Cholesterol–LXR axis in metabolic regulation of liver fibrosis and hepatocarcinogenesis 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.

Online Now: Cholesterol–LXR axis in metabolic regulation of liver fibrosis and hepatocarcinogenesis #trends #endocrinology #metabolism

H19 long noncoding RNA in maternal obesity-driven metabolic programming Maternal obesity alters H19 expression, disrupting epigenetic modifications during embryonic development, impairing muscle development, promoting fibrogenesis, and perturbing metabolic homeostasis, thereby predisposing offspring to fibrosis and metabolic dysfunction. Metformin in early pregnancy may mitigate these alterations by modulating placental H19 through AMP-activated protein kinase (AMPK) and epigenetic regulation, improving offspring metabolic health.

Online Now: H19 long noncoding RNA in maternal obesity-driven metabolic programming #trends #endocrinology #metabolism

So cool to have Trends in Endocrinology and Metabolism highlighting research from the lab!

Thanks @bdmanning.bsky.social
@cp-trendsendomet.bsky.social
www.sciencedirect.com/science/arti...

A fuel partitioning perspective on appetite suppression by GLP-1 receptor agonists 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.

Online Now: A fuel partitioning perspective on appetite suppression by GLP-1 receptor agonists #trends #endocrinology #metabolism

Understanding hypoparathyroidism as a disease of broad functional deficiency 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.

Online Now: Understanding hypoparathyroidism as a disease of broad functional deficiency #trends #endocrinology #metabolism

Delighted to see over review and concept on the cover of this month's @cp-trendsendomet.bsky.social where we cover GLP-1s & SGLT2i as anti-inflammatory agents- co-authored with @nickjonesimmuno.bsky.social

LIFe of the sugar-free party in cancer metabolism 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.

Online Now: LIFe of the sugar-free party in cancer metabolism #trends #endocrinology #metabolism

Calling metabolism researchers across the spectrum; from those investigating individual molecules, to those carrying out population studies and clinical trials.

Submit an abstract for the 4th Metabolism in Health & Disease conference by 13 April 2026: bit.ly/3Zjr29H @fusionconf.bsky.social

Register early and save

Don’t miss @jourdainlab.bsky.social present his talk “Harnessing nutrients and auxotrophies to study mitochondria” at Cell Press Symposia #CSMito2026
Early bird registration ends Friday!
http://dlvr.it/TRw8wL

Estradiol Estradiol (E2; primarily 17β-estradiol and, to a much lesser extent, 17α-estradiol) is the most potent endogenous estrogen and a key regulator of reproductive and metabolic physiology. Beyond its classical role in reproduction, E2 integrates endocrine, paracrine, and intracrine signals to preserve whole-body energy homeostasis. In metabolic tissues, where estrogen receptor α (ERα) is the predominant isoform, E2 regulates glucose and lipid metabolism, mitochondrial function, fuel utilization, inflammation, and cardiometabolic resilience in a sex- and age-dependent manner, contributing to sexual dimorphism.

Online Now: Estradiol #trends #endocrinology #metabolism

Glycine (aminoacetic acid) Glycine is mainly produced from serine by serine hydroxymethyltransferase (SHMT1/2) in both the cytoplasm and mitochondria, with additional contributions from threonine, choline, and glycolate metabolism. Functioning as a key metabolic hub, glycine integrates multiple biosynthetic pathways, including one-carbon metabolism and the production of glutathione (GSH), heme, and creatine.

Online Now: Glycine (aminoacetic acid) #trends #endocrinology #metabolism

Lipid signaling networks in pancreatic cancer progression and therapeutic perspectives 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.

Online Now: Lipid signaling networks in pancreatic cancer progression and therapeutic perspectives #trends #endocrinology #metabolism

Flip the fuel, and the heat is on! Carnitine synthesis as a physiological mediator of fuel adaptation 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.

Online Now: Flip the fuel, and the heat is on! Carnitine synthesis as a physiological mediator of fuel adaptation #trends #endocrinology #metabolism

Online Now: Substrate supply, compartmentation, and utilization in hepatic de novo lipogenesis #trends #endocrinology #metabolism

A new era in childhood obesity 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.

Online Now: A new era in childhood obesity #trends #endocrinology #metabolism

The immunoregulatory role of progesterone during embryo implantation and pregnancy 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.

Online Now: The immunoregulatory role of progesterone during embryo implantation and pregnancy #trends #endocrinology #metabolism

The 3M roles of the gut microbiome in pharmacotherapy for diabetes: mediator, modifier, and marker 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.

Online Now: The 3M roles of the gut microbiome in pharmacotherapy for diabetes: mediator, modifier, and marker #trends #endocrinology #metabolism

Citrate-mediated control of chromatin and mitosis 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.

Online Now: Citrate-mediated control of chromatin and mitosis #trends #endocrinology #metabolism

Reprogramming the mitochondrial–circadian energy code with incretins 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.

Online Now: Reprogramming the mitochondrial–circadian energy code with incretins #trends #endocrinology #metabolism

Targeting ferroptosis to halt MASLD and MASH 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.

Online Now: Targeting ferroptosis to halt MASLD and MASH #trends #endocrinology #metabolism

Palmitic and oleic acids in type 2 diabetes mellitus 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.

Online Now: Palmitic and oleic acids in type 2 diabetes mellitus #trends #endocrinology #metabolism

Improving incretin-mediated body weight loss via energy expenditure 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.

Online Now: Improving incretin-mediated body weight loss via energy expenditure #trends #endocrinology #metabolism

Polyamines Polyamines are small, positively charged metabolites ubiquitous in living organisms, with putrescine, spermidine, and spermine as the main types in mammalian cells. They act as critical substrates for protein synthesis and key signaling molecules, essential for tissue homeostasis and regulating immune cell proliferation, differentiation, and function. Additionally, polyamines are involved in fundamental processes such as aging and tumor progression, underscoring their broad physiological and pathophysiological significance.

Online Now: Polyamines #trends #endocrinology #metabolism

Acetate Acetate/acetic acid (CH3COO−/CH3COOH) acts as intracellular metabolic and extracellular signaling molecules. Intracellular concentration is an order of magnitude lower than that in the plasma, with the latter mostly supplied by gut microbiota. In animal cells, acetate is not a major end product of metabolism but is continuously produced by protein deacetylation, metabolic stress-induced acetyl-CoA overflow, peroxisomal lipid oxidation, and ethanol metabolism. It is rapidly reconverted to acetyl-coenzyme A (CoA) and utilized as the substrate for the tricarboxylic acid (TCA) cycle (mitochondria), as well as for fatty acid and cholesterol synthesis (cytosol and endoplasmic reticulum).

Online Now: Acetate #trends #endocrinology #metabolism

Endocrine control of one-carbon metabolism in cachexia 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.

Online Now: Endocrine control of one-carbon metabolism in cachexia #trends #endocrinology #metabolism

Exploring cell types and their dynamic states in adipose tissue 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.

Online Now: Exploring cell types and their dynamic states in adipose tissue #trends #endocrinology #metabolism

Adipose tissue-derived extracellular vesicles as drivers of endothelial dysfunction in obesity 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.

Online Now: Adipose tissue-derived extracellular vesicles as drivers of endothelial dysfunction in obesity #trends #endocrinology #metabolism

Interplays and functional divergences of one-carbon metabolic shunts 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.

Online Now: Interplays and functional divergences of one-carbon metabolic shunts #trends #endocrinology #metabolism

Mitochondrial NADP(H) integrates redox and metabolism 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.

Online Now: Mitochondrial NADP(H) integrates redox and metabolism #trends #endocrinology #metabolism

Regulation of skeletal muscle mitochondrial fuel utilization during exercise 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.

Online Now: Regulation of skeletal muscle mitochondrial fuel utilization during exercise #trends #endocrinology #metabolism