Neuro-endocrine-immune regulation of metabolic homeostasis

Metabolic homeostasis, essential for energy balance, is regulated by a highly integrated network involving the nervous, endocrine, and immune systems. While traditional models emphasized endocrine feedback mechanisms and autonomic nervous control, recent evidence reveals extensive cross-talk among these systems, forming a dynamic neuro-endocrine-immune network. The brain coordinates energy balance by integrating signals from peripheral organs, regulating appetite, metabolic rate, and nutrient utilization. Immune responses, particularly in obesity, contribute to metabolic dysfunction through chronic inflammation and cytokine cascades. This review synthesizes the cellular and molecular mechanisms underlying the neuro-endocrine-immune interactions that maintain glucose and energy homeostasis. We describe the functional roles of hypothalamic feeding circuits, peripheral autonomic pathways, adipokines, incretins, and immune cell subsets in metabolic tissues. We also highlight how chronic inflammation, neuroimmune signaling, and hormonal resistance contribute to homeostatic failure. Crucially, we examine emerging therapeutic strategies targeting obesity, type 2 diabetes, metabolic syndrome, and metabolic dysfunction-associated fatty liver disease—approaches that exert multi-system effects by precisely targeting key nodes within this regulatory triad. This integrative perspective not only offers novel paradigms for intervening in complex metabolic disorders but also heralds a future where decoding this network enables personalized medicine to transform clinical practice.