Neuroimmunometabolic Crosstalk in Obesity: From Pathophysiology to Emerging Therapies

Background: Obesity is increasingly recognized as a complex neuroimmunometabolic disorder rather than simply a consequence of excessive caloric intake. Chronic low-grade inflammation, oxidative stress, gut microbiota dysbiosis, hypothalamic dysfunction, and alterations in reward-related neural circuits interact to promote persistent weight gain and metabolic deterioration. Despite substantial advances in pharmacological management, achieving long-term obesity control remains challenging because of treatment discontinuation, interindividual variability in treatment response, and the multifactorial nature of the disease. Consequently, there is growing interest in integrative therapeutic strategies that target the interconnected nervous, immune, and metabolic pathways underlying obesity. Methods: A narrative literature review was conducted to examine the neuroimmunometabolic mechanisms underlying obesity and contemporary and emerging therapeutic strategies. The review covered neuroendocrine, inflammatory, metabolic, adipose tissue-related, gut microbiota-related, and therapeutic perspectives. Relevant publications were identified using available biomedical and scientific databases. Publications were screened using the following keywords: “obesity”, “neuroimmunometabolic dysregulation”, “inflammation”, “oxidative stress”, “gut microbiota”, “reward system”, “hypothalamic–pituitary–adrenal axis”, “personalized therapy”, “GLP-1 receptor agonists”, and “emerging therapeutics”. The evidence reviewed included findings from experimental and preclinical studies, as well as clinical studies involving human participants. The review aimed to summarize current knowledge of obesity pathophysiology and established and emerging therapeutic approaches. Results and Conclusions: Current evidence demonstrates that obesity arises from complex interactions involving genetic and epigenetic susceptibility, adipose tissue inflammation, mitochondrial dysfunction, oxidative stress, gut microbiota alterations, HPA axis hyperactivation, and dysregulated dopaminergic and serotonergic signaling. These mechanisms contribute to insulin resistance, impaired appetite regulation, maladaptive eating behaviors, and progressive metabolic dysfunction. Core lifestyle interventions, approved incretin-based pharmacotherapies, and metabolic-bariatric surgery represent established clinical standards. Meanwhile, a range of novel strategies is under investigation. These emerging approaches include anti-inflammatory and nutrigenomic dietary patterns, next-generation probiotics (Akkermansia muciniphila, Hafnia alvei), metabolic adjuvants (melatonin, N-acetylcysteine), mindfulness-based interventions, neuromodulation techniques, and experimental molecular therapies (antisense oligonucleotides, iPSC platforms). These findings support a neuroimmunometabolic model of obesity. However, further longitudinal and translational studies are essential to validate emerging approaches before their routine clinical implementation.