Bone marrow adipose tissue (BMAT) is a specialized fat depot located within the medullary cavities of long bones, accounting for over 10% of total body fat in humans. Once considered a passive filler, BMAT is now recognized as a metabolically active endocrine organ that influences bone homeostasis and systemic metabolism. Unlike white or brown adipose tissue, BMAT derives from bone marrow mesenchymal stromal cells and resides in close proximity to hematopoietic and stromal niche cells. Notably, BMAT expands in both obesity and under caloric restriction, highlighting its distinct regulatory mechanisms. Emerging evidence suggests that BMAT undergoes context-specific remodeling during metabolic stress, with obesity-associated BMAT acquiring inflammatory and metabolically dysfunctional features, whereas formation of energy deficit-associated BMAT may reflect adaptive stress responses within the bone marrow niche. This review synthesizes recent advances in BMAT heterogeneity, metabolic programming, and BMAT-hematopoietic interactions across states of nutrient excess and energy deficit.
Glucocorticoids are essential steroid hormones whose excess – whether from therapeutic use or endogenous overproduction – causes significant bone loss and fracture risk. In bone, glucocorticoids act directly on osteoblasts, osteocytes, and osteoclasts via the glucocorticoid receptor and indirectly through bone marrow adipose tissue and shared mesenchymal progenitors. An important mechanism involves suppression of canonical Wnt/β-catenin signaling, which reduces osteogenesis and increases marrow adiposity. Several pharmacological and plant-derived compounds with therapeutic promise target Wnt and other glucocorticoid-regulated signaling pathways. Emerging evidence highlights intermediary and potential therapeutic roles for niche-derived extracellular vesicles in bone loss associated with glucocorticoids. Comparing results between studies is complicated by underreporting of environmental and biological variables that may interact with glucocorticoids to affect bone or the marrow niche, which underscores the need for greater methodological rigor in preclinical studies.
Transgender and gender-diverse (TGD) individuals face unique cardiometabolic risks shaped by hormone exposure, social determinants, and structural inequities. This review summarizes the recent advances in understanding how gender-affirming hormone therapy affects cardiovascular outcomes, lipid metabolism, insulin sensitivity, and body composition. Estrogen therapy in transfeminine people may increase thrombotic risk and alter lipid profiles, while testosterone therapy in transmasculine individuals affects high-density lipoprotein (HDL) and hematocrit. Data in adolescents and individuals on puberty blockers remain limited. Social stressors, healthcare discrimination, and systemic barriers further compound risk. Methodologic challenges, including inadequate cohort designs and binary reference norms hinder progress. Further research must prioritize inclusive, longitudinal studies that integrate clinical and social exposures to improve cardiometabolic care for TGD populations.
Iron metabolism has emerged as a key regulator of immune function influencing both systemic and cellular metabolism. During physiological stress or infection, immune cells must tightly regulate iron availability and anabolic metabolism, ensuring sufficient supply to support immune effector functions while simultaneously restricting access to invading pathogens. This review examines the critical dependence of immunometabolism on efficient iron homeostasis, highlighting the bidirectional interplay between these processes, from the citric acid cycle, oxidative phosphorylation and glycolysis to the pentose phosphate pathway and fatty acid oxidation. We further discuss how disruptions in iron handling and immunometabolism contribute to health and disease in the lung and consider how these insights may inform novel therapeutic strategies.
Bone marrow adipose tissue (BMAT) is a dynamic component of the marrow microenvironment that influences tumor persistence, therapy response, and skeletal integrity. Recent work shows that marrow adipocytes function not only as metabolic partners for malignant cells but also as stress-responsive components of bone marrow niche remodeled by tumor progression and cancer therapy. Reciprocal signaling between tumor cells and adipogenic lineage populations alters lipid mobilization, redox balance, and stromal differentiation, creating microenvironments that support tumor cell survival under metabolic and therapeutic stress. Cancer therapies can reprogram adipocyte and stromal populations, generating inflammatory or senescent niches that persist beyond active disease and influence residual tumor behavior. At the same time, adipogenic cells contribute to marrow repair, highlighting the need to distinguish regenerative from tumor-permissive states. Spatial heterogeneity across skeletal sites, and its evolution during treatment, adds an additional layer of complexity to how BMAT regulates tumor behavior in bone. Here, we review recent advances that are redefining the role of BMAT in cancer progression and therapy response.
Carboxylesterases (CEs), from the alpha/beta hydrolase superfamily, play a major role in the hydrolysis of a wide variety of compounds, including fatty acids, hormones, and xenobiotics. Because of their promiscuous nature, CEs are detoxification enzymes also involved in diverse physiological functions, such as lipid metabolism. To date, several in vitro and in vivo evidences have reported the responsiveness of CEs to pesticides, plastic additives, or flame retardants in different aquatic species. Then, considering the role of CEs as the primary detoxification mechanism, this review will briefly examine 1) the link between environmental pollutants and CEs as a marker for general toxicity; 2) the role of CEs in environmental monitoring of aquatic fauna; 3) the relationship between CEs and the endocrine system, particularly, in lipid metabolism; and 4) CEs as key players in endocrine disruption.
Macrophages are highly adaptable innate immune cells whose functional states are shaped by microenvironmental cues, including locally generated steroids. Beyond systemic hormone effects, intracrine steroid metabolism within macrophages, particularly glucocorticoid activation by 11β-HSD1, emerges as a key regulator of inflammatory polarisation. Local glucocorticoid regeneration promotes a pro-resolving, tissue-repair phenotype by suppressing pro-inflammatory cytokines and enhancing phagocytic clearance. Inflammatory cues also remodel androgen metabolism through coordinated regulation of 11β-HSD1, AKR1C3 and 5α-reductase, enabling intracrine production of testosterone, dihydrotestosterone and aromatase-dependent oestradiol. Although sex steroids likely contribute to sexual dimorphism in inflammatory disease, their macrophage-specific functions remain incompletely defined. Overall, macrophage steroid metabolism represents a critical yet underappreciated determinant of inflammatory and malignant disease, with exciting biomarker and therapeutic application.
Endocrine-disrupting chemicals (EDCs) are exogenous compounds that interfere with hormonal signalling pathways and can lead to adverse biological effects in humans, wildlife, and ecosystems. This review examines advances in experimental models used to investigate EDC toxicity in humans, with particular emphasis on key health-related endpoints. A structured approach was used to identify relevant literature, focusing on studies that employ in vitro, animal, and human models of EDC toxicity. Well-characterised models, along with recent methodological advances, are discussed as tools to improve the physiological relevance of EDC toxicity studies. By integrating findings across experimental systems, this review provides a coherent framework for understanding how EDC exposure contributes to diverse biological outcomes and highlights current methodological challenges in assessing endocrine disruption.
The cell fate regulation of skeletal stem cells (SSCs) into bone marrow adipocytes (BMAd) during physiological and pathological conditions has been a subject of study. Identification, isolation, and characterization of progenitors that give rise to BMAd, is an extensive field of research. The skewing of the cell fate of SSCs to BMAd also alters the fate of the bone accrual process due to increased bone resorption. Among the several molecular pathways that alter cell fate of SSCs is accumulation of reactive oxygen species, DNA damage, and cellular senescence. The current short review will discuss the direct and indirect effects of cellular senescence in the marrow environment, that leads to SSC differentiation to BMAd. Preclinical studies using pharmacological and genetic clearance of senescent cells and suppression of the senescence associated pro-inflammatory signature lays the foundation for exploring these strategies as therapeutic interventions that could mitigate BMAd and associated bone loss.
Per and polyfluoroalkyl substances (PFAS) are recognized thyroid disruptors that impair the function of the hypothalamic-pituitary-thyroid axis in humans, rodents, and wildlife. In this review, we organized the available in vitro and in silico evidence around the molecular initiating events and key events that underpin established thyroid disruption adverse outcome pathways, enabling a mechanistic interpretation of PFAS effects. Interestingly, the available evidence converged on a recurrent set of PFAS-altered processes, including thyroid hormone (TH) synthesis, TH transport and distribution, TH receptor-mediated signaling, and cellular responses. Therefore, although important limitations remain, integrating in vitro and computational approaches offers a valuable strategy to clarify the molecular basis of PFAS-induced thyroid disruption and to guide the prioritization of compounds for more in-depth mechanistic studies and improved translational evaluation.
Recent research indicates that exposure to environmental agents can predispose individuals to metabolic disruptions across generations. It has been proposed that metabolism-disrupting agents, such as chemicals, and dietary stressors can disrupt chromatin organization during early development, thereby biasing the expression of genes that regulate metabolism. Studies in animal models demonstrated that such disruptions can propagate through development and into unexposed generations. Further evidence from exposure models spanning the preconception window of susceptibility and developing germ cells, and in vitro perturbations of early embryonic environments further suggests that altered chromatin establishment immediately after fertilization may underlie these multigenerational effects. Together, these findings identify chromatin organization as a key mechanism linking environmental exposures to inherited susceptibility to metabolic disruption.
The thyroid hormone (TH) system of humans, aquatic and terrestrial life forms is a major target for endocrine disrupting chemicals (EDC) during development and adult life. EDC adversely interfere with TH biosynthesis in vascularized thyroid follicles, secretion and distribution to target organs. EDC exposure may affect TH transmembrane transport, intracellular (in-)activation by deiodinases and conjugation reactions as well as T3 binding to intracellular T3 receptors in target cells. Predominant EDC interferences occur with TH distribution in the circulation and with cellular reactions controlling local availability of the active hormone T3 at the pre-receptor level. Developmental EDC interference may irreversible alter setpoints of the feedback regulation of the hypothalamus-pituitary-thyroid axis, TH-dependent brain development, and metabolic functions in adults. The worldwide still prevailing inadequate iodide status, especially during pregnancy and lactation, might exacerbate adverse effects of an increasing spectrum of identified and suspected EDC and their mixtures on human and environmental health.
Endocrine disrupting chemicals (EDCs) are found in a wide range of consumer products, making it impossible to avoid human exposure. There is significant and compelling evidence that EDC exposures are contributing to adverse health outcomes in human and wildlife populations. This has led to the conclusion that current approaches used to identify EDCs or quantify the risks of everyday exposures are ineffective at protecting human populations. In this review, we describe the approaches that are used to identify EDCs and characterize their hazards and risks. We then briefly review some of the most critical issues that affect the reliability of hazard and risk assessments for EDCs. These include the failure to properly test thousands of chemicals currently on the market, the inadequacy of current testing approaches which fail to evaluate important human health outcomes, and the insensitive health endpoints that are included in current testing approaches. We also discuss the rush to implement new approach methodologies (NAMs) which do not yet account for the complexity of the endocrine system, the limitations in exposure assessment methods, and the failure to account for either cumulative exposures or cumulative effects from complex chemical mixtures.
Osteoporosis represents a major global health burden, and emerging data suggest that bone marrow adipose tissue (BMAT) may contribute to skeletal fragility beyond bone mineral density (BMD). BMAT varies with age, sex, and skeletal site, and recent advances in MRI- and HR-pQCT–based techniques allow accurate quantification. Although BMAT is consistently inversely associated with BMD, evidence linking BMAT to fractures is heterogeneous. Cross-sectional and longitudinal studies have indicated the limited added predictive value of BMAT over established clinical risk factors and BMD. Large-scale imaging and genetic analyses reinforce the biological relevance of BMAT but not its clinical utility. Future research should clarify the role of BMAT in specific secondary osteoporosis settings and in combination with advanced analytical approaches.
Thyroid hormone system is crucial for numerous physiological processes, including development, growth and metabolism. Iodine, an indispensable micronutrient, is required for thyroid hormones (TH) synthesis. Inadequate supply or disruption of its metabolism can compromise thyroid function. Disruption of the thyroid hormones pathways by environmental endocrine-disrupting chemicals (EDCs) is being studied with growing interest. In several human populations exposure to EDCs frequently co-occur with insufficient iodine intake, impairing thyroid function and reducing the capacity to adapt to environmental changes. This brief review summarizes the current state of knowledge on the mechanisms through which EDCs and iodine deficiency can interfere with virtually every component of TH homeostasis. A better understanding of these combined effects is critical for maintaining a healthy population.
Environmental exposure to endocrine disrupting chemicals is a significant public health concern. Pesticides represent a subset of the potential environmental exposures impacting human health, including the thyroid. Some pesticides are considered persistent organic pollutants, so are present in the soil, water, and food chain long after they have been used, creating the potential for exposure for decades, even after they have been removed from the market. Exposures can occur through occupational exposure, but there is increasing evidence for residential exposure in non-agricultural workers. Some pesticides are considered endocrine disruptors, and there are epidemiologic associations reported between specific pesticides and thyroid hormone alteration and thyroid carcinogenesis. In this review, we will discuss the relationship between pesticides and the thyroid.
The thyroid gland is a sensitive target of endocrine-disrupting chemicals (EDCs), which can interfere with hormone synthesis, metabolism, and receptor signaling. Concurrently, obesity is increasingly recognized as both a modifier and potential amplifier of EDCs toxicity, particularly within the hypothalamic–pituitary–thyroid axis. Current evidence suggests that bisphenols, phthalates, perfluoroalkyl compounds, and polychlorinated biphenyls are linked to modest but measurable changes in thyroid hormone balance, often influenced by body weight. Adipose tissue may serve as a reservoir for lipophilic EDCs, sustaining internal exposure, and exacerbating metabolic dysregulation. However, the extent to which these associations reflect causal mechanisms remains unclear. Future research should prioritize longitudinal and mechanistic studies to clarify directionality, identify vulnerable populations, and inform precision-based approaches for exposure mitigation.
Cholesterol metabolism in the brain is tightly regulated and differs from the periphery due to the blood - brain barrier (BBB). Oxysterols, oxidized cholesterol metabolites, can cross the BBB and play key roles in brain cholesterol homeostasis and neurodegeneration, particularly in Alzheimer's disease (AD). This review highlights two major oxysterols: brain-derived 24Shydroxycholesterol (24-OH) and peripherally derived 27hydroxycholesterol (27-OH). Both have been studied as potential AD biomarkers, with altered levels observed in cerebrospinal fluid and plasma, though findings vary due to sex, age, and comorbidities. Animal studies suggest that CYP46A1 and its product 24-OH support cognitive function, reduce neuroinflammation, and attenuate AD pathology, especially in females. Conversely, increased 27-OH is linked to metabolic dysfunction, synaptic deficits, and memory loss, possibly bridging peripheral hypercholesterolemia and AD risk. This review summarizes recent advances in oxysterol research and their implications for AD, emphasizing sex-specific effects and their potential as biomarkers and therapeutic targets.
This review aims to highlight new advances in transgender medicine, including innovative approaches to pubertal and menstrual suppression, gender-affirming hormone therapy, and management of voice dysphoria for both adolescent and adult patients.
Perchlorate is an environmental contaminant found around the world. Perchlorate disrupts thyroid function by inhibiting the sodium iodide symporter, which transports iodide into the thyroid. The impact of perchlorate on thyroid function is of particular concern during gestation. This review focuses on human studies related to the thyroidal effects of perchlorate. Some of the earliest human studies of perchlorate and thyroid function studied high-dose exposure through randomized control trials and occupational studies. These gave way to epidemiologic and cohort studies focusing on environmental exposures. The results of these studies have been variable but suggest that high levels of environmental perchlorate exposure, particularly in the setting of iodine deficiency, may impair thyroid function and fetal neurological development. Regulatory efforts have been supported by the advent of biologically dose-dependent response models. Understanding this body of the literature is critical for developing policies aimed at regulating perchlorate exposures and protecting society’s most vulnerable populations.
