Brain iron dysregulation is linked to stress-related disorders, but its functional role remains opaque. Wang et al. define 'ferroplasticity', a form of experience-dependent, iron-mediated synaptic remodeling driven by a...Brain iron dysregulation is linked to stress-related disorders, but its functional role remains opaque. Wang et al. define 'ferroplasticity', a form of experience-dependent, iron-mediated synaptic remodeling driven by a glucocorticoid-transferrin receptor 1-α-synuclein axis. This positions iron as an active signal rewiring emotional circuits in anxiety, with profound implications for a growing global health crisis.
Avolio A, Morciano C, Gugliandolo S
… +10 more, Splendore A, Capece U, Mezza T, Di Giuseppe G, Ciccarelli G, Soldovieri L, Brunetti M, Pontecorvi A, Giaccari A, Cinti F
β-Cell dedifferentiation is a key mechanism of β-cell failure in type 2 diabetes (T2D). To survive metabolic stress, β-cells adopt a progenitor-like state, allowing for potential redifferentiation and T2D remission when...β-Cell dedifferentiation is a key mechanism of β-cell failure in type 2 diabetes (T2D). To survive metabolic stress, β-cells adopt a progenitor-like state, allowing for potential redifferentiation and T2D remission when conditions improve. Glucolipotoxicity is a known driver of β-cell failure, but the triggers of dedifferentiation remain unclear. Recent research has focused on pancreatic islet innervation, particularly the role of noradrenergic fibers in inhibiting insulin secretion. An increase in noradrenergic fibers has been correlated with β-cell dedifferentiation in humans, suggesting a role in T2D pathogenesis. This review explores the link between β-cell dedifferentiation and pancreatic noradrenergic innervation across murine and human models and examines the possibility of targeting innervation to reverse dedifferentiation, restore insulin secretion, and achieve T2D remission.
Parental metabolic health prior to conception can shape offspring's metabolic risk through germline epigenetic reprogramming. This forum advances a preconception-centered, dual-germline prevention paradigm that positions...Parental metabolic health prior to conception can shape offspring's metabolic risk through germline epigenetic reprogramming. This forum advances a preconception-centered, dual-germline prevention paradigm that positions interventions before fertilization as an upstream opportunity for the primary prevention of metabolic disease.
Black women and their infants experience higher mortality rates than their White counterparts. While systemic racism, socioeconomic disadvantage, and environmental stressors are recognized contributors, physiological pat...Black women and their infants experience higher mortality rates than their White counterparts. While systemic racism, socioeconomic disadvantage, and environmental stressors are recognized contributors, physiological pathways that mediate their effects on health disparities remain poorly understood. This review explores mechanisms through which stress-related epigenetic processes may contribute to more adverse pregnancy outcomes in Black women. Increased uteroplacental vascular resistance, oxidative stress, and inflammation are established mechanisms associated with leading causes of maternal and infant mortality, but there are differences in the expression of these mechanisms between Black and White women. We propose that these differences, which may reflect differences in social and environmental exposures, can help to explain the disparity in maternal and infant mortality rates between Black and White people.
Trends Endocrinol Metab
· 2026 Apr · PMID 42055925
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Heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Mechanical remodeling of the cardiac extracellular matrix (ECM) impairs cardiomyocyte contractility and causes cardiac stiffening. Chronic...Heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Mechanical remodeling of the cardiac extracellular matrix (ECM) impairs cardiomyocyte contractility and causes cardiac stiffening. Chronic low-grade inflammation, often fueled by metabolic stress, is emerging as a central regulator of cardiac stiffening and HF. A central axis in this process is the dynamic crosstalk between immune cells, cardiac fibroblasts, and the altered mechanical and metabolic cues they sense under stress. These interactions govern ECM synthesis, crosslinking, and tissue stiffening, which simultaneously perpetuate inflammation and mechanical stress in a vicious cycle. This review provides a view on the implications of tissue mechanics on inflammation, metabolic regulation, and cellular crosstalk in HF, and how this interplay may be therapeutically modulated.
Type 2 diabetes (T2D) is increasingly associated with cognitive impairment and dementia, reflecting the combined impact of metabolic dysregulation, vascular injury, neuroinflammation, and defective brain insulin signalin...Type 2 diabetes (T2D) is increasingly associated with cognitive impairment and dementia, reflecting the combined impact of metabolic dysregulation, vascular injury, neuroinflammation, and defective brain insulin signaling. While this link is now well recognized, it remains unclear whether cognitive decline in T2D is modifiable. This review focuses on emerging neuroprotective strategies, highlighting both pharmacological and lifestyle-based interventions. Recent evidence indicates that some glucose-lowering agents, notably metformin, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists, may exert pleiotropic effects on brain metabolism, inflammation, and vascular integrity beyond glycemic control. We propose a conceptual shift in T2D management in which cognitive preservation becomes an explicit therapeutic objective, integrating metabolic control with targeted brain-protective approaches.
Metabolic dysfunction-associated steatotic liver disease is increasing worldwide, and its progression to metabolic dysfunction-associated steatohepatitis (MASH) and ultimately hepatocellular carcinoma (HCC) remains a maj...Metabolic dysfunction-associated steatotic liver disease is increasing worldwide, and its progression to metabolic dysfunction-associated steatohepatitis (MASH) and ultimately hepatocellular carcinoma (HCC) remains a major clinical challenge. In this review, we discuss the role of liver X receptors (LXRs), transcriptional regulators of fatty acid synthesis, and cholesterol balance, which play an apparently paradoxical metabolic role: while their activation increases lipogenesis, driving steatosis, their inhibition leads to harmful cholesterol buildup and inflammation, central to the pathogenesis of MASH and HCC. In HCC, disrupted LXR signalling prevents cholesterol efflux, fuelling tumour growth. Therapeutic strategies targeting LXRs must therefore be stage-specific and cell type-specific to avoid worsening liver injury.
Behnke A, Shaulson E, Pontzer H
… +2 more, Kempes CP, Picard M
Trends Endocrinol Metab
· 2026 Apr · PMID 42025458
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Evolved constraints to human energy transformation force the body-brain system to operate an economy of energy. To survive and thrive, an organism's finite internal energy resources must be dynamically reallocated, forci...Evolved constraints to human energy transformation force the body-brain system to operate an economy of energy. To survive and thrive, an organism's finite internal energy resources must be dynamically reallocated, forcing trade-offs from organelle to organism. Building on an energy trade-off framework integrating life history theory and cellular biology, we propose that energy trade-offs occur between three main classes of processes relevant to health: (i) vital, (ii) stress, and (iii) growth, maintenance, and repair (GMR). Competing demands for these processes exist within a hierarchy of energy needs where more 'urgent' vital- and stress-related functions are prioritized by suppressing longevity-promoting growth, maintenance, and repair processes. The energy constraint model of human health provides an energy-based framework to address health/disease dynamics across the lifespan.
Appetite suppression by glucagon-like peptide-1 receptor agonists (GLP-1RAs) is thought to result from direct actions on neural circuits controlling food intake. In this article, we (1) propose that a shift in fuel parti...Appetite suppression by glucagon-like peptide-1 receptor agonists (GLP-1RAs) is thought to result from direct actions on neural circuits controlling food intake. In this article, we (1) propose that a shift in fuel partitioning toward fat oxidation caused by GLP-1RAs contributes to appetite suppression and (2) explore potential lines of research to test this hypothesis.
Hypoparathyroidism (HypoPT) is a rare disease defined by undetectable, low, or inappropriately normal parathyroid hormone (PTH) concentrations in the presence of hypocalcemia. Calcium and active vitamin D are often used...Hypoparathyroidism (HypoPT) is a rare disease defined by undetectable, low, or inappropriately normal parathyroid hormone (PTH) concentrations in the presence of hypocalcemia. Calcium and active vitamin D are often used for the treatment of HypoPT but do not address the underlying lack of physiological PTH activity. In this review, we discuss how the chronic inadequacy of PTH leads to broad functional consequences. This functional deficiency results in a wide spectrum of symptoms, impaired functioning and quality of life, and significant economic and healthcare costs. We consider how kidney complications could develop in patients with HypoPT and highlight recent developments in understanding the heterogeneity of bone health in HypoPT, including certain patient populations.
Trends Endocrinol Metab
· 2026 Jun · PMID 41963134
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Tumor cells can thrive in nutrient-scarce environments. Glucose deprivation can trigger adaptive responses that coordinate cell-cell communication within the tumor microenvironment (TME). Recently, Luciano-Mateo et al. d...Tumor cells can thrive in nutrient-scarce environments. Glucose deprivation can trigger adaptive responses that coordinate cell-cell communication within the tumor microenvironment (TME). Recently, Luciano-Mateo et al. demonstrated that glucose withdrawal promotes cancer cell secretion of the cytokine leukemia inhibitory factor (LIF), which exerts protumorigenic effects on the TME.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, driven by aggressive biology, profound therapy resistance, and scarce treatment options. Beyond classical metabolic rewiring, recent discoveri...Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, driven by aggressive biology, profound therapy resistance, and scarce treatment options. Beyond classical metabolic rewiring, recent discoveries reveal that lipid metabolism plays a central and previously underappreciated role in PDAC progression. Emerging evidence shows that fatty acids, cholesterol, lysophospholipids, sphingolipids, and oxidized lipid species actively shape oncogenic signaling, influence stromal and immune interactions, and contribute to metastasis and treatment evasion. In this review, we highlight these recent advances and discuss how lipid-driven circuits intersect with major oncogenic pathways, including KRAS effectors and phosphoinositide 3-kinase-AKT. By integrating mechanistic insights with therapeutic perspectives, we outline new opportunities to exploit lipid-based vulnerabilities in pancreatic cancer.
Trends Endocrinol Metab
· 2026 May · PMID 41933958
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To what extent does de novo carnitine synthesis in tissues dictate their fuel preference? Recently, Auger et al. identified Solute Carrier 25A45 (SLC25A45) as a mitochondrial trimethyllysine importer for carnitine biosyn...To what extent does de novo carnitine synthesis in tissues dictate their fuel preference? Recently, Auger et al. identified Solute Carrier 25A45 (SLC25A45) as a mitochondrial trimethyllysine importer for carnitine biosynthesis. SLC25A45 enables certain tissues to constitutively utilize fatty acids as fuel and, upon bioenergetic crisis, mediates a fuel switch that restores homeostasis.
Hepatic de novo lipogenesis (DNL) is a fundamental process that supports energy storage, membrane biogenesis, and lipid signaling. However, chronically elevated hepatic DNL is a risk factor for insulin resistance and liv...Hepatic de novo lipogenesis (DNL) is a fundamental process that supports energy storage, membrane biogenesis, and lipid signaling. However, chronically elevated hepatic DNL is a risk factor for insulin resistance and liver fat accumulation. If sustained, this can drive inflammation and fibrosis, with progression to cirrhosis and sometimes hepatocellular carcinoma, as well as numerous cardiometabolic comorbidities. Therefore, new discoveries on the basic mechanisms that control hepatic DNL may enable therapeutic modulation that improves major health outcomes. This review synthesizes recent advances in how the liver channels lipogenic substrates through mitochondrial and cytosolic pathways into DNL. It also highlights how these substrates regulate lipogenic flux by supplying cytosolic acetyl-CoA and NADPH.
Advances in our understanding of hypothalamic control of energy homeostasis have resulted in the identification of genetic forms of obesity, both syndromic and nonsyndromic, with some precision treatments now being emplo...Advances in our understanding of hypothalamic control of energy homeostasis have resulted in the identification of genetic forms of obesity, both syndromic and nonsyndromic, with some precision treatments now being employed. In this review article, we examine the progress being made in identifying new genes involved in the hypothalamic leptin-melanocortin system and their possible implications in obesity, as well as other potential clinical features. We include an update on clinical trials in genetic obesity with specific pharmacological treatments, such as agonists for the melanocortin 4 receptor, and for glucagon-like peptide-1 receptor. The possibility of employing new precision drug targets in specific forms of obesity is modifying the approach to disease treatment in the pediatric clinic.
The rising global prevalence of type 2 diabetes mellitus (T2DM) presents major challenges to healthcare systems; thus, more effective treatment strategies are urgently needed. In this context, the growing recognition of...The rising global prevalence of type 2 diabetes mellitus (T2DM) presents major challenges to healthcare systems; thus, more effective treatment strategies are urgently needed. In this context, the growing recognition of the gut microbiome's role in T2DM pharmacotherapy has shifted attention toward integrating microbiome-derived mechanisms to optimize drug response. This review proposes a structured '3M' framework that classifies the gut microbiome's roles in T2DM pharmacotherapy into three translational categories: mediator of drug action, modifier of therapeutic response, and marker for predicting efficacy or intolerance, based on recent clinical and mechanistic insights. Together, these insights support a translational framework that may guide the integration of microbiome-informed strategies into future T2DM pharmacotherapy.