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.