Progesterone (P4), the 'pregnancy hormone', plays a pivotal role in the establishment and maintenance of pregnancy by modulating maternal immune responses, thereby promoting immune tolerance toward the semi-allogeneic fe...Progesterone (P4), the 'pregnancy hormone', plays a pivotal role in the establishment and maintenance of pregnancy by modulating maternal immune responses, thereby promoting immune tolerance toward the semi-allogeneic fetus. In this review, we examine the key pathways through which P4 mediates its effects on maternal immune systems. We elucidate P4's immunomodulatory functions, with a focus on how altered P4 signaling may affect immune tolerance toward the fetus and contribute to the pathogenesis of pregnancy complications. We further discuss the potential role of P4 supplementation in improving embryo implantation and preventing miscarriage, as well as its role in modulating immune-mediated pathological conditions during pregnancy, while emphasizing unresolved questions and directions for future investigation.
Citrate metabolism remains poorly understood during mitosis, raising unresolved questions about citrate dynamics, compartmentalization, and targeting in cancer. Here, we propose a comprehensive model to explain how ATP-c...Citrate metabolism remains poorly understood during mitosis, raising unresolved questions about citrate dynamics, compartmentalization, and targeting in cancer. Here, we propose a comprehensive model to explain how ATP-citrate lyase degradation at mitotic onset induces a transient citrate peak, promoting histone H3 phosphorylation and mitotic progression, while mitotic exit relies on acetate-driven lipogenesis.
Mitochondrial dysfunction, circadian disruption, and the accumulation of senescent cells converge to impair metabolic flexibility, a unifying phenotype of obesity and aging. We frame obesity as a nutrient-driven and agin...Mitochondrial dysfunction, circadian disruption, and the accumulation of senescent cells converge to impair metabolic flexibility, a unifying phenotype of obesity and aging. We frame obesity as a nutrient-driven and aging as a time-driven expression of a disrupted mitochondrial-circadian energy code, with shared outputs: impaired substrate switching and flattened energy rhythms. This opinion argues that restoring code integrity, indexed clinically by gains in metabolic flexibility, should guide therapy. Beyond appetite and glycemia, GLP-1 (glucagon-like peptide-1) and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide) agonists may enhance mitochondrial efficiency, support circadian alignment, and temper prosenescent signaling across target tissues (muscle, liver, adipose, islets, and brain). We outline how node-specific and combination strategies (senolytics/senomorphics, mitophagy/NAD support, and chrono-entrainment) could reprogram systemic energy coordination, improve durability of response, and delay age-related metabolic decline.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic, with its inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), driving cirrhosis and hepatocellular carcinoma....Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic, with its inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), driving cirrhosis and hepatocellular carcinoma. Ferroptosis, an iron-dependent form of programmed cell death, is a central pathogenic mechanism in MASLD and MASH. The core drivers of ferroptosis include dysregulated iron metabolism, an increase in peroxidation-susceptible phospholipids, and impaired antioxidant defenses. These changes promote hepatocyte death via a so-called 'ferroptotic explosion' triggered by an increase in FerroLipid, thus driving the transition from a profibrotic state to overt fibrosis. Notably, targeting ferroptosis with iron chelators and ferroptosis inhibitors shows promise as a therapeutic strategy by restoring redox and lipid homeostasis. Furthermore, systemic crosstalk between the liver, adipose tissue, and gut microbiota modulates ferroptotic susceptibility, revealing new avenues for developing precision-targeted therapies.
The most common dietary and plasma fatty acids (FAs), palmitic and oleic acids, have opposing effects on the risk of developing insulin resistance and type 2 diabetes mellitus (T2DM). Palmitic acid has been strongly asso...The most common dietary and plasma fatty acids (FAs), palmitic and oleic acids, have opposing effects on the risk of developing insulin resistance and type 2 diabetes mellitus (T2DM). Palmitic acid has been strongly associated with the presence of T2DM, while oleic acid has not and may even counteract the detrimental effects of palmitic acid. Despite this, recent cohort studies have shown no association or even conflicting results, questioning these roles. This review summarizes the recently discovered molecular mechanisms by which palmitic acid inhibits insulin sensitivity and influences the development and progression of T2DM and how oleic acid can attenuate these effects. It also addresses future challenges in the growing field of dietary FA metabolism in T2DM research, which may help assess their actual impact on this condition.
Trends Endocrinol Metab
· 2026 Mar · PMID 41904104
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Incretin-based therapies have transformed obesity and type 2 diabetes treatment. While current therapeutics safely reduce food intake and lower body weight, a compensatory drop-in basal metabolic rate represents a barrie...Incretin-based therapies have transformed obesity and type 2 diabetes treatment. While current therapeutics safely reduce food intake and lower body weight, a compensatory drop-in basal metabolic rate represents a barrier to sustainable weight loss. Current efforts aim to incorporate energy expenditure (EE) stimulation with the anorectic actions currently available in the clinic. Glucagon receptor agonism, for instance, has demonstrated the benefit of a multipronged increase in EE; however, compensatory challenges persist. We detail peripheral mechanisms that can increase EE independent of activity and the key central mechanisms controlling them. Understanding the complex interplay between these mechanisms and their central modulation is critical for a coordinated engagement of EE pathways to complement and improve current weight loss treatments.
The functional versatility of adipose tissue is mediated by various cell types and their capacity to transition between distinct functional states upon pathophysiological stimuli. Recent advances in single-cell transcrip...The functional versatility of adipose tissue is mediated by various cell types and their capacity to transition between distinct functional states upon pathophysiological stimuli. Recent advances in single-cell transcriptomics have enabled the identification of novel and numerous cell types and states of adipocytes, adipose stem and progenitor cells, immune cells, vascular cells, and mesothelial cells. Significant efforts have been made to understand the key features and underlying processes of the cell subpopulations and to elucidate the cellular mechanisms of adipose tissue plasticity. In this review, we describe current knowledge of heterogeneous cell types and states in adipose tissue and emerging techniques to characterize them, offering fundamental knowledge for studying adipose tissue in the single-cell era.
Obesity and (white) adipose tissue (AT) inflammation are closely linked to endothelial dysfunction (ED) and neurological conditions associated with an impaired blood-brain barrier (BBB). AT-derived extracellular vesicles...Obesity and (white) adipose tissue (AT) inflammation are closely linked to endothelial dysfunction (ED) and neurological conditions associated with an impaired blood-brain barrier (BBB). AT-derived extracellular vesicles (AT-EVs), cell-derived particles involved in intercellular and interorgan communication, have emerged as active mediators of this process, yet the underlying mechanisms remain largely elusive. Molecular and functional profiling of AT-EVs' cargo has revealed obesity-related changes in miRNAs, proteins, and lipids that drive ED, primarily by activating proinflammatory signaling in endothelial cells. Importantly, these cargo changes in AT-EVs suggest a broader role, potentially modulating the neurovascular unit, thereby linking AT-EVs to brain pathologies. Collectively, these insights highlight AT-EVs as critical players in obesity-related ED and support their causal role in promoting neurological disease progression.
One-carbon (1C) metabolism serves as a central hub governing anabolism-supporting and epigenetic modification processes through its shunts, the tetrahydrofolate (THF) cycle, and the methionine cycle. The 1C shunts exhibi...One-carbon (1C) metabolism serves as a central hub governing anabolism-supporting and epigenetic modification processes through its shunts, the tetrahydrofolate (THF) cycle, and the methionine cycle. The 1C shunts exhibit divergent characteristics in mammalian cells in terms of methyl sources, regulatory networks, and supporting functions. Under specific physiological and pathological contexts, 1C metabolic shunts exhibit distinct biological functions and orchestrate metabolic crosstalk between cells and across organs. These findings have significantly advanced our understanding of systemic compartmentalization and functional cooperation between the divergent 1C shunts. In this review, we explore the intricate interplays and divergent biological roles between the THF and methionine cycles at the molecular, cellular, and systemic levels and further propose innovative avenues for research and clinical applications.
Cancer cachexia lacks effective therapies due to an incomplete understanding of its upstream drivers. A recent study by Morigny et al. identifies one-carbon metabolism as a conserved endocrine-metabolic program that link...Cancer cachexia lacks effective therapies due to an incomplete understanding of its upstream drivers. A recent study by Morigny et al. identifies one-carbon metabolism as a conserved endocrine-metabolic program that links tumor signals to skeletal muscle hypermetabolism and systemic energy imbalance, highlighting methyl-donor pathways as actionable targets for treating cachexia.
Trends Endocrinol Metab
· 2026 Mar · PMID 41887981
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The compartmentalization of NAD(H) and NADP(H) is fundamental to cellular metabolism, enabling precise coordination of redox balance, biosynthetic reactions, and energy homeostasis. Within mitochondria, NADP(H) has long...The compartmentalization of NAD(H) and NADP(H) is fundamental to cellular metabolism, enabling precise coordination of redox balance, biosynthetic reactions, and energy homeostasis. Within mitochondria, NADP(H) has long been viewed as a redox buffer supporting antioxidant defense and reductive biosynthesis. Emerging evidence, however, reveals that mitochondrial NADP(H) also drives oxidative metabolism and metabolic flexibility. Loss of the mitochondrial NAD kinase, which phosphorylates NAD(H) to generate mitochondrial NADP(H), disrupts NADP(H)-dependent pathways that sustain oxidative metabolism and systemic energy balance. These advances reposition mitochondrial NADP(H) as an integrative regulator that links redox homeostasis with energy metabolism across cellular and systemic levels, with broad implications for metabolic disease.
Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are leading causes of global liver morbidity. Addressing the complex interplay of metabolic and alcohol-related...Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are leading causes of global liver morbidity. Addressing the complex interplay of metabolic and alcohol-related factors has led to the 'MetALD' (metabolic dysfunction and alcohol-associated liver disease) concept, categorizing individuals with metabolic dysfunction who consume alcohol beyond MASLD thresholds but below ALD criteria. MetALD is associated with increased mortality and severe liver outcomes, including accelerated progression to advanced fibrosis, cancer, and cardiovascular complications. Accurate diagnosis requires precise alcohol quantification; novel biomarkers, particularly blood phosphatidylethanol, effectively address this by overcoming the frequent underreporting of ethanol intake. This review provides an overview of MetALD diagnostic and management strategies, emphasizing the need for integrated therapeutic approaches to improve patient outcomes.
Skeletal muscle exhibits remarkable metabolic plasticity, with mitochondria playing a central role in adapting to energy demands during exercise. These organelles form a dynamic and specialized system capable of remodeli...Skeletal muscle exhibits remarkable metabolic plasticity, with mitochondria playing a central role in adapting to energy demands during exercise. These organelles form a dynamic and specialized system capable of remodeling to meet metabolic challenges. Recent studies demonstrate that exercise not only stimulates mitochondrial biogenesis but also engages finely tuned quality-control mechanisms to sustain energy efficiency and performance. A key adaptation is mitochondrial fuel flexibility, the capacity to switch between lipid and carbohydrate oxidation, which underlies endurance and metabolic health. Importantly, efficient lipid utilization, rather than low lipid content, explains why trained muscle can accumulate lipids while remaining insulin sensitive. Here, we review emerging insights into how exercise reprograms skeletal muscle mitochondria to optimize fuel use and highlight implications for metabolic disease.
Following cold exposure, brown adipose tissue (BAT) generates heat through uncoupling protein 1-mediated thermogenesis. Intracellular lipolysis, mediated by neutral lipases, provides nonesterified fatty acids that fuel B...Following cold exposure, brown adipose tissue (BAT) generates heat through uncoupling protein 1-mediated thermogenesis. Intracellular lipolysis, mediated by neutral lipases, provides nonesterified fatty acids that fuel BAT mitochondrial respiration and uncoupling. In the present review, we provide current knowledge on the neuroendocrine control of intracellular lipolysis in brown adipocytes and discuss how the intracellular lipolytic machinery is important for the thermogenic activity of BAT. We also examine the importance of glycerolipid cycling and white adipose tissue (WAT) lipolysis in cold-induced thermogenesis. We discuss recent evidence suggesting a significant role for other organs, such as the liver and cardiovascular system, in nonshivering thermogenesis. Beyond BAT, interorgan glycerolipid cycling between WAT and lean organs may contribute significantly to whole-body thermogenic responses.
The circadian system regulates daily rhythms in metabolism and hormone secretion; however, in type 2 diabetes, disrupted clock gene oscillations in skeletal muscle impair metabolic regulation. Insulin resistance, mitocho...The circadian system regulates daily rhythms in metabolism and hormone secretion; however, in type 2 diabetes, disrupted clock gene oscillations in skeletal muscle impair metabolic regulation. Insulin resistance, mitochondrial dysfunction, and chronic inflammation contribute to this circadian misalignment. Exercise can restore circadian rhythms, yet optimal timing has only recently been explored. In individuals with type 2 diabetes, afternoon and evening exercise yield greater improvements in glycemic control and insulin sensitivity compared with morning exercise, with intensity appearing to influence these effects. Thus, appropriately timed exercise may help correct circadian disruption and glucose dysregulation in type 2 diabetes. Nonetheless, further research is needed to elucidate the underlying mechanisms of exercise timing effects and establish evidence-based recommendations for clinical practice.
Trends Endocrinol Metab
· 2026 Mar · PMID 41851000
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Familial partial lipodystrophy 2 (FPLD2) is a rare disease characterized by selective adipose tissue loss, expansion, and dysfunction, caused by pathogenic variants in LMNA encoding nuclear lamins A and C. Here, we synth...Familial partial lipodystrophy 2 (FPLD2) is a rare disease characterized by selective adipose tissue loss, expansion, and dysfunction, caused by pathogenic variants in LMNA encoding nuclear lamins A and C. Here, we synthesize current evidence on how nuclear shape abnormalities, impaired mechanosensing, blocked adipogenesis, chromatin remodeling, and altered lamin-binding partner interactions may contribute to FPLD2 pathology. Emerging data highlight chromatin and transcriptional dysregulation of lipogenic, mitochondrial, and inflammatory genes as central drivers, with other mechanisms acting in complementary ways. We also discuss depot-specific transcriptional remodeling that may explain differential adipose loss and expansion in FPLD2. Understanding how these mechanistic pathways converge across FPLD2 and other laminopathies may reveal new therapeutic targets to preserve adipose function.
RNA modifications constitute a dynamic regulatory code governing RNA structure, fate, and translation. Modified nucleosides, long dismissed as metabolic waste, are now recognized as stable biomarkers and active signaling...RNA modifications constitute a dynamic regulatory code governing RNA structure, fate, and translation. Modified nucleosides, long dismissed as metabolic waste, are now recognized as stable biomarkers and active signaling messengers involved in metabolic and reproductive regulation. Advances in methods for detecting modified nucleosides could accelerate translation toward clinical diagnostics and monitoring.
Metabolomes change with age. Yet, fluxomics points to a contradiction: Jankowski et al. in Cell Metabolism report shifts in metabolite concentrations in aged mice, alongside largely preserved metabolite fluxes, evoking i...Metabolomes change with age. Yet, fluxomics points to a contradiction: Jankowski et al. in Cell Metabolism report shifts in metabolite concentrations in aged mice, alongside largely preserved metabolite fluxes, evoking important questions on the nature of age-related metabolic disturbances. We discuss how this might recalibrate our understanding of aging metabolism.