Editorial: Interac/ons between /ssues and kingdoms and interplay with environmental factors: impact on metabolic health and diseases

Giselle Adriana Abruzzese^1*Victoria Ceperuelo-Mallafré^2,3,4,5*

• ¹Liver Disease Lab, CIC bioGUNE, Derio, Spain
• ²Departament de Medicina i Cirurgia, Universitat Rovira i Virgili, Tarragona, Spain
• ³Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
• ⁴Institut d'Investigacio Sanitaria Pere Virgili, Reus, Spain
• ⁵Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas, Madrid, Spain

Communicaeon between essues via secreted factors is esseneal for coordinaeng whole body metabolism. These include pepedes, lipids, small molecules, and other factors such as extracellular vesicles capable of transmigng informaeon about the metabolic state between distant organs and essues. The dysregulaeon of one or more of these signaling axes lies at the basis of the development of metabolic diseases. Understanding how organs communicate through secreted factors is crucial for discovering new and promising therapeuec targets. This Research Topic gather contribueons that highlight the role of major players in essue crosstalk and metabolic health regulaeon, emphasizing organ and system interaceons as a promising approach for the management of metabolic diseases. In recent years, advances in integraeve medicine have led to new insights into the contribueons of some essues and their derived molecules to physiology and metabolic diseases. Such is the case of adipose essue. Adipose essue, apart from storing energy, has been recognized as a complex and dynamic endocrine organ that regulates energy homeostasis and other important physiological processes. Extracellular vesicles (EVs) derived from adipose essue represent an esseneal part of the adipose secretome, parecipaeng in autocrine and paracrine interaceons within the different cells in it, as well as in endocrine communicaeons. The review by Yanwen Wang et al. provide a comprehensive evaluaeon on the content and funceon of different exosomes (a subtype of EVs) within adipose essue, highligheng the complex regulatory effects. The authors emphasize the diverse roles of these exosomes in modulaeng inflammaeon, adipogenesis, tumor progression, and insulin resistance. Moreover, they influence both physiological and pathological processes in distant organs such as the muscles, skin, hypothalamus, and kidneys. Interesengly, the cargo of these exosomes differs between healthy, obese, and diabeec individuals, suggeseng their poteneal as diagnosec biomarkers and therapeuec targets. However, clinical translaeon remains limited by several challenges, including difficulees in standardizing exosome isolaeon and storage, variability in therapeuec efficacy based on donor condieon, and concerns about poteneal immunogenicity or adverse effects. Therefore, despite their therapeuec poteneal, the clinical applicaeon of adipose essuederived exosomes will require robust protocols for quality control, deeper mechanisec understanding, and extensive safety validaeon.Increasing recognieon is being given to environmental factors and health habits, such as sleep, diet and physical acevity, as contributors to metabolic homeostasis and health. In this regard, Peiqing Wang et al. explored the role of sleep as a central regulator of glucose metabolism. The authors invesegated the poteneal benefits of sleep compensaeon, through weekend catch-up sleep, in individuals with diabetes, showing that short sleep compensaeon can improve glucose metabolic dysregulaeon in diabeec individuals. The study drew aoeneon to an important but sell understudied field, highligheng sleep as a poteneal key modulator in metabolic funceons. This study gains relevance in a context in which sleep loss or disrupeon is being recognized as a metabolic disorder (1) by affeceng the neuroendocrine system and negaevely impaceng energy balance. Further research is needed to deepen the understanding of the mechanisms related to the role and control of sleep in metabolic health and diseases, especially in the context of energy impairment diseases such as obesity and diabetes.A key contributor to metabolic health and disease is the gut microbiome, which further modulates inter-organ communicaeon, not only in the liver-gut axis but also by affeceng other distant organs and influencing a wide range of physiological funceons (2). A growing body of evidence posieons the gut microbiota as a dynamic endocrine organ, highligheng its bidireceonal communicaeon with host cells and its esseneal role in metabolic regulaeon via hormone modulaeon, metabolite synthesis, and immune signaling. Despite this growing recognieon, criecal queseons remain regarding the specific microbial taxa involved, their funceons, and their interaceon with host pathways. Xue et al. explored the effects of orlistat, a weight-loss drug, on gut microbial communiees in a mouse model of diet-induced obesity. Their findings reveal that orlistat reshapes microbial diversity and composieon, correlaeng with improved metabolic markers like faseng glucose and gut hormones GLP-1 and GIP. These results suggest that part of orlistat's efficacy may be mediated via microbiota modulaeon. However, further mechanisec studies are needed to confirm causal links beyond correlaeve analyses.In addieon to modulaeng digeseve hormones, the gut microbiome also influences sex hormone regulaeon. Haiqiang Wang et al. review how the gut microbiome impacts estrogen regulaeon in postmenopausal women. They highlight that decreased microbial diversity aqer menopause may reduce the acevity of β-glucuronidase, disrupeng estrogen reabsorpeon through enterohepaec circulaeon. This alteraeon is associated with metabolic, cognieve, and skeletal disorders commonly observed during this period. Furthermore, Mei et al. highlight the poteneal role of the microbiota in polycysec ovary syndrome (PCOS). PCOS, a common endocrine disorder characterized by hyperandrogenism, affects women of reproduceve age and is associated with by high androgen levels and disrupted gonadotropin regulaeon (3). The authors discuss how microbiota diversity and its derived metabolites may contribute to insulin resistance, a key metabolic feature of PCOS, based on evidence from both animal models and clinical studies.Expanding on the interplay between the gut microbiota, hormones, and metabolism, Chen et al. review the use of probioecs in addressing obesity during adolescence, a criecal period marked by hormonal changes. They point out the limitaeons of mouse models for studying puberty-related obesity and provide clinical data showing that probioec treatments may improve metabolic parameters. However, the authors emphasize the need for further research, parecularly in diverse populaeons, given the variability in outcomes. To beoer implement probioecs and prebioecs in the clinical management of metabolic diseases, large-scale, mulecenter studies are needed to assess long-term effects and define opemal treatment condieons.Together, these contribueons underscore the vital role of inter-essue and inter-kingdom communicaeon in metabolic regulaeon. Although they do not comprehensively address the full complexity of these interaceons, they highlight the need for further exploraeon of interessue and inter-kingdom signaling. Deeper mechanisec insights into host-microbe and other key pathways are esseneal and could ulemately pave the way for more precise and personalized therapies for complex metabolic disorders.