Role of Adiposity-Driven Inflammation in Depressive Morbidity

Abstract

Depression and metabolic disorders, including overweight and obesity, appear tightly interrelated. The prevalence of these conditions is concurrently growing worldwide, and both depression and overweight/obesity represent substantial risk factors for multiple medical complications. Moreover, there is now multiple evidence for a bidirectional relationship between depression and increased adiposity, with overweight/obesity being associated with an increased prevalence of depression, and in turn, depression augmenting the risk of weight gain and obesity. Although the reasons for this intricate link between depression and increased adiposity remain unclear, converging clinical and preclinical evidence points to a critical role for inflammatory processes and related alterations of brain functions. In support of this notion, increased adiposity leads to a chronic low-grade activation of inflammatory processes, which have been shown elsewhere to have a potent role in the pathophysiology of depression. It is therefore highly possible that adiposity-driven inflammation contributes to the development of depressive disorders and their growing prevalence worldwide. This review will present recent evidence in support of this hypothesis and will discuss the underlying mechanisms and potential therapeutic targets. Altogether, findings presented here should help to better understand the mechanisms linking adiposity to depression and facilitate the identification of new preventive and/or therapeutic strategies.

Figure 1

Inflammation as a link between adiposity, depression and related comorbidities. The relationship between adiposity and depression is bidirectional, with adiposity being associated with an increased prevalence of depression, and in turn, depression (in particular, with atypical features) augmenting the risk of overweight/obesity. Depressive comorbidities in obesity facilitate the development of additional complications, including cardiovascular diseases (CVD), metabolic syndrome and type 2 diabetes. Inflammation represents the underlying link between adiposity and depression and their effects on comorbidites, given its position at the interface between metabolic, vascular and central nervous system pathways and its pivotal role in the etiology of disorders affecting these different systems.

Figure 2

Inflammation induces alterations in monoamine biosynthesis. Alterations in adipose tissue and gut microbiota lead to the production of inflammatory factors and endotoxemia, thus promoting a state of chronic low-grade inflammation. Inflammatory factors activate GTP-cyclohydrolase-1 (GTP-CH1), leading to the production of neopterin at the expense of tetrahydrobiopterin (BH4) and reducing activity of the enzymes tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) involved in dopamine and serotonin syntheses. In addition, lower level of BH4 reduces nitric oxide synthase (NOS) activity and increased O₂ concentration, which exacerbates BH4 inhibition. Cytokines also activate the enzyme indoleamine 2,3-dioxygenase (IDO), which results in the degradation of tryptophan along the kynurenine pathway at the expense of serotonin. Kynurenine is then degraded into quinolinic acid in microglia, thus promoting neurotoxicity.

Figure 3

Overview of the mechanisms and pathways of adiposity-driven inflammation in depressive morbidity. Overweight/obesity is associated with low-grade inflammation originating from the adipose tissue and changes in gut microbiota composition. Immune-to-brain communication leads to the activation of brain inflammatory processes responsible for substantial changes in brain function, including alterations in neurotransmitter biosynthesis and changes in neurogenesis and synaptic plasticity. Concomitantly, brain cytokines promote neurotoxicity through activation of glutamate pathways. Altogether, these alterations contribute to the development of depressive symptoms. BH4: tetrahydrobiopterin; GTP-CH1: guanosine triphosphate cyclohydrolase-1; IDO: indoleamine 2,3-dioxygenase; LPS: lipopolysaccharide.