Traditional metabolic studies rely on bulk tissue analyses, masking the cellular heterogeneity that underlies disease progression. Genetically encoded fluorescent biosensors now enable real-time, single-cell imaging of d...Traditional metabolic studies rely on bulk tissue analyses, masking the cellular heterogeneity that underlies disease progression. Genetically encoded fluorescent biosensors now enable real-time, single-cell imaging of dynamic metabolic processes in the liver. These tools provide insights into the metabolic reprogramming in conditions such as chronic obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). By tracking specific metabolites involved in glycolysis, lipid oxidation, and the tricarboxylic acid (TCA) cycle, biosensors can reveal how these pathways respond to diverse stimuli. In this review we outline the core principles of fluorescent biosensors, provide specific recommendations for their usage, suggest possible applications in liver metabolism research, and discuss current technical challenges as well as emerging opportunities in this rapidly advancing field.
Rodriguez-Cortes B, Gomez-Martínez R, Spenle R
… +4 more, Schwaninger M, Nogueiras R, Rasika S, Prevot V
Trends Endocrinol Metab
· 2025 Nov · PMID 41176453
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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 - special...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.
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 cardiometabol...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.
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 sur...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.
Endocrine-disrupting chemicals (EDCs) pose health risks; yet, conventional in vitro and in vivo testing remains slow, costly, and animal-intensive. Enhanced use of in silico approaches can contribute to earlier and incre...Endocrine-disrupting chemicals (EDCs) pose health risks; yet, conventional in vitro and in vivo testing remains slow, costly, and animal-intensive. Enhanced use of in silico approaches can contribute to earlier and increased detection of potential EDCs. This review evaluates advances in computational toxicology for early identification and prioritization of EDCs, with a focus on estrogen, androgen, thyroid, and steroidogenesis pathways. We discuss various implementations of ligand- and structure-based approaches, covering machine learning, deep learning, docking, molecular dynamics, and free energy methods, as well as their application in a regulatory setting. Moreover, we outline the future prospects necessary to advance the field and improve the in silico identification of potential EDCs.
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 co...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.
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 conver...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.
Trends Endocrinol Metab
· 2026 Jun · PMID 41109800
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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...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.
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, disr...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.
Parkhitko AA, Pathak S, Johnson JE
… +2 more, Mittendorfer B, Steinhauser ML
Trends Endocrinol Metab
· 2026 Jun · PMID 41053925
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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 die...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.
Trends Endocrinol Metab
· 2026 May · PMID 41015698
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Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease posing a major global health concern, closely related to the rising prevalence of obesity. Liver fibrosis is the primary determinant...Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease posing a major global health concern, closely related to the rising prevalence of obesity. Liver fibrosis is the primary determinant of adverse outcomes in MASH. The increasing worldwide prevalence, economic impact, and adverse outcomes of MASH-associated fibrosis have spurred extensive research to elucidate its pathogenesis and to address its treatment. However, the intricate mechanism driving the transition from metabolic dysfunction to clinically significant fibrosis is not fully understood. Moreover, effective therapies, particularly direct antifibrotic agents, are still lacking, despite the recent approval of resmetirom and semaglutide for MASH-associated fibrosis. Here, we review current insights into the mechanism of MASH-associated fibrosis and provide a comprehensive overview of emerging therapeutic strategies.
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 misle...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.
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 finding...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.
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 caus...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.
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-fer...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.
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. T...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.
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 a...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.
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 rese...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.
Trends Endocrinol Metab
· 2026 May · PMID 40915859
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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...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.