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: The best-studied effects of insulin signaling in the brain are those regarding food intake and energy expenditure. As early as 1979, Woods et al. (35) showed that intracerebroventricular infusion of insulin in baboons could markedly decrease food intake and body weight gain. Insulin administration into the third ventricle in rodents has been shown to decrease food intake by decreasing expression of the orexigenic neuropeptides neuropeptide Y (NPY) and Agouti-related peptide (AgRP), and by increasing the expression of anorexigenic neuropeptides proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CaRT) in the arcuate nucleus, which together result in increased activity of α-melanocyte-stimulating hormone in neurons in the paraventricular nucleus (Fig. 2A) (36). Conversely, in the hypothalamus of insulin-deficient streptozotocin (STZ)-treated mice, there is an increase in NPY and AgRP accompanied by a decrease in POMC and CaRT (Fig. 2B). As a result, brain-specific deletion of IR in mice leads to increased food intake and mild obesity (6). This anorexigenic effect of insulin is, at least in part, a result of PI3K-dependent activation of ATP-dependent potassium channels in hypothalamic neurons, which hyperpolarize and inactivate the orexigenic AgRP neurons (37).
Affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA.