This narrative review synthesizes current evidence on the shared epidemiology and pathophysiology of obesity and major depressive disorder, examining how convergent biological pathways link two of the most prevalent and rising conditions worldwide. The authors describe a bidirectional relationship shaped by five interacting mechanisms: chronic low-grade inflammation involving elevated CRP, IL-6, TNF-α, and microglial activation; HPA axis dysregulation marked by altered cortisol dynamics, impaired feedback, and disrupted CRH and ACTH signaling; metabolic and neurotrophic disturbances such as insulin and leptin resistance, altered adipokine signaling, and reduced BDNF-supported synaptic plasticity; lipid-derived neurotoxicity and mitochondrial stress from saturated fatty acids, ceramides, and oxidative processes; and gut–brain axis perturbations including microbiota dysbiosis, increased intestinal permeability, LPS-driven endotoxemia, and altered short-chain fatty acid and tryptophan–kynurenine metabolism. Together, these pathways contribute to neuroinflammation and mood dysregulation in individuals with obesity, illustrating how metabolic and psychological processes are biologically intertwined rather than parallel. The authors highlight clinical implications for integrated screening and management approaches that address immune, neuroendocrine, metabolic, and microbial systems concurrently. They also outline priorities for identifying shared biomarkers and advancing personalized strategies through multi-omics and systems medicine to improve prevention, diagnosis, and treatment across both conditions. [NPID: Obesity and depression comorbidity, Neuroinflammation, HPA axis dysregulation, Gut–brain axis, Metabolic-mood pathways]
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