Uncoupling protein 1 (UCP1)-independent energy dissipation has been proven to serve physiological functions in beige adipocytes. Here we show that a futile sodium/potassium (Na+/K+) transport cycle is preferentially amplified in mouse and human beige adipocytes and contributes to UCP1-independent energy expenditure. In mice, cold exposure activates a sympathetic–thyroid hormone signaling axis that coordinatedly induces the Na+/K+-ATPase subunit ATP1A2 together with Na+ and K+ channels, increasing bidirectional ion flux across the plasma membrane while maintaining ionic balance. Atp1a2+Kcnk3+ adipocytes are detected in mouse inguinal white adipose tissue after cold exposure. Acute inhibition of Na+/K+-ATPase reduces energy expenditure in mouse and human beige adipocytes, whereas overexpressing Atp1a2 in murine adipocytes potentiates energy expenditure, independent of UCP1. Adipocyte-specific Atp1a2 deletion impairs thermogenic capacity and exacerbates diet-induced obesity in mice. Expression of a human ATP1A2 missense variant reduces ATP1A2-dependent respiration in mouse adipocytes. Together, these identify ion transport as a tunable ATP-consuming mechanism that expands the thermogenic repertoire of beige adipocytes. A futile Na+ K+ transport cycle, which is preferentially active in beige adipocytes, is shown to promote energy expenditure independent of uncoupling protein 1.
Polyendocrine metabolic ovarian syndrome (PMOS) features intertwined reproductive, endocrine and metabolic defects, yet its initiating mechanisms remain incompletely understood. Here we show that an epigenetic mechanism driven by nicotinamide N-methyltransferase (NNMT) in granulosa cells contributes to disease progression in PMOS. We observe that Nnmt overexpression in mouse granulosa cells reduces histone H3 lysine 27 trimethylation (H3K27me3), leading to increased retinoic acid receptor beta (RARB) expression. RARB, in turn, amplifies ovarian androgen synthesis. The resulting androgen excess further suppresses H3K27me3, locking cells into a feedforward loop that sustains hyperandrogenism and disrupts follicle development. Pharmacological inhibition of NNMT restores H3K27me3, disrupts the RARB–androgen feedback circuit, and ameliorates both metabolic and hormonal phenotypes in PMOS models. Our findings suggest NNMT as a regulator of PMOS through metabolic and epigenetic reprogramming. The NNMT–H3K27me3–RARB–androgen axis emerges as a mechanistic nexus linking methionine and epigenetic dysregulation to PMOS pathogenesis and represents a tractable therapeutic target. Nicotinamide N-methyltransferase promotes and sustains hyperandrogenism in polyendocrine metabolic ovarian syndrome through metabolic and epigenetic reprogramming.
Sex-specific differences in metabolic and immune function are shaped by endocrine–immune interactions, yet the complexity of this relationship remains poorly understood. Here, we identify an immune cell-like state of tanycytes, an ependymoglial cell type lining the third ventricle that mediates brain–body communication1,2 in both mice and humans. Using single-cell transcriptomics, we provide a high-resolution cellular map of the mouse and human mediobasal hypothalamus with cross-species comparison of tanycytes. We capture dynamic sex-, oestrous cycle- and high-fat diet-dependent transcriptomic changes in tanycytes, including a cyclic interferon response in tanycytes during the physiological oestrous cycle in female mice. We found that the oestrous cycle, with its changing hormonal milieu, especially oestradiol, affected the brain’s immune responses, characterized by the temporal and cyclic expression of interferon regulatory factor 7 (Irf7) gene, as well as downstream interferon-stimulated genes such as Cxcl10 in tanycytes of female mice, which are associated with increased infiltration of leukocytes and cytokine responses. Irf7 expression in tanycytes of physiological males remained stable and markedly lower, suggesting a distinct immune activation pattern in the brains of cycling females. By targeting oestrogen and interferon signaling in tanycytes, we show that balanced, cyclic leukocyte infiltration into the median eminence may have a role in oestrous cycle maintenance, whereas Irf7 in tanycytes modulates circulating monocyte proportions, revealing brain–immune system communication through tanycytes. Our findings reveal an immune-associated role for tanycytes, with potential implications for understanding the endocrine and immunological mechanisms underlying sex-biased diseases. This study reports a cellular map of the mouse and human mediobasal hypothalamus, revealing an immune cell-like state of tanycytes, which is influenced by sex and the ovarian cycle.
Metabolic homeostasis and female reproductive health are governed by tightly coupled regulatory systems, yet their reciprocal interactions have often been investigated in isolation. In this Review, we synthesize current epidemiological, mechanistic and clinical evidence to propose an integrated framework in which dynamic, bidirectional crosstalk between key metabolic organs and endocrine mediators constitutes a central determinant of female reproductive function across the life course. We delineate how disruption of this integrated network underpins a broad spectrum of reproductive dysfunction, particularly in polyendocrine metabolic ovarian syndrome and reproductive ageing, as well as cardiometabolic risk, highlighting the bidirectional nature of these associations. Finally, we critically evaluate current metabolism-targeted strategies, including lifestyle interventions, metabolic surgery and pharmacological therapies, and discuss emerging opportunities for precision approaches. By integrating mechanistic insights with clinical evidence, this Review reframes female reproductive disorders from a systemic metabolic perspective and outlines future directions for metabolism-focused strategies to improve reproductive health outcomes. This Review highlights the interplay between metabolic homeostasis and female reproductive health and examines metabolism-focused therapeutic strategies for disorders that intersect the reproductive and metabolic systems, such as polyendocrine metabolic ovarian syndrome.
An elevated NADH/NAD+ ratio (NADH-reductive stress) is a hallmark of mitochondrial dysfunction, yet how it drives pathologies ranging from primary mitochondrial disorders to ageing remains poorly understood1,2. Here, we show that mitochondrial respiratory chain inhibition in primary human fibroblasts induces NADH-reductive stress that coexists with profound NADPH depletion. Using the Escherichia coli soluble transhydrogenase (EcSTH)3 to model this redox coupling in cells with intact mitochondria, we demonstrate that perturbation of both NAD(H) and NADP(H) redox pairs elicits metabolomic and transcriptomic reprogramming, culminating in proliferation arrest with senescence features. Notably, normalizing the NADH/NAD+ ratio alone while NADPH depletion persists fails to rescue proliferation in EcSTH-expressing primary human cells, unlike in transformed HeLa cells. Stable isotope tracing reveals that primary fibroblasts rely more on NADPH-driven reductive carboxylation than HeLa cells, explaining why NADH/NAD+ normalization alone is insufficient for rescue. To test this NADPH dependency, we develop a constitutively active Staphylococcus aureus NAD kinase (SaNADK) that expands the mammalian NADP(H) pool. In fibroblasts, SaNADK restores reductive carboxylation and de novo pyrimidine biosynthesis, and reverses proliferation arrest and senescence features. Furthermore, hepatic SaNADK expression in aged male mice partially alleviates transcriptional signatures of inflammation and metabolic dysregulation. Together, these findings establish EcSTH and SaNADK as xenotopic tools for dissecting NAD(P)H redox coupling and provide a framework for counteracting ageing-associated metabolic decline. Using genetically encoded tools that shift the redox equilibrium, the authors identify a link between oxidative and reductive stress, suggesting that simultaneously targeting NAD(P)H homeostasis could be a therapeutic strategy for age-related redox-driven metabolic vulnerabilities.
