Abstract
Depression and obesity are amongst the most serious global health challenges. Each of them is associated with high morbidity, chronicity, and socioeconomic burden. Increasing evidence suggests that these conditions are not merely comorbid but share convergent biological pathways (e.g., hypothalamic-pituitary-adrenal axis dysregulation, chronic inflammation, gut dysbiosis, and mitochondrial dysfunction). All these components contribute together to the development and persistence of depressive symptoms as well as to an increase in adiposity. Within this framework, adipose tissue has emerged as an essential endocrine organ that has a deep impact on neuroimmune signalling and mood regulation through its secreted molecules, such as leptin, adiponectin, resistin, omentin, apelin, chemerin, and visfatin. The current management of depression involves a comprehensive, multidisciplinary approach that includes pharmacological treatment and psychotherapeutic support, alongside lifestyle changes. Here we highlight the molecular crosstalk between adipose tissue and the brain, summarising the evidence of adipokines' dysregulation role in connecting metabolic dysfunction to depressive neurobiology. By integrating metabolic, immunological, and neuroendocrine perspectives, this narrative review underscores the need to reconceptualise depression as an immunometabolic disorder. Understanding adipokine-mediated pathways may reveal new biomarkers and therapeutic targets, fostering interdisciplinary approaches. This would allow for the development of new treatment strategies, which include recombinant adipokines, anti-inflammatory agents, and microbial modulation. These new strategies might provide a significant benefit in selected patients, in addition to conventional antidepressants.