Neuropsychiatric comorbidity in obesity: role of inflammatory processes

Abstract

Neuropsychiatric symptoms are frequent in obesity. In addition to their substantial economic and health impact, these symptoms significantly interfere with the quality of life and social function of obese individuals. While the pathophysiological mechanisms underlying obesity-related neuropsychiatric symptoms are still under investigation and remain to be clearly identified, there is increasing evidence for a role of inflammatory processes. Obesity is characterized by a chronic low-grade inflammatory state that is likely to influence neuropsychiatric status given the well-known and highly documented effects of inflammation on brain activity/function and behavior. This hypothesis is supported by recent findings emanating from clinical investigations in obese subjects and from experimentations conducted in animal models of obesity. These studies converge to show that obesity-related inflammatory processes, originating either from the adipose tissue or gut microbiota environment, spread to the brain where they lead to substantial changes in neurocircuitry, neuroendocrine activity, neurotransmitter metabolism and activity, and neurogenesis. Together, these alterations contribute to shape the propitious bases for the development of obesity-related neuropsychiatric comorbidities.

Keywords: cognition; cytokines; gut-brain axis; inflammation; mood; neuroinflammation; neuropsychiatric symptoms; obesity.

Figure 1

Mechanisms underlying chronic low-grade inflammatory state in obesity. The adipose tissue is an important contributor of chronic low-grade inflammation in obesity (A). Weight gain is associated with substantial changes in the function of adipocytes that increase their secretion of adipokines, including inflammatory factors. Moreover, infiltration of immune cells, i.e., macrophages and T cells, in the adipose tissue is also responsible for the adipose secretion of inflammatory cytokines. Additional mechanisms, including alterations in the gut microbiota, contribute also to the instauration of obesity-related inflammation (B). Obesity is associated with modifications in gut microbial population and with an increased permeability of the intestinal wall that promotes the passage of LPS in the circulation, leading thus to the development of chronic low-grade endotoxemia and the increased production of inflammatory factors. IL-1β, interleukin-1β; IL-6, interleukin-6; LPS, lipopolysaccharide; TNF-α, tumor necrosis factor-α.

Figure 2

Pathophysiological mechanisms likely to underlie neuropsychiatric comorbidities associated with obesity. The activation of systemic inflammatory processes, originating from alterations in adipose tissue and gut functions, can contribute to the development of obesity-associated neuropsychiatric comorbidities. Proinflammatory cytokines released at the periphery can access the brain via several pathways (e.g., neural, humoral, and cellular routes) and induce the activation of neuroinflammatory processes, primarily by activating microglia. In the brain, proinflammatory cytokines impair neuroendocrine activity, neurotransmitter function (e.g., 5HT, DA, glutamate), and neurocircuitry, involving notably the hippocampus, the hypothalamus, the basal ganglia, and the prefrontal cortex. Cytokines can also disturb neurogenesis and induce neurotoxic effects through induction of IDO-derived neuroactive/neurotoxic metabolites. Altogether, these brain alterations lead ultimately to the development of behavioral/neuropsychiatric symptoms. Deregulations of the gut–brain axis, originating from changes in gut microbiota and permeability, may also contribute to mood and cognitive symptoms. These behavioral/neuropsychiatric symptoms can in turn promote the development or maintenance of obesity through risky or unadjusted eating behaviors. 5HT, serotonin; BG, basal ganglia; CNS, central nervous system; DA, dopamine; IDO, indoleamine 2,3-dioxygenase; HC, hippocampus; HPA, hypothalamic–pituitary–adrenal axis; LPS, lipopolysaccharide; PFC, prefrontal cortex; neurogen, neurogenesis; neurotox, neurotoxicity.