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Ghrelin

Ghrelin. facts of ghrelin.

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Ghrelin

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  1. Ghrelin

  2. facts of ghrelin First therewas the receptor, discovered as the binding site of synthetic compounds thatcaused the immediatesecretion of growth hormone (GH) from the somatotrophiccells of the anteriorpituitary. These compounds weredeveloped as potentialmedicamentsaiming to restore body growth (by boosting the production of GH). The orphanreceptor, lacking a physiological ligand, wasnamedgrowth hormone secretagoguereceptor (GSH-R, twosplicevariants: 1a (full length) and 1b (truncated). Thentherewas the ligand which, surprise, wasisolatedfromextractsfrom the stomach and not, as expected, from the pituitary or hypothalamus. Because the newlyidentifiedphysiological ligand controledsecretion of growth hormone, itwasnamedghrelin, afterghre, the proto-indo-europeanroot of the word « grow ». Strangelyenough, micelackingeitherghrelin or itsreceptorgrownormally .

  3. facts of ghrelin Then it was discovered that, when injected into the bloodstream or into cerebral ventricles, ghrelin also stimulates food intake in rodents. The attention shifted from studying its role in growth to studying its role in appetite control. Important evidence for its role in control of appetite came from the observation that mice lacking either ghrelin or its receptor are protected from diet-induced obesity (although there feeding behaviour does not differ from control mice under normal feeding conditions ). Soon after, it was also shown that blood levels of ghrelin rise in starvation and decrease postprandilly (after having eaten) Ghrelin is low in obese, high in anorexia nervosa (empty stomach) and in Prader-Willi syndrome (complex genetic disorder characterized by hyperphagia, mental retardation, short stature, muscular hypotonia and distinctive behavioral features).

  4. facts of ghrelin Ghrelin is a peptide hormone comprising 28 amino-acids that arise from a 94 amino-acid long precursor (proghrelin). Other products of proghrelin are; des-Gln14-ghrelin (27 ghrelin), C-ghrelin and obestatin.

  5. facts of ghrelin About 20% of ghrelin is modified (on Ser-3) by n-octanoic acid (process referred to as octanoylation), through the action of membrane-bound “ghrelin O-acyltransferase “(named GOAT). This occurs in the rough-endoplasmic reticulum. Octanoylation is essential for binding to the GHS receptor and thus for the induction of appetite (and other functions). H2N-GSSFLSPEHQRVQQRKESKKPPAKLQPR-COOH Ghrelin (28) n-octanoic acid (n-octanoyl or C8:0) O-C-CH2-CH2-CH2-CH2-CH2-CH2-CH3 O

  6. facts of ghrelin Ghrelin qualifies as an orexigenic hormone It is produced by X/A-cells of oxyntic glands, abundantly present in the mucosal layer of the fundus region of the stomach Ghrelin is produced in small quantities in other parts of the digestive tract. It is also produced in the pancreas, in ghrelin neurons in the hypothalamus, in glomeruli of the kidney and in syncytio-trophoblast cells of placenta

  7. whichghrelin affects the NPY/AgRPneurons in the arcuate nucleus: the one produced by the stomach or by ghrelin-containingneurons in the hypothalamus? ? the blood-brainbarrier Problems: -very little ghrelin is transported across the blood-brain barrier in the direction of blood-to-brain: how does it reach its receptor? -vagotomy prevents ghrelin-mediated appetite ?

  8. Ghrelin-producingneurons are present in the hypothalamus, in an area adjacent to the arcuate nucleus: a modified neural circuit emerges

  9. Ghrelinreceptors, GSHR, are present on Npy/AgRP/GABA neurons in the arcuate nucleus

  10. the ghrelinreceptor (GHS-R1a) is a 7TM G-proteincoupledreceptor

  11. Ghrelinsignals to phospholipase C-b via Gaq

  12. Structure of phospholipase C-d1

  13. cleavage of phosphatidyl 4,5-inositol by phospholipase C (DAG) (IP3)

  14. the phospholipase C family

  15. Inositol 3,4,5-phosphate (IP3) bindsitsreceptor and causes release of Ca2+from the smoothendoplasmicreticulum IP3 membrane Ca2+

  16. IP3-mediatedopening of the IP3receptorleads to an transientincrease in intracellular free Ca2+

  17. intracellular free Ca2+ bindscalmodulin (CaM), thisbinds to CaMkinase kinase (CaMKK) whichacts as the activator of AMPK. This leads to phosphorylation and activation of TSC1/TSC2. The excess of RhebGDPprevents activation of mTOR, givingrise to an orectic signal (appetite)

  18. Acetyl-CoA carboxylase (ACC) isanothertarget of ghrelin-activated AMPK. In moments of « plentitude » (high glucose) the ACC-mediated production of malonyl-CoAleads to inhibition of b-oxidation

  19. Structure of carnitine, CoA, malonyl and palmitate Malonyl-CoA

  20. Ghrelin-mediated activation of AMPK leads to phosphorylation and inactivation of acetyl-CoA carboxylase. The ensuinglack of fattyacidsynthesis and subsequentincrease in b-oxidationplays a role in the generation of an orectic signal

  21. Ghrelin augments the firing rate of NPY, AgRP, GABA neurons and augments the production of AgRP/NPY (neurotransmitters). Subsequent GABA release reduces the firing rate of POMC neurons (hyperpolarization). Result: dominant activity of orexigenicneurons Image from Cowley et al Neuron 2003;37:649

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