Exploring Neuroendocrine Mechanisms in Psychiatric and Metabolic Comorbidities

Santosh Chokkakula¹Balaji Pathakumari²Ge Hong^3*Bing Yang^4,5*

• ¹Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea
• ²Department of Medicine, Mayo Clinic, Rochester, United States
• ³Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
• ⁴Department of Cell Biology, College of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
• ⁵Department of Public Health, International School, Krirk University, Bangkok, Thailand

The human body functions as a highly integrated biochemical network governed by intricate regulatory and feedback mechanisms. This biological "chemical plant" operates through tightly coordinated neuroendocrine and metabolic pathways that maintain systemic homeostasis. Throughout scientific history, sustained efforts have been made to unravel the fundamental principles governing these processes; however, their complexity continues to pose challenges long before a comprehensive understanding has been achieved. When any component of this regulatory framework, hormonal, neuronal, or molecular, malfunctions, the effects can propagate across multiple organ systems. Even subtle cellular perturbations may accumulate over time, predisposing individuals to complex pathological states, including psychiatric and metabolic disorders. Among these interconnected systems, neuroendocrine signaling plays a central role in linking brain function with peripheral metabolism. Dysregulation of the hypothalamicpituitary-adrenal (HPA) axis has been consistently implicated in the pathophysiology of numerous mental illnesses (1,2). Contemporary neuropeptidergic models highlight the importance of stress-responsive peptides such as corticotropin-releasing hormone, oxytocin, and vasopressin in modulating emotional regulation, cognitive processing, and social behavior (3). Aberrant activity within these neuroendocrine circuits contributes to the pathogenesis of depression, anxiety, and schizophrenia, partly through their downstream metabolic interactions (4,5). Neuropeptides, secreted in circadian patterns that are dynamically altered by stress, exert both central and peripheral influences, forming key molecular bridges among mood, cognition, and energy homeostasis.The high prevalence of comorbidity between psychiatric disorders and metabolic diseases, particularly obesity and type 2 diabetes, underscores a multidirectional disruption of the brain-body axis (6,7). Meta-analytic evidence indicates that individuals with schizophrenia, bipolar disorder, or major depressive disorder exhibit persistent alterations in glucose regulation, lipid metabolism, and autonomic function, even in the absence of pharmacological confounders (8). Conversely, metabolic dysregulation can amplify neuroinflammatory and oxidative stress pathways, accelerating psychiatric symptom progression and cognitive decline. Despite growing recognition of this bidirectional relationship, clinical management remains suboptimal. Diagnostic biases, social stigma, and the metabolic side effects of psychopharmacological agents continue to obscure accurate assessment and timely intervention.Recent research extends this concept by linking systemic metabolic imbalance to organspecific abnormalities in psychiatric populations. Metabolically-dysfunctionassociated fatty liver disease (MAFLD), for example, has been identified even in lean individuals with bipolar disorder, indicating underlying metabolic vulnerability irrespective of body mass index (9). Similarly, autonomic markers such as heart rate deceleration capacity have shown prognostic value in acute ischemic stroke, a condition influenced by both metabolic and neuropsychiatric factors (10). These observations reinforce the hypothesis that cardiovascular, neuroendocrine, and psychiatric systems form a dynamically regulated continuum rather than discrete entities.Parallel advances in biomarker research provide new diagnostic perspectives. Altered circulating levels of norepinephrine and melatonin have emerged as reproducible neuroendocrine signatures in schizophrenia, reflecting disruptions in circadianmetabolic coupling (11). Meanwhile, advances in cardiac imaging, such as twodimensional speckle tracking echocardiography, have enabled non-invasive assessment of myocardial strain and therapeutic outcomes in patients with combined heart failure and metabolic syndrome, further illustrating the systemic reach of neuroendocrine regulation.Recent developments in computational modeling and biomarker integration demonstrate the translational potential of multi-parametric diagnostics. Predictive nomograms incorporating blood-derived biomarkers have successfully forecasted short-term recovery outcomes in stroke patients, where neuroendocrine stress reactivity serves as a critical determinant. Collectively, such findings highlight a paradigm shift: psychiatric and metabolic disorders must be conceptualized as interconnected manifestations of a shared neuroendocrine framework rather than as isolated conditions.Ultimately, elucidating neuroendocrine mechanisms underlying psychiatric-metabolic comorbidity presents an opportunity to redefine both disease classification and therapeutic intervention. Future strategies aimed at modulating neuropeptide signaling, circadian alignment, and stress reactivity hold promise for enhancing mental and metabolic health concurrently. Progress in this field will depend on interdisciplinary collaboration across neurobiology, psychiatry, and endocrinology, coupled with the integration of multi-omic datasets, longitudinal biomarker profiling, and advanced computational modeling to comprehensively characterize the bidirectional dialogue between the brain and body.