Editorial: Insulin and The Brain

International audienceThe role of insulin in the brain has been suggested in the late 1950's based on experiments showing that insulin was able to increase glucose uptake in spinal cord tissue, in several brain regions such as the choroid plexus the pineal gland, and in the pituitary (1). Since then, increasing evidence attributed to insulin action in the brain numerous critical roles in the control of vital physiological functions: energy homeostasis, neuronal plasticity, and growth, lipid, and glucose metabolism through the control of peripheral organs. Furthermore, the alteration of insulin action observed in insulin-resistant state or obesity is considered a risk factor for several pathologies including neurodegenerative diseases and metabolic disorders. Nowadays, many studies aim to decipher the mechanisms of insulin action in different brain regions and the related physio-pathological outputs

Insulin regulates neurovascular coupling through astrocytes.

Circulating insulin enters the brain through mechanisms incompletely characterized. We now report that mice lacking insulin receptors (IR) in astrocytes (GFAP-IR KO mice) show blunted brain responses to insulin, uncoupling of brain blood flow with glucose uptake with concomitant changes in brain vasculature and glucose transporter 1 levels. IR-deficient astrocytes show increased expression of HIF-1α/VEGF, promote growth of co-cultured endothelial cells, display increased reactive oxidant species (ROS) and disturbed mitochondrial activity. Treatment with the antioxidant N-acetylcysteine (NAC), ameliorated high ROS levels, normalized angiogenic signaling, and mitochondrial function including mitochondrial glucose and oxygen sensors. In vivo treatment with NAC also normalized brain perfusion. Thus, insulin receptors in astrocytes regulate neuro-vascular coupling.pre-print4711 K

Interaction of gonadal steroids and growth factors in brain sex differentiation

Sex hormones have developmental trophic actions on neurons and glial cells and activational effects in the adult brain. It has been proposed that sex steroids may interact with peptide trophic factors to induce part of their biological effects in the nervous system. The first evidence of such an interaction was provided by Toran-Allerand et al (Brain Research 1980; 184: 517-524), showing that in explant cultures of fetal rodent hypothalamus, estrogen and insulin have synergistic effects on neurite growth, an effect probably mediated by insulin-like growth factor-1 receptors. Recent data indicate that estrogen and insulin-like growth factor-1 signaling pathways interact on hypothalamic neurons to regulate survival and differentiation and that sex steroids interact with a variety of different trophic signals in vivo to regulate neuroendocrine events. These findings suggest that trophic factors may be involved in the genesis of sex differences in the developing brain and in the maintenance of a sexually differentiated brain function in the adult.Biomedical Reviews 1997; 7: 67-74

Response Facilitation Induced by Insulin-like Growth Factor-I in the Primary Somatosensory Cortex of MiceWas Reduced in Aging.

Aging is accompanied by a decline in cognition that can be due to a lower IGF-I level. We studied response facilitation induced in primary somatosensory (S1) cortical neurons by repetitive stimulation of whiskers in young and old mice. Layer 2/3 and 5/6 neurons were extracellularly recorded in young ( 6 months of age) and old ( 20 month of age) anesthetized mice. IGF-I injection in S1 cortex (10 nM; 0.2 L) increased whisker responses in young and old animals. A stimulation train at 8 Hz induced a long-lasting response facilitation in only layer 2/3 neurons of young animals. However, all cortical neurons from young and old animals showed long-lasting response facilitation when IGF-I was applied in the S1 cortex. The reduction in response facilitation in old animals can be due to a reduction in the IGF-I receptors as was indicated by the immunohistochemistry study. Furthermore, a reduction in the performance of a whisker discrimination task was observed in old animals. In conclusion, our findings indicate that there is a reduction in the synaptic plasticity of S1 neurons during aging that can be recovered by IGF-I. Therefore, it opens the possibility of use IGF-I as a therapeutic tool to ameliorate the effects of heathy aging.post-print2685 K

Astrocytes require insulin-like growth factor I to protect neurons against oxidative injury

Oxidative stress is a proposed mechanism in brain aging, making the study of its regulatory processes an important aspect of current neurobiological research. In this regard, the role of the aging regulator insulin-like growth factor I (IGF-I) in brain responses to oxidative stress remains elusive as both beneficial and detrimental actions have been ascribed to this growth factor. Because astrocytes protect neurons against oxidative injury, we explored whether IGF-I participates in astrocyte neuroprotection and found that blockade of the IGF-I receptor in astrocytes abrogated their rescuing effect on neurons. The protection mediated by IGF-I against oxidative stress (H2O2) in astrocytes is probably needed for these cells to provide adequate neuroprotection. Indeed, in astrocytes but not in neurons, IGF-I helps decrease the pro-oxidant protein thioredoxin-interacting protein 1 and normalizes the levels of reactive oxygen species. Furthermore, IGF-I cooperates with trophic signals produced by astrocytes in response to H2O2 such as stem cell factor (SCF) to protect neurons against oxidative insult. After stroke, a condition associated with brain aging where oxidative injury affects peri-infarcted regions, a simultaneous increase in SCF and IGF-I expression was found in the cortex, suggesting that a similar cooperative response takes place in vivo. Cell-specific modulation by IGF-I of brain responses to oxidative stress may contribute in clarifying the role of IGF-I in brain aging

Blockade of the Interaction of Calcineurin with FOXO in Astrocytes Protects Against Amyloid-beta-Induced Neuronal Death

Astrocytes actively participate in neuro-inflammatory processes associated to Alzheimer's disease (AD), and other brain pathologies. We recently showed that an astrocyte-specific intracellular signaling pathway involving an interaction of the phosphatase calcineurin with the transcription factor FOXO3 is a major driver in AD-associated pathological inflammation, suggesting a potential new druggable target for this devastating disease. We have now developed decoy molecules to interfere with calcineurin/FOXO3 interactions, and tested them in astrocytes and neuronal co-cultures exposed to amyloid-beta (A beta) toxicity. We observed that interference of calcineurin/FOXO3 interactions exerts a protective action against A beta-induced neuronal death and favors the production of a set of growth factors that we hypothesize form part of a cytoprotective pathway to resolve inflammation. Furthermore, interference of the A beta-induced interaction of calcineurin with FOXO3 by decoy compounds significantly decreased amyloid-beta protein precursor (A beta PP) synthesis, reduced the A beta PP amyloidogenic pathway, resulting in lower A beta levels, and blocked the expression of pro-inflammatory cytokines TNF alpha and IL-6 in astrocytes. Collectively, these data indicate that interrupting pro-inflammatory calcineurin/FOXO3 interactions in astrocytes triggered by A beta accumulation in brain may constitute an effective new therapeutic approach in AD. Future studies with intranasal delivery, or brain barrier permeable decoy compounds, are warranted.Peer ReviewedPostprint (author's final draft

Insulin regulates neurovascular coupling through astrocytes

Mice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IRdeficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1¿ and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N-acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.We are thankful to M.Garcia and R. Cañadas for technical support. This work was funded by Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (Instituto de Salud CarlosIII, Spain) to I.T.A., A.G., and T.I.; an Inter-CIBER project (PIE14/00061) to I.T.A.that forms part of the projects PID2019-104376RB-I00 (I.T.A.) and RTI2018-094887-B-I00 (M.N.) funded by MCIN/AEI/10.13039/501100011033; a grant from Junta de Andalucia Consejería de Economía y Conocimiento (P18-RT-2233 to A.G.) cofinanced by Programa Operativo FEDER 2014–2020; a grant from Instituto de Salud Carlos III Spain (cofinanced by FEDER funds from the European Union; PI21/00915 to A.G.); Grant PID2020-115218RB-I00 to T.I. funded by Ministerio de Ciencia e Innovación/Agencia Española de Investigación (MCIN/AEI/10.13039/501100011033); and a grant from Comunidad de Madrid through the European Social Fund (ESF)–financed programme Neurometabolismo-Comunidad de Madrid (NEUROMETAB-CM) (B2017/BMD-3700 to I.T.A.and T.I.). M.N. was also supported by the Spanish Ministry of Science and Innovation (Ramón y Cajal RYC-2016-20414). J.P.-U. was contracted by CIBERNED

Circulating insulin-like growth factor I and cognitive function:Neuromodulation throughout the lifespan

Insulin-like growth factor I (IGF-I) is central to the somatotropic (growth hormone) axis. It promotes tissue growth and continues to have anabolic effects in adulthood. Accumulating evidence from the last decade, however, reveals that circulating levels of IGF-I also significantly affects cognitive brain function. Specifically, the decline of serum IGF-I might be associated with the age-related cognitive decline in elderly people. Moreover, psychiatric and neurological conditions characterized by cognitive impairment may be characterized by altered levels of IGF-I. Some evidence is emerging that interventions that target the GH/IGF-I axis may improve cognitive functioning, at least in deficient states. As there is evidence linking high serum IGF-I levels with cancer risk these interventions should be carefully evaluated. On a cellular and molecular level, IGF-I may be a crucial component of neural homeostasis since disturbed IGF-I input is inevitably linked to perturbed function. Consistent with this, all nerve cells are potential targets of IGF-I actions, including neurons, glia, endothelial, epithelial, and perivascular cells. Indeed, many key cellular processes in the brain are affected by IGF-I's neurotrophic and modulatory actions. We review the regulation by IGF-I of neurotransmission and neuronal plasticity and conclude that serum IGF-I is an important mediator of neuronal growth, survival and function throughout the lifespan. The role of IGF-I in synaptic plasticity render its neurotrophic potential a key target for remediating the cognitive impairment associated with a range of neurological conditions. (C) 2009 Elsevier Ltd. All rights reserved