The Hypothalamic Neuropeptides' Role in Metabolic Diseases and Immunoregulation

Dear Colleagues,

Interdisciplinary studies in the research fields of endocrinology and immunology show that obesity-associated overnutrition leads to neuroinflammatory molecular changes, particularly in the hypothalamus, chronically causing various disorders known as elements of metabolic syndrome. In this process, neural or hypothalamic inflammation impairs the neuroendocrine and autonomic regulation of the brain in relation to blood pressure, glucose homeostasis, and insulin secretion, and elevated sympathetic activation is appreciated as a critical mediator.

Hypothalamic inflammation is an important factor in the pathogenesis of diabetes and hypertension. Indeed, an overnutrition and aging leads to hypothalamic inflammation. This inflammation can stem from, in part, the activation of IKKβ/NF-κB cascade in association with functional changes of intracellular organelles such as RNA stress responses, endoplasmic reticulum, and oxidative stresses, and, more chronically, autophagic defects. Such hypothalamic inflammation affects not only neuroendocrine signaling but also the connections between the hypothalamus and the autonomic nervous system, leading to increased sympathetic outflow. Consequently, the autonomic control over peripheral organs, including the liver, skeletal muscle, pancreas, and cardiovascular system, is perturbed, resulting in glucose disorder, insulin resistance, insulin secretion impairment, and increased blood pressure, which are predicted to chronically contribute to the development of diabetes and hypertension. It is well known that there is an important and intricate relationship between the immune system and the nervous system. These systems are communicate through the production of molecules such as cytokines, hormones, and peptides from the CNS and through the activation of afferent and efferent neurological pathways in lymphoid organs, with both immuno-suppressive and immuno-stimulating effects. On the other hand, the cytokines are able to communicate with the CNS and ensure the passage of specific signals and information from the periphery to the brain.

Moreover, these pathways’ activation may be relevant in many chronic diseases such as neurodevelopmental disorders (i.e., autism spectrum disorders, Rett disease, X-Fragile) with relevant neurovegetative dysregulation.

Having a comprehensive and extensive understanding of the mechanisms underlying the interaction between the CNS and immune systems may be important for understanding the modulation of certain brain functions as a possible clinic therapeutic approach for immune-mediated diseases. In this context, many cytokines and neuropeptides, for example, orexin-A, adiponectin, leptin, and other neuropeptides, may represent key factors linking the immune system, metabolism, and CNS functions. Recent reports have shown that caloric restriction can significantly increase overall survival in several experimental animal models of autoimmune diseases. More specifically, CR has anti-inflammatory, antioxidant, and neuroprotective effects that could be instrumental in the improvement of clinical outcomes in many autoimmune diseases such as multiple sclerosis, or reumatoid arthritis, since this regimen is able to impair pathological proliferation of autoreactive cells and pro-inflammatory cytokine production. We have summarized the most recent advances and the key players linking the central nervous system, immune tolerance, and the metabolic status. For these reasons, it is important understand that molecular pathways and biological mechanisms undergo a strong interaction between the central nervous system, the immune system, and metabolic functions to use new, more targeted, and specific therapeutic approaches in metabolic and immune diseases.

Prof. Dr. Giovanni Messina
Prof. Dr. Marco Carotenuto
Guest Editors

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• Central nervous system
• Nueropeptides
• Sleep regulation
• Metabolic disorders
• Cardiovascular diseases
• Autoimmune diseases
• Neurodevelopmental disorders
• Rett disorder
• Cognitive disabilities
• Autism spectrum disorders