High-fat diet induces neuroinflammation and reduces the serotonergic response to escitalopram in the hippocampus of obese rats.

Clinical studies indicate that obese individuals have an increased risk of developing co-morbid depressive illness and that these patients have reduced responses to antidepressant therapy, including selective serotonin reuptake inhibitors (SSRIs). Obesity, a condition of chronic mild inflammation including obesity-induced neuroinflammation, is proposed to contribute to decreases in synaptic concentrations of neurotransmitters like serotonin (5HT) by decreasing 5HT synthesis in the dorsal raphe nucleus (DRN) and/or affecting 5HT reuptake in DRN target regions like the hippocampus. In view of these observations, the goal of the current study was to examine inflammatory markers and serotonergic dynamics in co-morbid obesity and depression. Biochemical and behavioral assays revealed that high-fat diet produced an obesity and depressive-like phenotype in one cohort of rats and that these changes were marked by increases in key pro-inflammatory cytokines in the hippocampus. In real time using fast scan cyclic voltammetry (FSCV), we observed no changes in basal levels of hippocampal 5HT; however responses to escitalopram were significantly impaired in the hippocampus of obese rats compared to diet resistant rats and control rats. Further studies revealed that these neurochemical observations could be explained by increases in serotonin transporter (SERT) expression in the hippocampus driven by elevated neuroinflammation. Collectively, these results demonstrate that obesity-induced increases in neuroinflammation adversely affect SERT expression in the hippocampus of obese rats, thereby providing a potential synaptic mechanism for reduced SSRI responsiveness in obese subjects with co-morbid depressive illness.

Insulin resistance and hippocampal dysfunction: Disentangling peripheral and brain causes from consequences.

In the periphery insulin plays a critical role in the regulation of metabolic homeostasis by stimulating glucose uptake into peripheral organs. In the central nervous system (CNS), insulin plays a critical role in the formation of neural circuits and synaptic connections from the earliest stages of development and facilitates and promotes neuroplasticity in the adult brain. Beyond these physiological roles of insulin, a shared feature between the periphery and CNS is that decreases in insulin receptor activity and signaling (i.e. insulin resistance) contributes to the pathological consequences of type 2 diabetes (T2DM) and obesity. Indeed, clinical and preclinical studies illustrate that CNS insulin resistance elicits neuroplasticity deficits that lead to decreases in cognitive function and increased risk of neuropsychiatric disorders. The goals of this review are to provide an overview of the literature that have identified the neuroplasticity deficits observed in T2DM and obesity, as well as to discuss the potential causes and consequences of insulin resistance in the CNS, with a particular focus on how insulin resistance impacts hippocampal neuroplasticity. Interestingly, studies that have examined the effects of hippocampal-specific insulin resistance illustrate that brain insulin resistance may impair neuroplasticity independent of peripheral insulin resistance, thereby supporting the concept that restoration of brain insulin activity is an attractive therapeutic strategy to ameliorate or reverse cognitive decline observed in patients with CNS insulin resistance such as T2DM and Alzheimer's Disease.