Dear Editor,

Obesity and depression are both common medical conditions with major public health implications and high worldwide prevalence, increasing in recent decades.^1-4 Obesity and depression frequently co-occur and epidemiological evidence strongly supports a bidirectional relationship between these conditions, with shared biological mechanisms and interventional opportunities.^1,3 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.¹ Shared mechanisms involve genes, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, inflammation, oxidative stress, endocrine and metabolic derangement and gut microbiota alterations.^1,2 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.³

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.³ 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.^1,3 Depressive states and obesity are associated with chronic low-grade inflammation, with increased pro-inflammatory cytokines.^1,3 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.³ 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.¹ Endocrine/metabolic dysregulation includes leptin, melanocortin and insulin alterations.³ 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.^2,3

Obesity and depression are thus interconnected through a vicious, mutually reinforcing cycle of adverse physiological adaptations.³ Reducing obesity-induced neuroinflammation may conduct to beneficial effects on depression.²

In patients with co-occurring obesity and depression, the inclusion of dietary interventions, with calorie-restricted diets, along with psychopharmacologic and/or psychotherapeutic treatments, may result in improvement of depression symptoms, in relation to immunoendocrine and psychosocial mechanisms.⁴ When treating this subgroup of patients, we must focus on multidisciplinary interventions and remember that obesity and depression appear to be two sides of the same coin.