In a groundbreaking study published in Cell Death Discovery, researchers have unveiled a novel mechanism by which cold exposure triggers metabolic adaptation through liver-derived exosomes, paving the way for fresh insights into the regulation of energy homeostasis. This discovery centers on how hepatocytes, the predominant cell type in the liver, communicate with distant brown adipose tissue (BAT) to promote thermogenesis—the process by which heat is produced in the body to maintain temperature. The study identifies a specific exosomal microRNA, miR-293-5p, as a critical mediator driving transcriptional reprogramming in brown fat cells, thus enhancing their thermogenic capacity.
The human body’s response to cold is not merely a passive reaction but an actively regulated process involving multiple organ systems working in concert to preserve core temperature. Brown adipose tissue, distinguished by its abundance of mitochondria and ability to combust lipids through uncoupling protein 1 (UCP1), plays a pivotal role in this adaptive thermogenesis. While sympathetic nervous inputs have long been recognized as key activators of BAT, the current research illuminates an additional layer of regulation emanating from the liver via exosomal signaling.
Exosomes are nanoscale extracellular vesicles known to ferry molecular cargo—including microRNAs, proteins, and lipids—between cells. They have emerged as integral players in intercellular communication, often modulating physiological and pathological processes remotely. This study provides compelling evidence that cold stimuli provoke hepatocytes to release exosomes enriched with miR-293-5p, which are subsequently taken up by brown adipocytes. Once inside BAT cells, miR-293-5p orchestrates changes in gene expression that augment the transcription of thermogenic genes.
The researchers conducted extensive in vivo and in vitro experiments to delineate this pathway. Mice subjected to acute cold exposure exhibited a significant surge in circulating hepatocyte-derived exosomes carrying miR-293-5p. These vesicles preferentially homed to brown adipose depots, where intracellular delivery of miR-293-5p resulted in the upregulation of key transcription factors known to drive the thermogenic program, including PGC-1α and PRDM16. Notably, the administration of miR-293-5p mimics enhanced oxygen consumption rates and heat production in brown fat cells, confirming the functional consequence of this molecular signaling.
What distinguishes this pathway is its ability to extend the influence of the liver beyond its classical metabolic functions to actively modulate systemic energy expenditure. The liver, traditionally viewed primarily as a hub for glucose and lipid metabolism, emerges here as a crucial endocrine organ with an active role in thermogenic regulation. The induction of a cold-specific exosomal signature suggests a sophisticated mode of organ crosstalk fine-tuned by environmental stimuli.
To understand the transcriptional landscape influenced by miR-293-5p, RNA sequencing of brown adipocytes treated with the hepatocyte-derived exosomes was performed. The results revealed broad transcriptional reprogramming consistent with enhanced mitochondrial biogenesis and fatty acid oxidation pathways. The upregulation of oxidative phosphorylation components and mitochondrial uncoupling machinery aligns with the observed thermogenic phenotype. Importantly, the modulation of these pathways offers a potential therapeutic target for metabolic diseases characterized by impaired energy balance, such as obesity and type 2 diabetes.
Further mechanistic investigation pinpointed that miR-293-5p directly represses regulatory elements that normally inhibit brown fat thermogenesis. This relief of transcriptional repression facilitates the activation of a complex gene network governing energy dissipation. Moreover, blocking the release of hepatocyte exosomes or silencing miR-293-5p in vivo led to blunted thermogenic responses and decreased cold tolerance, underscoring the physiological relevance of this inter-organ signaling axis.
The implications of this study extend beyond basic physiology into clinical contexts. Harnessing exosome-mediated delivery of specific microRNAs like miR-293-5p could become a novel strategy to enhance brown fat activity and combat metabolic diseases. Additionally, the identification of cold-induced exosomal signatures opens avenues for biomarkers reflective of thermogenic capacity and metabolic health. These findings highlight the potential for modulating exosomal communication as a paradigm-shifting therapeutic avenue.
The study also raises intriguing questions about the integration of nervous and endocrine signals in orchestrating the body’s response to cold. While sympathetic innervation remains critical for BAT activation, it is evident that exosomal cargo from the liver provides an ancillary, possibly synergistic, regulatory input. Deciphering how these signals are coordinated may reveal multilayered feedback loops essential for maintaining homeostasis under environmental challenges.
Technological advances underpinning this study were pivotal in capturing the subtle but functionally critical exosomal cargo changes induced by cold stress. The use of high-resolution sequencing and sensitive vesicle isolation techniques allowed precise characterization of miRNA profiles within circulating exosomes. Coupled with genetically modified mouse models and real-time metabolic assessments, the research presents a comprehensive mechanistic picture with translational potential.
Another significant takeaway is the context-dependent nature of exosome biogenesis and cargo loading. The selective enrichment of miR-293-5p within hepatocyte exosomes upon cold exposure suggests dynamic regulation of RNA packaging dependent on physiological states. This adaptability might reflect an evolutionary advantage, enabling swift systemic adjustment to environmental perturbations.
In the broader scope of metabolic research, this study enriches our understanding of how organ crosstalk fine-tunes energy balance beyond the classical hormonal realm. It invites a reconsideration of the liver’s role from a metabolic workhorse to a master regulator capable of dispatching molecular messengers that guide remote tissues. The identification of miR-293-5p as a key thermogenic driver adds a crucial piece to the puzzle of metabolic homeostasis.
The work also encourages exploration into whether similar exosomal communications exist between other organs in response to diverse stressors. If so, therapeutic modulation of these vesicular networks could revolutionize treatment options across a spectrum of diseases, including those related to inflammation, cancer, and neurodegeneration, where intercellular messaging is pivotal.
Looking ahead, elucidating the full repertoire of hepatocyte-derived exosomal contents and their respective targets in peripheral tissues will be essential. Integrative ‘omics’ approaches, combined with functional assays and clinical studies, could map a comprehensive inter-organ communication network, transforming our strategies for managing metabolic health.
In conclusion, the discovery that cold-induced hepatocyte-derived exosomes modulate brown adipose thermogenesis via miR-293-5p-mediated transcriptional reprogramming represents a paradigm shift. It reveals an elegant molecular dialogue between liver and brown fat, emphasizing the significance of exosome-mediated signaling in adaptive thermogenesis. This insight not only deepens our understanding of energy metabolism but also holds promise for innovative interventions addressing obesity and metabolic syndrome.
Subject of Research:
Cold-induced hepatocyte-derived exosomes mediate brown adipose tissue thermogenesis through microRNA-driven transcriptional changes.
Article Title:
Cold-induced hepatocyte-derived exosomes activate brown adipose thermogenesis via miR-293-5p-mediated transcriptional reprogramming.
Article References:
Gao, X., Xu, J., Xu, Z. et al. Cold-induced hepatocyte-derived exosomes activate brown adipose thermogenesis via miR-293-5p-mediated transcriptional reprogramming. Cell Death Discov. 11, 396 (2025). https://doi.org/10.1038/s41420-025-02697-1
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