Insulin action in the brain regulates both central and peripheral functions

Abstract

The brain has been traditionally thought to be insensitive to insulin, primarily because insulin does not stimulate glucose uptake/metabolism in the brain (as it does in classic insulin-sensitive tissues such as muscle, liver, and fat). However, over the past 20 years, research in this field has identified unique actions of insulin in the brain. There is accumulating evidence that insulin crosses into the brain and regulates central nervous system functions such as feeding, depression, and cognitive behavior. In addition, insulin acts in the brain to regulate systemic functions such as hepatic glucose production, lipolysis, lipogenesis, reproductive competence, and the sympathoadrenal response to hypoglycemia. Decrements in brain insulin action (or brain insulin resistance) can be observed in obesity, type 2 diabetes (T2DM), aging, and Alzheimer's disease (AD), indicating a possible link between metabolic and cognitive health. Here, we describe recent findings on the pleiotropic actions of insulin in the brain and highlight the precise sites, specific neuronal population, and roles for supportive astrocytic cells through which insulin acts in the brain. In addition, we also discuss how boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Overall, this perspective article serves to highlight some of these key scientific findings, identify unresolved issues, and indicate future directions of research in this field that would serve to improve the lives of people with metabolic and cognitive dysfunctions.

Keywords: brain; diabetes; hypoglycemia; hypothalamus; insulin.

Graphical abstract

Figure 1.

In addition to regulating CNS (via neurons and/or astrocytes) functions (such as cognition, depression, and food intake), insulin acts in the brain to regulate peripheral functions via the autonomic nervous system (ANS) and the hypothalamic pituitary axis (HPA). Specifically, insulin acts in the prefrontal cortex and hippocampus to improve cognitive function and reduce depressive symptoms. Insulin acts in the hypothalamic nuclei to decrease food intake and reduce body weight. Via the efferent autonomic nervous system to target organs, insulin acts in the brain to decrease hepatic glucose production, increase lipogenesis, decrease lipolysis, and increase the sympathoadrenal response to hypoglycemia. Insulin acts via the hypothalamic-pituitary-gonadal axis to improve reproductive competence. CNS, central nervous system.