Insulin action in brain regulates systemic metabolism and brain function.
Bottom Line: Insulin receptors, as well as IGF-1 receptors and their postreceptor signaling partners, are distributed throughout the brain.In addition, insulin signaling modulates phosphorylation of tau protein, an early component in the development of Alzheimer disease.Thus, alterations in insulin action in the brain can contribute to metabolic syndrome, and the development of mood disorders and neurodegenerative diseases.
Affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA.Show MeSH
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Mentions: Experiments manipulating the levels of insulin or IR in the brain have demonstrated a role of central insulin signaling in the regulation of several peripheral tissues (Fig. 3). For example, insulin suppression of glucose production in the liver (gluconeogenesis) is regulated by IRs in both the liver and brain, such that genetic inactivation of IRs in either of these tissues causes a loss of insulin suppression of hepatic glucose production (65,66). In the brain, this appears to involve IRs specifically in the AgRP neurons (37,65,67). Insulin action at the brain acts on gluconeogenesis also in part through stimulation of tyrosine phosphorylation of STAT3 in the liver (63). This results in an increase in hepatic interleukin-6 production, which inhibits hepatic glucose production, contributing further to the brain-liver control of gluconeogenesis. Conversely, CNS injection of insulin increases hepatic insulin sensitivity, and this occurs through central pathways involving PI3K and ATP-dependent potassium channels (66). Additionally, administration of insulin into the CNS promotes lipogenesis and peripheral fat accumulation (68). Insulin action in the brain also modulates the counter-regulatory response to hypoglycemia (69). Consistent with this, mice with a knockout of IR in the brain display a blunted sympathoadrenal response to hypoglycemia (67,70), showing that central insulin signaling directly alters glucose sensing in hypothalamic neurons. Central insulin does not, however, appear to affect glucose uptake in skeletal muscle or adipose tissue.
Affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA.