands of deaths, rivaling cancer operations’ impact. Urgent screening reforms are needed.

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Online Now: In silico prediction of endocrine activity #trends #endocrinology #metabolism

Art breaks obesity’s health information silos Conventional obesity interventions create ‘health information silos’, isolating scientific knowledge from lived experience and systemic drivers. Artistic interventions can uniquely dismantle these silos by translating complex data into visceral, co-created experiences, connecting urban design, behavioral science, and community action to transform obesogenic systems into equitable health ecosystems.

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Dietary medium-chain triacylglycerols in metabolic regulation Dietary medium-chain triacylglycerols (MCTs; C8:0–C12:0) are absorbed and utilized differently compared with long-chain fats. They directly enter the portal vein as free medium-chain fatty acids, most of which are converted to ketone bodies in the liver, with a significant proportion entering the circulation. Accumulating evidence links MCT intake to improved glucose homeostasis; increased energy expenditure and satiety with concomitant modest weight loss; and chain length-dependent modulation of circulating lipoprotein profiles and liver metabolism. Emerging data also suggest direct benefits for cardiac contractility, hinting at a broader cardiometabolic advantage. Here, we synthesize the current evidence, outlining how MCTs influence cardiometabolic health. We further discuss mechanistic insights, from cellular substrate partitioning and mitochondrial dynamics to gut–liver signaling to propose mechanisms of MCT action.

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Mitophagy in the adaptation to pancreatic β cell stress in diabetes Mitophagy is a crucial quality control process that preserves metabolic efficiency by selectively targeting damaged mitochondria for removal. Given the high metabolic demand of pancreatic β cells’ insulin secretion, disruption of mitophagy contributes to the mitochondrial dysfunction and β cell failure that are a common feature of both type 1 and type 2 diabetes (T1D and T2D). We review the impact of mitophagy on β cell responses to (patho)physiologic stressors that underlie the development of T1D and T2D. We examine how β cells engage mitophagy in the adaptive response to metabolic, inflammatory, and oxidative damage. We also dissect the importance of ubiquitin- and receptor-mediated mitophagy, methodological advances to quantify mitophagy in β cells, and ongoing efforts to pharmacologically target mitophagy to preserve β cell health and improve glycemic control.

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Systemic and metabolic control of liver regeneration The liver possesses a unique regenerative capacity, driven by mechanisms that extend beyond classical growth factor signaling. Recent studies underscore the importance of metabolic reprogramming, mitochondrial adaptation, and signaling metabolites in promoting tissue injury repair. Dynamic crosstalk between hepatocytes, non-parenchymal cells, and other organs governs the regenerative process. Spatial compartmentalization within the liver and systemic cues from adipose tissue, the pancreas, the gut, the brain, skeletal muscle, and other organs play critical roles in shaping regenerative outcomes. In this review we discuss how the liver’s tissue microenvironment and inter-organ communication networks regulate liver regeneration, providing new insights into the complex biology underlying tissue repair.

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You can find the full issue at: www.cell.com/issue/S1043-...
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NEW ISSUE! With a focus on the risk and management of type 2 diabetes (T2D) and its complications, from the role of (epi)genetics in gestational diabetes development to the policy changes needed to reshape the future of youth-onset T2D and a global perspective on the prevalence of prediabetes (1/2)

Methionine restriction and mimetics to ameliorate human aging and disease Methionine restriction (MetR) attenuates the severity of numerous age-related diseases and extends lifespan across multiple species. Implementing MetR in humans remains challenging due to the low palatability of MetR diets, unfavorable side effects associated with continuous dietary MetR, and interindividual variation in factors that can diminish its efficacy, including microbiota activity, compensatory effects from cysteine, and methionine transfer from neighboring cells. Several novel approaches that target methionine metabolism have been developed – including small molecules, synthetic biotics, and xenotopic tools – with some already translated into early-stage clinical trials. In this review, we discuss a variety of approaches that either produce or mimic MetR, as well as their potential applications for human healthspan improvement.

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Formate Formate (the anion of formic acid) is a short-chain monocarboxylic acid. In eukaryotes, it represents the predominant transferable form of one-carbon (1C) units between the mitochondrial and cytosolic compartments. At the cellular level, formate is generated mainly through serine catabolism. At the whole-body level, it is derived from multiple amino acids, anaerobic fermentation by gut bacteria, and the detoxification of methanol and formaldehyde.

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Cold-season programming reinforces the brown fat–cardiometabolic health link Recent work by Yoneshiro et al. links brown adipose tissue (BAT) activity to environmental temperatures during conception, highlighting intergenerational influences shaping BAT function. Here we explore how these findings translate into a cardiometabolic health phenotype and discuss how it can be mediated through sperm epigenetic programming.

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Rethinking ‘normal’: are pubertal milestones and growth charts obsolete? Childhood development and pubertal milestones continue to be pillars of pediatric growth monitoring, but increasing trends in childhood obesity and precocious puberty indicate that existing ‘normal’ criteria may be misleading. Here, we suggest a shift from anthropometry-based growth references to metabolically informed benchmarks that better reflect long-term health outcomes.

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Online Now: Mechanisms and therapeutic insights into MASH-associated fibrosis #trends #endocrinology #metabolism

CD8+ T cell stressors converge on shared metabolic–epigenetic networks CD8+ T cells are vital for antiviral and antitumor immunity, yet in hostile microenvironments, they experience metabolic stress, leading to mitochondrial damage, metabolic dysregulation, and chromatin remodeling that cause immune dysfunction. Aging further exacerbates these processes, with intrinsic metabolic collapse and extrinsic environmental factors jointly impairing T cell immunity. Metabolites orchestrate key epigenetic modifications, shaping transcriptional programs essential for T cell differentiation and memory formation. This review explores the interconnected metabolic and epigenetic mechanisms governing CD8+ T cell fate decisions, emphasizing how mitochondrial dysfunction, metabolic inflexibility, and nutrient competition drive CD8+ T cell exhaustion, senescence, and age-associated dysfunction. Understanding these metabolic–epigenetic circuits offers novel therapeutic avenues, including metabolic reprogramming and senescence-targeted strategies, to rejuvenate immune responses and enhance immunotherapy outcomes.

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Save the date for Multifaceted mitochondria!

Announcing Cell Symposia: Multifaceted Mitochondria, June 21–23, 2026, Glasgow, Scotland, UK
@CellSymposia #CSMito2026 Save the date!
Keynote speakers: Judy Hirst (University of Cambridge) & Jared Rutter (University of Utah)
Find out more: http://dlvr.it/TN9ZsL

Hydroxyestradiol alleviates acute kidney injury via blockade of ferroptosis The molecular mechanisms underlying sex differences in acute kidney injury (AKI) remain incompletely understood. In a study recently published in Nature, Tonnus et al. reported that 17β-estradiol (E2) induces an anti-ferroptotic state in renal tubules through both genomic and non-genomic mechanisms, thereby providing renal protection against AKI.

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Metabolic hallmarks of type 2 diabetes compromise T cell function Type 2 diabetes (T2D) manifests as profound systemic metabolic dysregulation. Mounting evidence indicates T2D significantly impairs T cell immunity, compromising both protective immune responses and immune homeostasis. This dysfunction stems from the multitude roles of metabolites in T cell biology: energy substrates, signaling molecules, and epigenetic regulators. In this review, we synthesize current evidence on how the metabolic hallmarks of T2D (hyperglycemia, hyperinsulinemia, and dyslipidemia) reprogram T cell metabolism and their functionalities. Notably, most patients with T2D receive combination antidiabetic therapies which not only correct systemic metabolism but also exert direct immunomodulatory effects on T cells. Unraveling the interplay between disease-driven metabolic perturbations and pharmacologically induced immunomodulation is essential to advance therapeutic strategies that restore immune competence while preserving immunoregulatory balance.

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Target compartmentalized metabolism to regulate epigenetics Metabolites are donors of epigenetic modifications. Zhao et al. demonstrated that an ELMSAN1 regulated nuclear pyruvate dehydrogenase complex (nPDC) generates an independent nuclear acetyl-CoA pool dedicated to histone acetylation. Disrupting ELMSAN1–nPDC interaction reprograms histone acetylation and impedes tumor progression, highlighting the regulation of epigenetics and cell signaling by targeting compartmentalized metabolism.

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NEW ISSUE! With articles on cancer cachexia, circadian dysruption, lipid metabolism in T cell antitumor activity, brain myelin as an energy source and more!

www.cell.com/issue/S1043-...

The interplay between organized lymphoid structures and thermogenic adipose tissue Advances in the immunometabolism field have shown that infiltrated immune cells play a pivotal role in the development and function of thermogenic adipose tissue (TAT), including brown and beige fat. However, scarce research has focused on the role that organized lymphoid structures, like lymph nodes and lymphatics vessels, may exert on TAT. In this review we summarize the evidence suggesting that a significant link exists between the lymphoid tissues and adipose tissue, and we describe the most important in vitro and in vivo findings indicating that organized lymphoid tissues also play an important role in TAT biogenesis and function, raising relevant questions which are still unsolved in this emerging field.

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Our Editor @sfabb.bsky.social is on his way to Heidelberg for the EMBO workshop @events.embl.org on developmental metabolism! Get in touch if you'd like to chat about your research and publishing at Cell Press! #EMBODevMet

Contribution of metabolism-independent glucose sensing to metabolic homeostasis Glucose sensing and signaling are central to cellular metabolic machinery for the regulation of metabolic homeostasis. Glucose sensing has been almost always assumed to be coupled with glucose metabolism; however, recent findings have unraveled metabolism-independent sensing mechanisms. Here, we discuss whether glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) may also function as glucose sensors independent of their roles in transporting glucose. Moreover, we review the emerging roles of G protein-coupled receptors (GPCRs) in sensing glucose and, consequently, initiating its signaling pathways in a cell-specific manner. Altogether, this review offers insights into the newly identified glucose sensing mechanisms and highlights the therapeutic potential of targeting the downstream glucose signaling pathways for more efficient treatment of diabetes, obesity, and their complications.

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Biliverdin reductase-A is a key modulator in insulin signaling and metabolism Biliverdin reductase-A (BVRA) is a pleiotropic enzyme traditionally known for its antioxidant role in the heme degradation pathway. Recent findings have redefined BVRA as a master regulator of insulin signaling, acting as a kinase, scaffold, and redox-sensitive integrator of metabolic cues. BVRA modulates key nodes of the insulin cascade and sustains mitochondrial and synaptic function. Notably, BVRA loss precedes the accumulation of canonical markers of insulin resistance both peripherally and in the brain. Here we discuss how BVRA could represent an early cross-tissue biomarker of metabolic vulnerability. Its dysfunction contributes to mitochondrial stress, impaired proteostasis, and cognitive decline, thus linking metabolic and neurodegenerative disorders.

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Decoding microbial volatile signals in host–microbiome crosstalk The human gut microbiome is a complex microbial ecosystem which has a profound impact on host health and disease. The research focus in this area is rapidly moving from taxonomy to functionality, elucidating the biological role of small molecules produced by the gut microbiome in regulating host metabolism. Among these, microbial volatile organic compounds (mVOCs) play several roles in bacterial communication and microbe–host signaling. Volatilomics, the comprehensive study of volatile metabolites, is emerging as a powerful tool for discovering and investigating these interactions. In this review we examine the current understanding of mVOCs in the gut and highlight how dedicated in vitro and ex vivo volatilomics experiments, alongside in vivo studies, can uncover the biological roles for these emerging small molecules.

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The dual role of taurine in cancer and immune metabolism Taurine is a conditionally essential amino acid with paradoxical roles in cancer, as both tumor and immune cells rely on it for vital functions Here, we discuss the emerging context-dependent functions of taurine and propose therapeutic strategies that leverage or inhibit its metabolism to modulate cancer progression and immunity.

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Redefining senescence through hepatocyte fate changes in liver diseases Hepatocyte senescence is increasingly recognized as a key contributor to liver pathophysiology. While traditionally viewed as a state of permanent growth arrest, hepatocyte senescence is now understood to be more dynamic and potentially reversible, particularly during liver repair. In this opinion article, we propose reframing senescence as a continuum rather than a terminal fate. We focus on early stress-responsive states, especially those marked by p21 expression, which may be adaptive or pro-regenerative depending on the context. We highlight the roles of p21-associated secretory phenotypes (PASPs), senescence-associated secretory phenotypes (SASPs), epithelial plasticity, and partial epithelial-to-mesenchymal transition (EMT) in modulating hepatocyte behavior, immune surveillance, and cancer risk. Viewing hepatocyte senescence as a trajectory opens new opportunities for context-specific and temporally targeted therapeutic strategies in liver disease.

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Exploiting metabolic vulnerabilities to improve cancer therapeutics Over the past decade, our understanding of cancer metabolism has advanced significantly, revealing a complex and dynamic landscape of metabolic reprogramming that facilitates tumor progression and promotes therapeutic resistance. To survive under stressful conditions, cancer cells undergo crucial metabolic adaptations while also creating vulnerabilities that can be exploited for therapeutic purposes. Here, we discuss the evolving understanding of cancer cell metabolic adaptation in the tumor environment and the recent advances in identifying potential therapeutic mechanisms, including synthetic lethality, post-translational modifications (PTMs), as well as the interplay between metabolism and epigenetics. Furthermore, we discuss the integration of metabolic targeting with immune-based therapies and provide insights underscoring the potential of metabolic interventions to resensitize drug-resistant cancers and enhance efficacy for cancer treatment.

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Glucagon receptor antagonism requires further mechanistic attention on α-cell physiology Glucagon receptor (GCGR) antagonism improves glycemic control; however, it also brings adverse effects through unclear underlying mechanisms. Here, we summarize emerging findings about the impact of GCGR blockade on α cells and discuss the challenges and potential of GCGR antagonism on clinical application.

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