Exosomes can transport regulatory biomolecules and are mediators of cellular signaling among metabolic tissues through endocrine mechanisms. Understanding the pathways and processes underlying exosome-mediated inter-tissue communication is critical for elucidating the molecular pathophysiology of metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disorders. Consequently, these mechanisms represent novel and promising targets for pharmacological regulation. We examined the current knowledge regarding exosome physiology, the mechanisms of interaction with target tissues, and its role in metabolic tissue communication. We also analyzed the secretory profiles of exosomes in metabolic tissues, emphasizing their regulatory roles in adipose tissue, liver, pancreas, skeletal muscle, and the small intestine, while discussing their association with metabolic diseases. In this sense, we propose the exosomal pentad as a novel framework highlighting exosome-mediated inter-organ communication, where exosomes may regulate a metabolic axis involving these tissues. This model aligns with the ominous octet in type 2 diabetes but emphasizes exosomes as key regulators of metabolic homeostasis and potential therapeutic targets. The role of exosomes for the treatment of metabolic diseases emerges as a critical area of pharmacologic exploration. For instance, therapeutic strategies that prevent target tissue binding or expression of cargo molecules such as miRNAs could be designed, using antagomiRs or nanoparticles. Additionally, integrins like αvβ5 on the exosomal membrane can be blocked with monoclonal antibodies or engineered for targeted delivery of therapeutic molecules. Exosomes, critical mediators of inter-organ communication and metabolic regulation, hold potential to design precise molecular-level therapies while minimizing systemic side effects.

Obesity is a multifactorial health condition influenced by genetic predisposition and environmental factors, identified as a condition of persistent, mild systemic inflammation marked by an abnormal buildup of fat tissue, becoming clinical when accompanied by functional impairment of organs. This review explores the role of hyperinsulinemia and hypertriglyceridemia in driving the transition from a preclinical to a clinical state of obesity. Insulin resistance leads to compensatory hyperinsulinemia, impairing glucose homeostasis in skeletal muscle, liver, and adipose tissue. Concurrently, excessive dietary fat intake contributes to elevated triglyceride levels, which promote systemic inflammation and facilitate the onset of endocrine and cardio vascular disorders. Early risk factors, such as childhood obesity, as well as other contributors, including chronic psychological stress, alterations in gut microbiota, sleep disturbances, and vitamin D deficiency, are discussed in the context of their role in disease progression. Critically, the concept of a ‘borderline’ stage is introduced–a transitional phase characterized by elevated triglycerides, insulin resistance, and low-grade chronic inflammation–representing a critical point in the progression toward clinical obesity. Identifying this intermediary stage, even present in other pathologies, offers a valuable window for early interven tion, potentially preventing the establishment of chronic degenerative diseases associated with advanced obesity. Current strategies aimed at controlling hyperinsulinemia and hypertriglyceridemia, including dietary interventions, physical activity, and pharmacological approaches such as GLP-1 receptor agonists and SGLT2 inhibitors, should be considered.