Affecting hundreds of millions of women worldwide, polyendocrine metabolic ovarian syndrome (PMOS, formerly polycystic ovary syndrome) carries a significantly higher risk of cardiovascular and metabolic diseases. Here we discuss how renaming this disease reframes a profoundly misunderstood condition for which basic metabolic research remains critically underfunded and fragmented.
Women with polyendocrine metabolic ovarian syndrome (PMOS) represent a particularly challenging patient population, characterized by the convergence of reproductive dysfunction, obesity, insulin resistance, and chronic inflammation. The emergence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) offers a transformative therapeutic opportunity, addressing the complex endocrine and reproductive disturbances that underpin this disorder.
The metabolic mechanisms by which aging blunts CD8+ T cell antitumor and pathogen defense remain unknown. We demonstrate that the aged microenvironment induces CD8+ T cell exhaustion by reducing β-hydroxybutyrate (3HB) bioavailability. Aging represses hepatic BDH1-dependent 3HB synthesis, restricting SLC16A1-mediated 3HB uptake. Hepatic BDH1 ablation recapitulates age-associated CD8+ T cell dysfunction, compromising antiviral and antitumor immunity, whereas 3HB supplementation reverses these deficits via protein β-hydroxybutyrylation. Using a 3HB-derived chemical probe, 3Halk, together with functional screening, we identify PRKAR1B as a primary effector of 3HB signaling. PRKAR1B β-hydroxybutyrylation inhibits the transcription factor cyclic AMP (cAMP)-responsive element modulator (CREM), which activates T cell exhaustion-related gene expression. Age-associated 3HB depletion enhances CREM-dependent transcription, sustaining CD8+ T cell exhaustion. Consistently, the aged microenvironment compromises chimeric antigen receptor (CAR) T antitumor activity, which is substantially restored by 3HB treatment. Collectively, this study uncovers a hepatic metabolism-derived 3HB-CREM axis governing CD8+ T cell immunosenescence, highlighting 3HB as a viable immunorestorative strategy to improve immunotherapy outcomes in aged individuals.
Newborns emerge from a sterile womb into a microbe-rich environment that necessitates balancing immune tolerance with protection. Zheng et al. revealed that hyocholic acids help establish this balance by promoting colonization of beneficial bacteria and modulating T cell differentiation to support immune regulation.1.
Whether reversal of biological age and/or aging is possible is among the most actively debated topics in the field of aging. Here, we consider the meaning of biological age reversal and its burden of proof, focusing on foundational issues and the language we use to debate these questions.
Competitive catabolism mechanistically links increased fat mass to hyperglycemia and hyperinsulinemia. Weilandt et al. develop a differential equation model of metabolic homeostasis incorporating four circulating nutrients and insulin, which extends the framework of the Randle cycle and reveals a physiological circuit by which obesity drives type 2 diabetes.
In contrast to the case in mice, where thermogenesis in brown adipose tissue is mediated via the beta3-adrenergic receptor, it has been suggested that in humans, it is mediated through the beta2-adrenergic receptor. A new study in humans sees thermogenesis through beta2 stimulation-but not in brown adipose tissue.
Lactate, known for its metabolic functions, has recently emerged as a signaling molecule. In a recent issue of Immunity, Guo and colleagues report that lactate is a competitive antagonist of STING and propose an epidermal growth factor receptor (EGFR)-mediated signaling cascade that enhances lactate dehydrogenase A (LDHA) activity, lactate production, and immunosuppression.1.
Vitamin B12 deficiency is common among pregnant and lactating women and is linked to adverse birth outcomes and offspring obesity. In this issue of Cell Metabolism, Liu et al. examine how maternal B12 deficiency mediates these effects through reduced abundance of Bifidobacterium pseudolongum.
Cancer progression is systemically influenced by distant organ dysfunction induced by primary tumors, yet how long-distance tumor-organ crosstalk regulates antitumor immunity remains unclear. Here, we identify host metadherin (MTDH) as a critical regulator of tumor-induced immunosuppression and metabolic reprogramming via tumor-liver interactions. Using Mtdh knockout mouse models, we show that concurrent MTDH loss in hepatocytes and CD8+ T cells enhances effector T cell function and suppresses tumor growth and metastasis. Mechanistically, tumor-derived extracellular vesicles and particles (EVPs) activate Kupffer cells to secrete tumor necrosis factor α (TNF-α) and TGF-β, which suppress hepatic PPARα-mediated lipid oxidation via nuclear factor κB (NF-κB) signaling. MTDH loss restores hepatic lipid catabolism, reduces systemic lipid levels, and promotes mitochondrial metabolic reprogramming in CD8+ T cells under lipid-reduced conditions, thereby boosting antitumor immunity. Genetic or pharmacological targeting of MTDH synergizes with anti-PD-1 therapy. These findings establish host MTDH as a key mediator of tumor-liver crosstalk through metabolic and immune interactions, driving systemic cancer progression.
Throughout life, humans are exposed to a diverse array of xenobiotics originating from diet, pharmaceuticals, and environmental contaminants. Positioned at the interface between the host and the external environment, the gut microbiota is uniquely situated to both sense and modify the effects of these exposures prior to systemic circulation and delivery to their host targets. Growing evidence indicates that the microbiota play critical roles in shaping xenobiotic fate through both direct metabolic transformation and modulation of host detoxification pathways, barrier integrity, and immune signaling. In this review, we summarize the impacts of disease-relevant environmental neurotoxicants on both the brain and microbial composition. We further integrate emerging mechanistic insights illustrating how microbiota-dependent processes can influence host toxicant responses and detoxification capacity, ultimately modifying exposure outcomes. Collectively, these findings position the gut microbiota as central mediators between environmental exposures and neurological health, providing a framework to better understand potential risk-modifying relationships.
Type 2 diabetes (T2D) is a heterogeneous disease, yet current classifications do not capture its clinico-biological complexity or support precision-based care. We developed an endotyping strategy based on routine blood immune cell counts across more than 1,500 individuals with newly diagnosed T2D from three European cohorts. Unsupervised clustering identified four reproducible immune endotypes: severe inflammatory diabetes (SIND), mild inflammatory diabetes (MIND), lymphocyte-rich diabetes (LYRD), and lymphocyte-deficient diabetes (LYDD). Endotypes were stable, robust to de novo clustering, and independent of age, sex, BMI, and HbA1c. SIND and LYDD were associated with increased cardiovascular, renal, and mortality risk across cohorts. Immune endotyping improved cardiovascular risk prediction beyond SCORE2-Diabetes. Multi-omic profiling revealed immunopathological states, with high-risk endotypes characterized by monocyte-driven inflammation and dysregulated lymphocyte programs. The inflammatory profile of SIND was attenuated by IL-1β antagonism and bariatric surgery. These findings establish immune endotyping as a scalable framework for immunometabolic risk stratification in T2D.
Protein restriction extends lifespan across species and engages many hallmarks of aging. We propose that these diverse responses can be understood as components of a single coordinated physiological state. This response involves both cellular nutrient sensing and endocrine and neural coordination, with enhanced longevity emerging from this adaptive response.
Systemic metabolic homeostasis maintains circulating nutrient concentrations within physiological ranges. Insulin is central to this process, lowering circulating levels of glucose, lactate, free fatty acids, and ketones. Yet how the simultaneous homeostasis of these nutrients is achieved remains unclear. Here, we develop a differential equation model of fasting metabolic homeostasis. Grounded in mass action kinetics, this multi-nutrient model reveals how a fixed energy demand naturally leads to competition between major circulating nutrients for oxidation (“competitive catabolism”). Perturbative nutrient infusions confirm this emergent behavior. The multi-nutrient model predicts that insulin promotes fasting glucose homeostasis primarily indirectly by slowing lipolysis. It further identifies a physiological circuit by which obesity causes insulin resistance: increased fat mass promotes lipolysis, releasing fatty acids into circulation that compete with glucose for oxidation, elevating glucose and thus insulin, which acts to restore proper lipid catabolic flux. Thus, quantitative modeling reveals a physiological homeostatic circuit through which obesity causes type 2 diabetes.
The pancreas plays a central role in major human diseases, yet our understanding of its cellular diversity and plasticity remains incomplete. Here, we present a single-cell multiomics atlas of the human pancreas, profiling over four million cells and nuclei from 57 donors across fetal development, adult homeostasis, and type 2 diabetes (T2D). Integrating single-cell RNA sequencing (scRNA-seq)/single-nucleus RNA sequencing (snRNA-seq), snATAC-seq, VASA-seq, spatial transcriptomics (Xenium), and multiplexed proteomics (CODEX), we resolve gene expression, chromatin accessibility, and spatial organization at high resolution. We identify transcriptionally plastic centroacinar-like cells (pCACs) in adults with fetal-like features, delineate endocrine and exocrine lineage trajectories during development, and define HNF1A-defined beta cell epigenetic states. In T2D, we observe shifts in beta cell subtypes and altered regulatory programs. Glucose perturbation of healthy islets reveals cell-type-specific adaptation and stress responses. This atlas provides a foundational framework to understand pancreas biology and the role of cellular plasticity in regeneration and disease.
Brown adipose tissue (BAT) can increase whole-body energy expenditure (EE) and is associated with metabolic health, making it a promising pharmacologic target. In rodents, BAT activation by norepinephrine is mainly mediated by beta3-adrenergic receptor (AR) stimulation. However, recent evidence suggests that, in humans, the beta2-AR may be more important for the activation of BAT than the beta3-AR. We investigated in 12 healthy volunteers whether the specific beta2-AR agonist fenoterol activates human BAT comparable to the natural stimulus, cold exposure. Both interventions robustly increased EE, but only cold exposure activated BAT as assessed by FDG uptake. RNA sequencing (RNA-seq) analysis of human BAT revealed that the expression of beta3-AR, but not of beta2-AR, correlates with the expression of UCP1, the hallmark of thermogenic brown adipocytes. Our data indicate that the beta2-AR is not the main activating receptor of human BAT and suggest that beta2-AR agonism increases EE in tissues other than BAT.
One of the fundamental challenges with human nutrition research is the difficulty of knowing what people actually eat. Asking people to live in the laboratory enables precise control and measurement of food intake, but the environment does not reflect real-world conditions. Here, we present a bedside-to-outside model, which aims to address this gap by combining controlled feeding studies (prioritizing efficacy) with free-living intervention studies (incorporating effectiveness) within the same cohort. This approach will enable translation of the efficacy and effectiveness of dietary interventions with causal inference within the same cohort, offering novel insights into the real-world impact of controlled dietary interventions.
