The many faces of insulin-like peptide signalling in the brain

Fernández, Adolfo; Torres‐Alemán, Ignacio

doi:10.1038/nrn3209

Cited by 737 publications

(559 citation statements)

References 178 publications

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“…For example, we observed early effects of the treatment on Mecp2 −/y behavior, but saw efficacy only at later stages in locomotor activity. This variability could partly be due to the contribution of different brain regions to a given endophenotype and region-specific responses to rhIGF1, given the availability of peripheral IGF1 and the heterogeneous expression pattern of IGF1 receptors in the adult mouse brain (16). The cortex, choroid plexus, and endothelial cells are regions with the highest expression of receptors-the last two are major entry points of systemic IGF1 into the CNS, consistent with the importance of peripheral IGF1 in the maintenance of CNS levels.…”

Section: Discussionmentioning

confidence: 99%

“…Another major activator of these signaling pathways is insulinlike growth factor-1 (IGF1), which is primarily expressed in the liver and acts in an endocrine fashion throughout the body, crossing the BBB in a neuronal activity-dependent manner (14); IGF1 is also produced in the brain, especially during early stages of development (15,16). A previous study showed that administering the tripeptide fragment Glutamate-Proline-Glycine (GPE) or (1-3)IGF1, the first 3 (of 70) amino acids of IGF1, to Mecp2 KO mice was effective in correcting several symptoms and restoring key synaptic molecules (5).…”

mentioning

confidence: 99%

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Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome

Castro

Garcia

Kwok

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

178

167

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Rett Syndrome is a neurodevelopmental disorder that arises from mutations in the X-linked gene methyl-CpG binding protein 2 (MeCP2). MeCP2 has a large number of targets and a wide range of functions, suggesting the hypothesis that functional signaling mechanisms upstream of synaptic and circuit maturation may contribute to our understanding of the disorder and provide insight into potential treatment. Here, we show that insulin-like growth factor-1 (IGF1) levels are reduced in young male Mecp2-null (Mecp2 −/y ) mice, and systemic treatment with recombinant human IGF1 (rhIGF1) improves lifespan, locomotor activity, heart rate, respiration patterns, and social and anxiety behavior. Furthermore, Mecp2-null mice treated with rhIGF1 show increased synaptic and activated signaling pathway proteins, enhanced cortical excitatory synaptic transmission, and restored dendritic spine densities. IGF1 levels are also reduced in older, fully symptomatic heterozygous (Mecp2 −/+ ) female mice, and short-term treatment with rhIGF1 in these animals improves respiratory patterns, reduces anxiety levels, and increases exploratory behavior. In addition, rhIGF1 treatment normalizes abnormally prolonged plasticity in visual cortex circuits of adult Mecp2 −/+ female mice. Our results provide characterization of the phenotypic development of Rett Syndrome in a mouse model at the molecular, circuit, and organismal levels and demonstrate a mechanism-based therapeutic role for rhIGF1 in treating Rett Syndrome. molecular therapeutic | respiration | synaptic function | male mice | female mice R ett Syndrome (RTT) is a devastating, rare neurodevelopmental disorder that primarily afflicts girls. Over 90% of individuals with RTT have sporadic mutations in the X-linked gene coding for methyl-CpG binding protein 2 (MeCP2). Affected girls are initially asymptomatic, but later develop a wide range of symptoms. Mouse models of RTT with deletion of Mecp2 recapitulate many of the key physiological, autonomic, motor, and cognitive aspects of the disorder (1, 2).MeCP2 binds widely across the genome and has complex roles that encompass activating or inhibiting gene transcription, repressing methylation, regulating chromatin remodeling, and altering noncoding RNAs (3). This wide range of functions has led to the proposal that a focus on functional signaling pathways is needed to drive an understanding of RTT and its possible therapeutics (1, 2, 4). Several lines of evidence indicate an arrested brain maturation phenotype in RTT, suggesting that loss of functional MeCP2 leads to immature synapses and circuits in the brain (5). Importantly, mouse models have suggested reversibility of specific symptoms once MeCP2 function is restored (6, 7). One well-documented target of MeCP2 is brain-derived neurotrophic factor (BDNF), which is known to be critical for neuronal and synaptic maturation and is down-regulated in Mecp2 mutant mice and RTT patients (8, 9). BDNF exerts influence on neurons and synapses mainly via the phosphoinositide 3-kinase (PI3K)/Akt pathway ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome

Castro

Garcia

Kwok

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

178

167

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“…In addition to its peripheral effects, insulin may affect energy balance and peripheral metabolism via central actions, such as through modulation of food intake; insulin signaling in the brain has been extensively reviewed elsewhere (e.g. Stockhorst et al 2004, Schwartz & Porte 2005, Fernandez & Torres-Aleman 2012, Lee et al 2016. Insulin clearly has essential roles in regulating energy balance and metabolic pathways, but there is still much to be learned about these and other critical functions of this hormone.…”

Section: Insulin As a Key Metabolic Hormonementioning

confidence: 99%

“…In mammals, the superfamily of insulin-like genes includes insulin, two insulin-like 232:3 growth factors (IGF1 and IGF2), relaxins (three relaxin genes in humans) and four additional insulin-like peptides (insulin-like peptides 3-6; Nakae et al 2001, Shabanpoor et al 2009, Fernandez & Torres-Aleman 2012. These mammalian peptides appear to be derived from a shared ancestral gene and have structural similarities, although the known biological functions of the majority of these peptides appear largely distinct from those of insulin and IGF1 (Shabanpoor et al 2009).…”

Section: Phylogeny and Complexity Of Insulin-like Peptides And The Inmentioning

confidence: 99%

A causal role for hyperinsulinemia in obesity

Templeman

Skovsø

Page

et al. 2017

Journal of Endocrinology

127

108

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Insulin modulates the biochemical pathways controlling lipid uptake, lipolysis and lipogenesis at multiple levels. Elevated insulin levels are associated with obesity, and conversely, dietary and pharmacological manipulations that reduce insulin have occasionally been reported to cause weight loss. However, the causal role of insulin hypersecretion in the development of mammalian obesity remained controversial in the absence of direct loss-of-function experiments. Here, we discuss theoretical considerations around the causal role of excess insulin for obesity, as well as recent studies employing mice that are genetically incapable of the rapid and sustained hyperinsulinemia that normally accompanies a high-fat diet. We also discuss new evidence demonstrating that modest reductions in circulating insulin prevent weight gain, with sustained effects that can persist after insulin levels normalize. Importantly, evidence from long-term studies reveals that a modest reduction in circulating insulin is not associated with impaired glucose homeostasis, meaning that body weight and lipid homeostasis are actually more sensitive to small changes in circulating insulin than glucose homeostasis in these models. Collectively, the evidence from new studies on genetic loss-of-function models forces a re-evaluation of current paradigms related to obesity, insulin resistance and diabetes. The potential for translation of these findings to humans is briefly discussed.

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“…The gene itself is subject to differential splicing and the protein can be modified after translation by proteolysis and glycosylation (52). IGF1 is part of a larger family of proteins including INS and IGF2, and each can interact with each other's receptors (INSR, IGF1R, and IGF2R) (53). The effective concentration of IGF1 and IGF2 for receptor interactions depends upon concentrations of 6 separate IGF-binding proteins, which prevent receptor binding while also increasing the half-life of IGF1 (52).…”

Section: Insulin-like Growth Factormentioning

confidence: 99%

Maternal embryokines that regulate development of the bovine preimplantation embryo

Hansen¹,

Denicol²,

Dobbs³

2014

Turk J Vet Anim Sci

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The zygote contains within its genome and epigenome the program to direct development through the embryonic, fetal, and postnatal periods. The execution of that program is dependent on the embryo's nongenetic inheritance from the oocyte and sperm (1,2) as well as on the environment in which development proceeds. Variation in the maternal environment can affect the ability of the preimplantation embryo to establish pregnancy. In cattle, the focus of this review, competence of the preimplantation embryo for growth and survival can be affected by maternal parity (3), lactational status (4), and circulating concentrations of progesterone (5). Moreover, patterns of gene expression in the endometrium are associated with survival of an embryo transferred to the uterus in the next ovulatory cycle (6,7).Development of the bovine embryo to the blastocyst in the absence of maternal signals (i.e. through in vitro production procedures) results in embryos with aberrant gene expression (8,9), lipid content (10,11), DNA methylation (12), and, as shown in the Table, reduced competence to establish pregnancy after transfer into recipients (13-17). Additionally, an increased proportion of embryos produced in vitro have developmental abnormalities that lead to increased neonatal death losses (18-20). Some of the problems with the in vitro-produced embryo could result from selection of incompetent oocytes or inadequate oocyte maturation. However, the importance of the maternal environment during development is indicated by observations that transfer of in vitro-produced embryos to the oviduct after fertilization limits some of the abnormalities associated with in vitro production (9,21).One function of the reproductive tract is to secrete bioactive molecules that regulate the embryo, oviduct, or endometrium. Genes for 115 ligands expressed in the endometrium had the corresponding receptor gene expressed by the embryo (22). Regulatory molecules produced by the oviduct and endometrium, which include hormones, growth factors, and cytokines, are referred to as embryokines when they function to regulate embryonic growth and development (23).It is likely that some of the variation in the ability of the reproductive tract to support embryonic development represents variation in secretion of embryokines. Indeed, several genes that were overexpressed in the endometrium of cows that subsequently became pregnant after embryo transfer as compared to cows that did not establish pregnancy are potential embryokines. These include NGF,

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The many faces of insulin-like peptide signalling in the brain

Cited by 737 publications

References 178 publications

Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome

Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome

A causal role for hyperinsulinemia in obesity

Maternal embryokines that regulate development of the bovine preimplantation embryo

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