Search Results (55)

Forkhead box protein O1 (Foxo1) is an insulin-suppressed transcription factor that governs multiple biological processes, including cell proliferation, apoptosis, autophagy, mitochondrial function, and energy metabolism. Over the past 25 years, Foxo1 has evolved from a liner insulin effector to a pleiotropic integrator of systemic metabolic stress during obesity and aging. Foxo1 integrates hormonal signals with energy balance and plays a central role in glucose and lipid metabolism, organ homeostasis, and immune responses. Given its pleiotropic functions, therapeutic targeting of Foxo1 pathway will require a nuanced, context-specific approach. Here, we reviewed key advances in Foxo1 studies over the past 25 years, including multi-hormonal control of Foxo1 activity, Foxo1-mediated inter-organ crosstalk, immune modulation, and contributions to aging-associated pathologies. Understanding the regulation of Foxo1 and its pleiotropic function across multiple tissues will advance insight into the pathogenesis of metabolic diseases and promote the translation potential of Foxo1 signaling manipulation for the treatment of metabolic disorders, including insulin resistance and type 2 diabetes. Full article

Dysregulated lipid metabolism constitutes the fundamental etiology underlying the global burden of obesity and its associated metabolic disorders. N⁶-methyladenosine (m⁶A) is the most abundant reversible chemical modification on messenger RNA and influences virtually every aspect of RNA metabolism. Recent studies demonstrate that m⁶A mediates regulatory networks governing lipid metabolism and contributes to the pathogenesis of multiple metabolic diseases. However, the precise roles of m⁶A in lipid metabolism and related metabolic disorders remain incompletely understood. This review positions m⁶A modification as a central epigenetic switch that governs lipid homeostasis. We first summarize the molecular components of the dynamic m⁶A regulatory machinery and delineate the mechanisms by which it controls key lipid metabolic processes, with an emphasis on adipogenesis, thermogenesis and lipolysis. Building on this, we further discuss how dysregulated m⁶A acts as a shared upstream driver linking obesity, type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD), and insulin resistance through tissue-specific and inter-organ communication mechanisms. We also evaluate the potential of targeting m⁶A regulators as therapeutic strategies for precision intervention in metabolic diseases. Ultimately, deciphering the complex interplay between m⁶A modification and lipid homeostasis offers a promising frontier for the development of epitranscriptome-targeted precision medicine against obesity and its associated metabolic disorders. Full article

Gestational diabetes mellitus (GDM) is a multifactorial metabolic disorder arising from impaired insulin sensitivity and altered maternal–fetal energy regulation. Beyond classical mechanisms involving β-cell dysfunction and pregnancy-induced insulin resistance, emerging evidence suggests a bidirectional interaction between the maternal gut microbiota and the placenta, forming a dynamic placenta–gut axis. Microbial dysbiosis alters levels of metabolites, inflammatory mediators, and bile acids, which influence placental signaling, trophoblast metabolism, immune activation, and nutrient transport. Conversely, the placenta secretes hormones, cytokines, lipids, and exosomal miRNAs that shape maternal metabolism and potentially modulate the gut microbiota. This review synthesizes current mechanistic insights underlying the placenta–gut microbiota axis in GDM, describes immune and metabolic crosstalk, and highlights therapeutic opportunities targeting this inter-organ communication system. Addressing these interactions may advance precision strategies for managing GDM and improving outcomes across generations. Full article

Nuclear receptors (NRs) are ligand-activated transcription factors that mediate diverse cellular processes, including signalling, survival, proliferation, immune response and metabolism, through both genomic and non-genomic mechanisms in response to hormones and metabolic ligands. Given their central role in inter-organ, tissue, and cellular communication, NRs are critical for maintaining homeostasis and have become a major focus in biomedical research and drug discovery due to their association with numerous diseases. Among NRs, the NR4A subfamily (NR4A1/Nur77, NR4A2/Nurr1, and NR4A3/Nor1) responds to various stimuli—such as insulin, growth factors, inflammatory cytokines, and β-adrenergic signals—though their endogenous ligands remain unidentified. Their expression is tissue-dependent, particularly in energy-demanding tissues, where they modulate leukocyte function and promote an anti-inflammatory profile. Like other NRs, NR4As regulate acute and chronic inflammation by suppressing pro-inflammatory transcription factors (e.g., NF-κB) or enhancing their inhibitors, thereby polarising macrophages toward an anti-inflammatory phenotype. This review summarises current knowledge on the role of NR4A receptors in immune responses. Given their well-documented involvement in autoimmune diseases, inflammatory conditions, and cancer, elucidating their contributions to neuro–immune–endocrine crosstalk may uncover their therapeutic potential for immunopathological disorders. Full article

Background: Periprostatic adipose tissue (PPAT) has been shown to play a significant role in prostate cancer (PCa) development and progression. This relationship is further exacerbated by obesity, as PPAT-secreted factors increase PCa aggressiveness and have also been implicated in chemotherapy resistance. Therefore, identifying the molecular mediators of PPAT–prostate interorgan communication and the factors that disrupt this crosstalk is pivotal for better disease management. Obesogens, i.e., endocrine-disrupting chemicals that dysregulate adipose tissue towards an “obese” phenotype, have recently been implicated in disrupting this crosstalk, with an impact on prostate cell fate. Objectives: This study aimed to investigate whether obesogenic dysregulation of human PPAT secretory activity affects PCa cell viability and their response to docetaxel and cabazitaxel. Methods/Results: Through ex vivo culture of human PPAT and conditioned medium assays, we demonstrated that exposure to the model obesogen tributyltin (TBT) induced an “obese” phenotype in human PPAT, characterised by adipocyte enlargement and increased secretion of leptin and C-C motif chemokine ligand 7. The TBT-treated PPAT secretome enhanced cell viability and decreased the sensitivity of PCa cells to taxanes. Conclusions: This study provides preliminary evidence that lays the groundwork for future investigations, dissecting the molecular pathways underpinning prostate carcinogenesis and resistance to chemotherapy induced by obesogen-dysregulated PPAT. Full article

Background: Aging elevates reactive oxygen species (ROS) and weakens antioxidant defenses, contributing to cardiac dysfunction. The objective of this study was to determine whether sustained activation of skeletal muscle (SkM) Nrf2 preserves cardiac function during aging and to explore the underlying mechanisms, focusing on myocardial antioxidant pathways. Methods: Tamoxifen-induced SkM-specific Keap1 knockout male mice (iMS-Keap1^flox/flox; SkM-Nrf2 overexpression) were divided into young wild-type (Y-WT), aged wild-type (A-WT), and aged knockout (A-KO) groups. Cardiac performance was evaluated by echocardiography and invasive hemodynamics. Myocardial proteomics identified differentially expressed proteins (DEPs) and enriched biological pathways. Results: Compared with Y-WT, A-WT mice showed impaired left ventricular function, including reduced ejection fraction, prolonged isovolumic relaxation time, blunted inotropic response to dobutamine, and elevated Tau index. These age-related deficits were partially reversed in A-KO mice. Proteomic analysis revealed 561 DEPs between A-WT and Y-WT, and 741 DEPs between A-KO and A-WT, enriched in calcium signaling, Nrf2-mediated oxidative stress response, oxidative phosphorylation, ROS detoxification, and cardiac-specific processes, such as hypertrophy, conduction, and dilated cardiomyopathy. Conclusions: Lifelong SkM-Nrf2 activation strengthens myocardial antioxidant capacity and alleviates age-related cardiac dysfunction. These data support an antioxidant crosstalk between skeletal muscle and the heart, highlighting a potential therapeutic target for aging-associated heart failure. Full article

Inter-organ communication plays a vital role in the pathogenesis of neurodegenerative diseases (ND), including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS). Emerging research highlights the involvement of the gut–brain axis, immune system, and peripheral metabolic systems in modulating neuroinflammation, protein misfolding, and neuronal dysfunction by releasing cytokines, adipokines, growth factors, and other soluble factors, which in turn affect neuronal health and systemic inflammation. This review explores the complex bidirectional interactions between the brain and peripheral organs, including the gut, adipose tissue, liver, muscle, bone and immune system. Notably, the gut microbiome’s role in neurodegenerative diseases through the gut–brain axis, the impact of adipose tissue in inflammation and metabolic regulation, and the muscle–brain axis with its neuroprotective myokines are also discussed. Additionally, we examine the neuro-immune axis, which mediates inflammatory responses and exacerbates neurodegeneration, and liver–brain axis that is implicated in regulating neuroinflammation and promoting disease progression. Dysregulation of inter-organ pathways contributes to the systemic manifestations of neurodegenerative diseases, offering insights into both potential biomarkers and therapeutic targets, and, in turn, promising strategies for preventing, diagnosing, and treating neurodegenerative diseases. Full article

The bone and brain, though distinct in structure and function, share remarkable physical, molecular, and developmental similarities. Emerging evidence reveals dynamic bidirectional crosstalk between these systems mediated by hormones, cytokines, extracellular vesicles (EVs), and neural signals. Bone-derived factors such as osteocalcin (OCN), lipocalin-2, and fibroblast growth factor (FGF) 23 influence cognitive functions, mood, and neurogenesis, while brain- and nerve-derived mediators, including leptin, serotonin, and sympathetic signals, modulate bone remodeling. Inflammation and aging disrupt this communication, contributing to cognitive decline, osteoporosis, and other age-related disorders. Stem cells and EVs have also been implicated as mediators in this axis, offering insights into regenerative strategies. Molecular signaling pathways and transcriptional regulators, such as Wnt/β-catenin, leptin, receptor activator of nuclear factor kappa-B ligand (RANKL), sclerostin (SOST), and nuclear factor kappa-B (NF-κB), play critical roles in maintaining bone–brain homeostasis. Additionally, shared biomarkers and pathological links between neurodegeneration and bone loss suggest new diagnostic and therapeutic opportunities. Studies support this inter-organ communication, yet further mechanistic and translational research is needed. This review highlights the molecular basis of bone–brain crosstalk, emphasizing inflammation, aging, and regulatory pathways, with a focus on future directions in biomarker discovery and therapeutic targeting. Understanding this crosstalk may help in early diagnosis and dual-targeted interventions for both bone and brain disorders. Full article

We investigated the impact of liver damage on systemic inter-organ communication in an extensive observational case–control study of 923 patients with severe obesity and biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH) undergoing bariatric surgery. Using a comprehensive panel of circulating organokines, including fibroblast growth factor (FGF) 19, FGF21, adiponectin, galectin-3, irisin, and leptin, along with choline metabolites, we characterized metabolic signaling patterns associated with liver disease severity. Compared to controls, patients with MASLD/MASH exhibited significantly lower levels of FGF19, choline, and trimethylamine, while FGF21, galectin-3, irisin, and leptin were elevated. Sex-specific alterations in leptin and adiponectin were observed in patients with severe obesity but not in controls. Network analysis revealed a complex and individualized interplay among organokines, shaped by age, sex, and anthropometric factors. Despite this complexity, a dysregulation of the FGF21–adiponectin axis was associated with more advanced liver involvement. The large cohort and comprehensive organokine profiling studied provide valuable insights into the role of the FGF21–adiponectin axis on systemic metabolic alterations in severe obesity and their potential clinical implications. Full article

Background/Objectives: Obesity and type 2 diabetes mellitus (T2DM) profoundly disrupt lipid metabolism within local microenvironments of skeletal muscle and its associated connective tissues, including adipose tissue, bone, and fascia. However, the role of local communication between skeletal muscle and its proximal connective tissues in propagating metabolic dysfunction is incompletely understood. This narrative review synthesizes current evidence on these local metabolic interactions, highlighting novel insights and existing gaps. Methods: We conducted a comprehensive literature analysis of primary research published in the last decade, sourced from PubMed, Web of Science, and ScienceDirect. Studies were selected for relevance to skeletal muscle, adipose tissue, fascia, and bone lipid metabolism in the context of obesity and T2DM, with emphasis on molecular, cellular, and paracrine mechanisms of local crosstalk. Findings were organized into thematic sections addressing physiological regulation, pathological remodeling, and inter-organ signaling pathways. Results: Our synthesis reveals that local lipid dysregulation in obesity and T2DM involves altered fatty acid transporter dynamics, mitochondrial overload, fibro-adipogenic remodeling, and compartment-specific adipose tissue dysfunction. Crosstalk via myokines, adipokines, osteokines, bioactive lipids, and exosomal miRNAs integrates metabolic responses across these tissues, amplifying insulin resistance and lipotoxic stress. Emerging evidence highlights the underappreciated roles of fascia and marrow adipocytes in regional lipid handling. Conclusions: Collectively, these insights underscore the pivotal role of inter-tissue crosstalk among skeletal muscle, adipose tissue, bone, and fascia in orchestrating lipid-induced insulin resistance, and highlight the need for integrative strategies that target this multicompartmental network to mitigate metabolic dysfunction in obesity and T2DM. Full article

The renin–angiotensin–aldosterone system (RAAS) plays a pivotal role in regulating cardiovascular function, fluid balance, and blood pressure. Recent research has revealed the RAAS’s influence extends beyond cardiovascular physiology, encompassing key roles in inflammation, fibrosis, immune regulation, cancer progression, and organ-specific disease mechanisms. This review provides a comprehensive overview of classical and alternative RAAS pathways, focusing on the dual roles of angiotensin II (Ang II) and angiotensin-(1–7) (Ang 1–7), mediated through AT1R, AT2R, MasR, and MrgD receptors. We discuss molecular signaling cascades, including mitochondrial, nuclear, and caveolae-mediated mechanisms, and explore the impact of RAAS modulation on hepatic fibrosis, vascular remodeling, and autoimmune inflammation. Genetic models and emerging pharmacologic strategies illustrate tissue-specific RAAS actions, emphasizing the therapeutic potential of enhancing the ACE2/Ang 1–7/Mas axis while inhibiting the deleterious ACE/Ang II/AT1R signaling. Furthermore, we highlight implications for veterinary medicine, particularly in canine chronic inflammatory enteropathies, where RAAS dysfunction may contribute to treatment resistance. Understanding RAAS complexity and inter-receptor crosstalk is essential for developing new therapeutic strategies targeting cardiovascular, hepatic, and inflammatory diseases in both human and veterinary contexts. Full article

Efficient mitochondrial matrix protein quality control (mPQC), regulated by the mitochondrial matrix protease LONP1, is essential for preserving cardiac bioenergetics, particularly in post-mitotic cardiomyocytes, which are highly susceptible to mitochondrial dysfunction. While cardiac mPQC defects could impair heart function, it remains unclear whether such defects can be mitigated through inter-organ crosstalk by modulating mPQC in extra-cardiac tissues, a potentially valuable strategy given the challenges of directly targeting the heart. To investigate this, we examined two mouse models of Lonp1 haploinsufficiency at young adulthood: a cardiomyocyte-specific heterozygous knockout (Lonp1^CKO-HET) and a whole-body heterozygous knockout (Lonp1^GKO-HET). Despite similar reductions in Lonp1 mRNA expression in the hearts, Lonp1^GKO-HET mice exhibited no cardiac dysfunction, whereas Lonp1^CKO-HET mice showed mild cardiac dysfunction accompanied by activation of the mitochondrial stress response, including induction of genes such as Clpx, Spg7, Hspa9, and Hspd1, increased mitochondrial dynamics (Pink1, Dnm1l), reduced mitochondrial biogenesis, and compensatory upregulation of the mtDNA transcriptional regulator Tfam, all occurring without overt structural remodeling. These alterations were absent in Lonp1^GKO-HET hearts. Our findings reveal a novel adaptive mechanism in which systemic mPQC deficiency can buffer mitochondrial dysfunction in the heart through inter-organ communication that is lost with cardiomyocyte-specific mPQC disruption. This study identifies systemic modulation of Lonp1-mediated mitochondrial stress pathways as a promising strategy to promote cardiac resilience through protective inter-organ signaling. Full article

The liver is a vital organ responsible for a broad range of metabolic functions, including glucose and lipid metabolism, detoxification, and protein synthesis. Its structural complexity, characterized by hexagonal hepatic lobules composed of diverse parenchymal and non-parenchymal cell types, supports its broad spectrum of physiological activities. Traditional in vitro liver models have contributed significantly to our understanding of hepatic biology and the development of therapies for liver-related diseases. However, static culture systems fail to replicate the dynamic in vivo microenvironment, particularly the continuous blood flow and shear stress that are critical for maintaining hepatocyte function and metabolic zonation. Recent advances in microphysiological systems (MPS) incorporating dynamic fluid flow have addressed these limitations by providing more physiologically relevant platforms for modeling liver function. These systems offer improved fidelity for applications in drug screening, toxicity testing, and disease modeling. Furthermore, the integration of liver MPS with other organ models in multi-organ-on-chip platforms has enabled the investigation of inter-organ crosstalk, enhancing the translational potential of in vitro systems. This review summarizes recent progress in the development of dynamic liver MPS, highlights their biomedical applications, and discusses future directions for creating more comprehensive and predictive in vitro models. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a global health burden, however, therapeutic advancements remain hindered by incomplete insights on mechanisms and suboptimal clinical interventions. This review focused on the transcription factors (TFs) associated with the gut–liver axis, emphasizing their roles as molecular interpreters of systemic crosstalk in MAFLD. We delineate how TF networks integrate metabolic, immune, and gut microbial signals to manage hepatic steatosis, inflammation, and fibrosis. For instance, metabolic TFs such as peroxisome proliferator-activated receptor α (PPARα) and farnesoid X receptor (FXR) are responsible for regulating lipid oxidation and bile acid homeostasis, while immune-related TFs like signal transducer and activator of transcription 3 (STAT3) modulate inflammatory cascades involving immune cells. Emerging evidence highlights microbiota-responsive TFs, like hypoxia-inducible factor 2α (HIF2α) and aryl hydrocarbon receptor (AHR), linking microbial metabolite signaling to hepatic metabolic reprogramming. Critically, TF-centric therapeutic strategies, including selective TF-agonists, small molecules targeted to degrade TF, and microbiota modulation, hold considerable promise for treating MAFLD. By synthesizing these insights, this review underscores the necessity to dissect TF-mediated interorgan communication and proposes a roadmap for translating mechanism discoveries into precision therapies. Future research should prioritize the use of multi-omics approaches to map TF interactions and validate their clinical relevance to MAFLD. Full article

Obesity is an important risk factor for the development of metabolic syndrome disorders. We previously showed that the liver fatty acid-binding protein null mouse (LFABP^−/−) becomes obese upon high-fat diet (HFD) feeding but remains metabolically healthy. Here, we find that the obese LFABP^−/− mouse increases subcutaneous adipose tissue (SAT) mass by markedly increasing the number rather than the size of adipocytes, as is typical with HFD. Indeed, while HFD-fed LFABP^−/− mice had almost double the fat mass of WT, SAT adipocyte size was >4-fold smaller and adipocyte number was 5-fold higher in the LFABP^−/−. Transcriptomic analysis of SAT revealed that Lfabp deletion alters the expression of multiple pathways that modulate adipose expansion and function including cholesterol biosynthesis, adipogenesis, and extracellular matrix remodeling. LFABP is expressed in the liver and small intestine but not in adipose tissues; thus, its ablation may promote interorgan crosstalk that drives the hyperplastic expansion of metabolically beneficial SAT, contributing to the healthy obese phenotype of the LFABP^−/− mouse. Full article