Obesity and Depression: Two Sides of The Same Coin?

1. Serviço de Psiquiatria e Saúde Mental Hospital Garcia de Orta, Almada, Portugal. Recebido/Received: 20/01/2022 Aceite/Accepted: 12/08/2022 Publicado online/Published online: 14/09/2022 Publicado/Published: 30/09/2022 © Autor (es) (ou seu (s) empregador (es)) e Gazeta Médica 2022. Reutilização permitida de acordo com CC BY-NC. Nenhuma reutilização comercial. © Author(s) (or their employer(s)) and Gazeta Médica 2022. Re-use permitted under CC BY-NC. No commercial re-use. Dear Editor, Obesity and depression are both common medical conditions with major public health implications and high worldwide prevalence, increasing in recent decades. Obesity and depression frequently co-occur and epidemiological evidence strongly supports a bidirectional relationship between these conditions, with shared biological mechanisms and interventional opportunities. A better understanding of this comorbidity should be a priority, deserving our clinical attention. Literature suggests that both obesity and depression are disorders of stress with dysregulation of the stress system. Shared mechanisms involve genes, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, inflammation, oxidative stress, endocrine and metabolic derangement and gut microbiota alterations. These biological pathways may act in two, non-mutually exclusive, ways: as common underlying mechanisms influencing the liability to both conditions, or as mediating mechanisms in causal links between them. The phenotypic relationship between obesity and depression is rooted in partially overlapping genetic bases, involving genes such as NEGR1 – neuronal growth regulator-1 – modulating synaptic plasticity in brain areas essential for mood and appetite regulation. Hyperactivation of HPA axis represents a potentially relevant mechanism connecting obesity and depression, determining hypercortisolism that, in the long-term, may lead to neuronal damage and loss in limbic regions vulnerable to stress and associated with depression, like hippocampus and amygdala. Depressive states and obesity are associated with chronic low-grade inflammation, with increased pro-inflammatory cytokines. Peripheral immune activation, as occurs in obesity, can be translated via humoral, neural and cellular pathways into brain inflammation, with impact in depression pathophysiological processes, such as monoaminergic neurotransmission alteration. Findings support a decrease in cytokines upon resolution of depressive symptoms, inhibitory effect on cytokine production of antidepressants, and persistent upregulation of pro-inflammatory cytokines in treatment resistant depression. Endocrine/metabolic dysregulation includes leptin, melanocortin and insulin alterations. Gut microbiota, a complex active network that directly affects host metabolic phenotypes, may trigger inflammation and depression-related brain processes, creating a gut microbiota-brain axis potentially impacting on mood states through its metabolites.