Insulin receptors and signal transduction proteins in the hypothalamo-hypophyseal system: a review on morphological findings and functional implications.

Receptors for insulin are widely distributed in the brain and pituitary. The current hypothesis on receptor function in these regions points to a role of insulin as a mediator in the communication of the peripheral endocrine system with the brain via various steps of the neuroendocrine axis. Recent data demonstrate that receptor-positive neurons in the brain, i.e. in the hypothalamus, and secretory cells in the anterior pituitary gland possess specific proteins that are thought to be involved in key steps of post receptor signal transduction, in particular insulin receptor substrate-1 and phosphatidylinositol 3'-kinase (PI3k). PI3k is a critical enzyme of the intracellular signaling pathway that is activated by a number of receptor tyrosine kinases, including receptors for insulin and IGF-1. This information further completes the framework indicating in vivo activity of insulin receptors in central neuroendocrine cells and their involvement in one branch of several physiological mechanisms that control body metabolism and nutritional behaviour.

[1]  M. White,et al.  Regulation of Phosphatidylinositol 3′-Kinase by Tyrosyl Phosphoproteins , 1995, The Journal of Biological Chemistry.

[2]  T. Pawson,et al.  The association of insulin-elicited phosphotyrosine proteins with src homology 2 domains. , 1992, The Journal of biological chemistry.

[3]  T Pawson,et al.  SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. , 1991, Science.

[4]  M. White,et al.  The IRS-1 signaling system. , 1994, Trends in biochemical sciences.

[5]  S. Gauthier,et al.  Origin of insulin-receptive nerve terminals in rat median eminence. , 1983, Endocrinology.

[6]  D. Leroith,et al.  Insulin and insulin-like growth factor-I stimulate a common endogenous phosphoprotein substrate (pp185) in intact neuroblastoma cells. , 1987, The Journal of biological chemistry.

[7]  C. Kahn,et al.  Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells , 1985, Nature.

[8]  S. Woods,et al.  Insulin in the brain: a hormonal regulator of energy balance. , 1992, Endocrine reviews.

[9]  J. Pessin,et al.  Functional expression of insulin receptor substrate-1 is required for insulin-stimulated mitogenic signaling. , 1993, The Journal of biological chemistry.

[10]  J. Grizard,et al.  Metabolic clearance of insulin from the cerebrospinal fluid in the anesthetized rat , 1990, Peptides.

[11]  G. Lienhard,et al.  Insulin signalling: the role of insulin receptor substrate 1. , 1994, Trends in cell biology.

[12]  A. Cagnacci,et al.  Insulin, insulin-like growth factor I (IGF-I) and IGF-II enhance basal and gonadotrophin-releasing hormone-stimulated luteinizing hormone release from rat anterior pituitary cells in vitro. , 1994, European journal of endocrinology.

[13]  B. Jeanrenaud,et al.  Effect of Sustained Physiological Hyperinsulinaemia on Hypothalamic Neuropeptide Y and NPY mRNA Levels in the Rat , 1995, Journal of neuroendocrinology.

[14]  C. Kahn,et al.  Insulin Receptor Substrate-l (IRS-I) Distribution in the Rat Central Nervous System , 1994 .

[15]  C. Kahn,et al.  Interactive roles of Ras, insulin receptor substrate-1, and proteins with Src homology-2 domains in insulin signaling in Xenopus oocytes. , 1994, The Journal of biological chemistry.

[16]  J. Unger,et al.  Insulin receptors in the pituitary gland: morphological evidence for influence on opioid peptide-synthesizing cells , 1997, Cell and Tissue Research.

[17]  G. King,et al.  Receptor-mediated transport of insulin across endothelial cells. , 1985, Science.

[18]  C. Kahn,et al.  Cascade of autophosphorylation in the β‐subunit of the insulin receptor , 1989 .

[19]  Y. Yarden,et al.  Insulin and insulinomimetic agents induce activation of phosphatidylinositol 3'-kinase upon its association with pp185 (IRS-1) in intact rat livers. , 1992, The Journal of biological chemistry.

[20]  G. Lienhard,et al.  Components of signaling pathways for insulin and insulin-like growth factor-I in muscle myoblasts and myotubes. , 1992, Endocrinology.

[21]  C. Kahn,et al.  Insulin stimulation of phosphatidylinositol 3-kinase activity and association with insulin receptor substrate 1 in liver and muscle of the intact rat. , 1992, The Journal of biological chemistry.

[22]  D. James,et al.  Hyperinsulinemia suppresses glucose utilization in specific brain regions: in vivo studies using the euglycemic clamp in the rat. , 1985, Endocrinology.

[23]  R. U. Margolis,et al.  Insulin in the Cerebrospinal Fluid , 1967, Nature.

[24]  G. Werther,et al.  Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. , 1987, Endocrinology.

[25]  C. Kahn,et al.  Purification and partial sequence analysis of pp185, the major cellular substrate of the insulin receptor tyrosine kinase. , 1991, The Journal of biological chemistry.

[26]  T. Pawson,et al.  The insulin receptor substrate 1 associates with the SH2-containing phosphotyrosine phosphatase Syp. , 1993, The Journal of biological chemistry.

[27]  W. Pardridge,et al.  Receptor-mediated peptide transport through the blood-brain barrier. , 1986, Endocrine reviews.

[28]  R. Moxley,et al.  Distribution of insulin receptor-like immunoreactivity in the rat forebrain , 1989, Neuroscience.

[29]  J. Downing,et al.  Phospholipase C‐gamma, a substrate for PDGF receptor kinase, is not phosphorylated on tyrosine during the mitogenic response to CSF‐1. , 1989, The EMBO journal.

[30]  C Collins,et al.  Insulin‐like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. , 1986, The EMBO journal.

[31]  G. C. Kennedy,et al.  The role of depot fat in the hypothalamic control of food intake in the rat , 1953, Proceedings of the Royal Society of London. Series B - Biological Sciences.

[32]  R. Moxley,et al.  Location of phosphotyrosine-containing proteins by immunocytochemistry in the rat forebrain corresponds to the distribution of the insulin receptor. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[33]  S. Leibowitz Neurochemical-neuroendocrine systems in the brain controlling macronutrient intake and metabolism , 1992, Trends in Neurosciences.

[34]  C Crone,et al.  Facilitated transfer of glucose from blood into brain tissue. , 1965, The Journal of physiology.

[35]  P. Pilch,et al.  The insulin receptor: structure, function, and signaling. , 1994, The American journal of physiology.

[36]  M. Irahara,et al.  Effect of insulin-like growth factor I on gonadotropin release from the hypothalamus-pituitary axis in vitro. , 1991, Acta endocrinologica.

[37]  J. Pessin,et al.  Insulin receptor substrate 1 and 2 (IRS1 and IRS2): what a tangled web we weave. , 1996, Trends in cell biology.

[38]  S. Woods,et al.  Inhibition of hypothalamic neuropeptide Y gene expression by insulin. , 1992, Endocrinology.

[39]  A. Levine,et al.  Effects of opioid antagonists naloxone and naltrexone on neuropeptide Y-induced feeding and brown fat thermogenesis in the rat. Neural site of action. , 1995, The Journal of clinical investigation.

[40]  H. Vaudry,et al.  Effect of centrally administered neuropeptide Y on hypothalamic and hypophyseal proopiomelanocortin-derived peptides in the rat , 1995, Neuroscience.

[41]  R. Johnson Opioid involvement in feeding behaviour and the pathogenesis of certain eating disorders. , 1995, Medical hypotheses.

[42]  S. Bloom,et al.  Increased Neuropeptide Y Concentrations in Specific Hypothalamic Regions of Streptozocin-Induced Diabetic Rats , 1989, Diabetes.

[43]  C. Kahn,et al.  The insulin signaling system. , 1994, The Journal of biological chemistry.

[44]  C. Kahn,et al.  Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein , 1991, Nature.

[45]  G. Werther,et al.  Localization and Characterization of Insulin‐Like Growth Factor‐I Receptors in Rat Brain and Pituitary Gland Using in vitro Autoradiography and Computerized Densitometry * A Distinct Distribution from Insulin Receptors , 1989, Journal of neuroendocrinology.

[46]  T. Pawson,et al.  SH2 and SH3 domains: From structure to function , 1992, Cell.

[47]  P. H. Seeburg,et al.  Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes , 1985, Nature.

[48]  S. Woods,et al.  Insulin in the brain. , 1987, Annual review of physiology.

[49]  H. Matsuba,et al.  [Insulin receptor]. , 1997, Nihon rinsho. Japanese journal of clinical medicine.

[50]  W. Young Periventricular hypothalamic cells in the rat brain contain insulin mRNA , 1986, Neuropeptides.

[51]  Jeffrey H. D. White Neuropeptide Y: a central regulator of energy homeostasis , 1993, Regulatory Peptides.

[52]  Y. Yazaki,et al.  Identification of a 190-kDa Protein as a Novel Substrate for the Insulin Receptor Kinase Functionally Similar to Insulin Receptor Substrate-1 (*) , 1995, The Journal of Biological Chemistry.

[53]  J. Saavedra,et al.  Up-regulation of pituitary [125I]insulin-like growth factor-I (IGF-I) binding and IGF binding protein-2 and IGF-I gene expression by estrogen. , 1993, Endocrinology.

[54]  C. J. Goodner,et al.  A (3H)2-Deoxyglucose Method for Comparing Rates of Glucose Metabolism and Insulin Responses Among Rat Tissues In Vivo: Validation of the Model and the Absence of an Insulin Effect on Brain , 1984, Diabetes.

[55]  J. Livingston,et al.  Insulin receptors in the central nervous system: Localization, signalling mechanisms and functional aspects , 1991, Progress in Neurobiology.

[56]  M. White,et al.  YMXM motifs of IRS-1 define substrate specificity of the insulin receptor kinase. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[57]  L. Cantley,et al.  Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit. , 1993, The Journal of biological chemistry.

[58]  M. Classen,et al.  Effect of galanin on food intake in rats: involvement of lateral and ventromedial hypothalamic sites. , 1993, The American journal of physiology.

[59]  M. White,et al.  Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1 , 1993, Molecular and cellular biology.

[60]  S. Woods,et al.  Insulin: its relationship to the central nervous system and to the control of food intake and body weight. , 1985, The American journal of clinical nutrition.

[61]  C. Saper,et al.  Leptin activates neurons in ventrobasal hypothalamus and brainstem. , 1997, Endocrinology.

[62]  T. Pawson,et al.  The Steel/W transduction pathway: kit autophosphorylation and its association with a unique subset of cytoplasmic signaling proteins is induced by the Steel factor , 1991, Molecular and cellular biology.

[63]  B. Posner,et al.  Insulin-binding sites in the rat brain: in vivo localization to the circumventricular organs by quantitative radioautography. , 1979, Endocrinology.

[64]  S. Leibowitz,et al.  Neuropeptide Y chronically injected into the hypothalamus: A powerful neurochemical inducer of hyperphagia and obesity , 1986, Peptides.

[65]  R. Baxter,et al.  A comparison of the insulin and insulin-like growth factor I receptors from rat brain and liver. , 1988, Endocrinology.

[66]  A. Ullrich,et al.  Growth factor signaling by receptor tyrosine kinases , 1992, Neuron.