Limits...
Insulin action in brain regulates systemic metabolism and brain function.

Kleinridders A, Ferris HA, Cai W, Kahn CR - Diabetes (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA.

Show MeSH

Related in: MedlinePlus

Insulin regulates orexigenic and anorexigenic peptides and body temperature. A: Insulin regulates appetite through the hypothalamus. In the arcuate nucleus (ARC) of the hypothalamus, insulin binds to IRs on POMC neurons to increase the expression of anorexigenic peptides, POMC, and CaRT, which results in increased activity of α-melanocyte–stimulating hormone (α-MSH) on melanin-concentrating hormone (MCH) neurons in the paraventricular nucleus (PVN). Conversely, insulin acts on AgRP neurons to inhibit the expression of orexigenic peptides AgRP and NPY. In addition, upon insulin binding, IR activates PI3K, triggering ATP-dependent potassium (KATP) channels, K+ efflux, and hyperpolarization of AgRP neurons. This results in the attenuation of the inhibitory effect of AgRP neurons on both MCH and POMC neurons. In parallel, insulin and leptin act to decrease food intake. B: Transcription of the orexigenic peptides AgRP and NPY is increased, and transcription of the anorexigenic peptides POMC and CaRT is decreased in the hypothalami of STZ-treated mice compared with controls, as determined by microarray analysis on isolated hypothalami of C57BL/6 mice 10 days after treatment with vehicle or STZ to induce diabetes. Data are expressed as the percentage change over vehicle-treated mice. P < 0.01 for all genes. C: Brain IR knockout (NIRKO) mice show a significant drop in body temperature compared with controls when exposed to 4°C cold stress, indicating a defect in thermogenesis. Experiments were performed on 17-month-old female mice. ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4066341&req=5

Figure 2: Insulin regulates orexigenic and anorexigenic peptides and body temperature. A: Insulin regulates appetite through the hypothalamus. In the arcuate nucleus (ARC) of the hypothalamus, insulin binds to IRs on POMC neurons to increase the expression of anorexigenic peptides, POMC, and CaRT, which results in increased activity of α-melanocyte–stimulating hormone (α-MSH) on melanin-concentrating hormone (MCH) neurons in the paraventricular nucleus (PVN). Conversely, insulin acts on AgRP neurons to inhibit the expression of orexigenic peptides AgRP and NPY. In addition, upon insulin binding, IR activates PI3K, triggering ATP-dependent potassium (KATP) channels, K+ efflux, and hyperpolarization of AgRP neurons. This results in the attenuation of the inhibitory effect of AgRP neurons on both MCH and POMC neurons. In parallel, insulin and leptin act to decrease food intake. B: Transcription of the orexigenic peptides AgRP and NPY is increased, and transcription of the anorexigenic peptides POMC and CaRT is decreased in the hypothalami of STZ-treated mice compared with controls, as determined by microarray analysis on isolated hypothalami of C57BL/6 mice 10 days after treatment with vehicle or STZ to induce diabetes. Data are expressed as the percentage change over vehicle-treated mice. P < 0.01 for all genes. C: Brain IR knockout (NIRKO) mice show a significant drop in body temperature compared with controls when exposed to 4°C cold stress, indicating a defect in thermogenesis. Experiments were performed on 17-month-old female mice. ***P < 0.001.

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).


Insulin action in brain regulates systemic metabolism and brain function.

Kleinridders A, Ferris HA, Cai W, Kahn CR - Diabetes (2014)

Insulin regulates orexigenic and anorexigenic peptides and body temperature. A: Insulin regulates appetite through the hypothalamus. In the arcuate nucleus (ARC) of the hypothalamus, insulin binds to IRs on POMC neurons to increase the expression of anorexigenic peptides, POMC, and CaRT, which results in increased activity of α-melanocyte–stimulating hormone (α-MSH) on melanin-concentrating hormone (MCH) neurons in the paraventricular nucleus (PVN). Conversely, insulin acts on AgRP neurons to inhibit the expression of orexigenic peptides AgRP and NPY. In addition, upon insulin binding, IR activates PI3K, triggering ATP-dependent potassium (KATP) channels, K+ efflux, and hyperpolarization of AgRP neurons. This results in the attenuation of the inhibitory effect of AgRP neurons on both MCH and POMC neurons. In parallel, insulin and leptin act to decrease food intake. B: Transcription of the orexigenic peptides AgRP and NPY is increased, and transcription of the anorexigenic peptides POMC and CaRT is decreased in the hypothalami of STZ-treated mice compared with controls, as determined by microarray analysis on isolated hypothalami of C57BL/6 mice 10 days after treatment with vehicle or STZ to induce diabetes. Data are expressed as the percentage change over vehicle-treated mice. P < 0.01 for all genes. C: Brain IR knockout (NIRKO) mice show a significant drop in body temperature compared with controls when exposed to 4°C cold stress, indicating a defect in thermogenesis. Experiments were performed on 17-month-old female mice. ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4066341&req=5

Figure 2: Insulin regulates orexigenic and anorexigenic peptides and body temperature. A: Insulin regulates appetite through the hypothalamus. In the arcuate nucleus (ARC) of the hypothalamus, insulin binds to IRs on POMC neurons to increase the expression of anorexigenic peptides, POMC, and CaRT, which results in increased activity of α-melanocyte–stimulating hormone (α-MSH) on melanin-concentrating hormone (MCH) neurons in the paraventricular nucleus (PVN). Conversely, insulin acts on AgRP neurons to inhibit the expression of orexigenic peptides AgRP and NPY. In addition, upon insulin binding, IR activates PI3K, triggering ATP-dependent potassium (KATP) channels, K+ efflux, and hyperpolarization of AgRP neurons. This results in the attenuation of the inhibitory effect of AgRP neurons on both MCH and POMC neurons. In parallel, insulin and leptin act to decrease food intake. B: Transcription of the orexigenic peptides AgRP and NPY is increased, and transcription of the anorexigenic peptides POMC and CaRT is decreased in the hypothalami of STZ-treated mice compared with controls, as determined by microarray analysis on isolated hypothalami of C57BL/6 mice 10 days after treatment with vehicle or STZ to induce diabetes. Data are expressed as the percentage change over vehicle-treated mice. P < 0.01 for all genes. C: Brain IR knockout (NIRKO) mice show a significant drop in body temperature compared with controls when exposed to 4°C cold stress, indicating a defect in thermogenesis. Experiments were performed on 17-month-old female mice. ***P < 0.001.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA.

Show MeSH
Related in: MedlinePlus