1. Ghrelin and obestatin The gut-brain relationship
Authors: Mureșan Patricia Coordinator: Julia Szakacs MD
Kiss Szabolcs
L’Hoste Loïck

2. What are you more afraid of?
300,000 deaths/year
75 attacks
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3. Contents
Introduction
Ghrelin
Obestatin
Discussion
Future resolutions

4. INTRODUCTION 1.9 billions of adults overweight
600 million obeses
Increase the risk for several diseases
Gut peptides: very active research field for their implications in metabolism and apetite
Relation gut-brain also includes: mood, stress and reward
increase the risk for several diseases such as atherosclerosis, high blood pressure, type 2 diabetes, coronary heart disease, stroke and several cancer types, among others

5. GHRELIN 28 AA, Kojima et al (1999) From preproghrelin
peptide (stomach)
GPR39
GH secretion and release ++
Effects:
OREXIGENIC
Food intake and body weight
CNS
Elevated levels before meals
but also it affects the central nervous system by increasing memory, modulating rewarding behavior and motivation, and exerting neuroprotective effects.
However, by far the most noticeable effect of ghrelin is its orexigenic action on food intake, energy homeostasis and weight control. It has been shown that the secretion of ghrelin is stimulated before the meals or in conditions of starvation, while it is decreased after meals. These effects may be due to its ability to cross the blood brain barrier, even in an extremely low quantity. For this effect in particular it has been given the name of the “hormone of hunger”.
“hormone of hunger”
A.Labarthe; O. Fiquet, R. Hassouna, P. Zizzari, L. Lanfumey et al, Ghrelin-derived peptides: a link between appetite/reward, GH axis, and psychiatric disorders ? Frontiers in Endocrinology 5 (2014) 1-19.

6. BIOLOGICAL EFFECTS Food consumption FOOD Gh OREXIGENIC
This term is used basically for every action that precedes or succeeds a meal. It has been proven that ghrelin secretion is increased before and decreased after meals, thus inducing weight gain. This effect, as well as the others, is closely linked to the relationship between ghrelin and distinct nuclei of the CNS. For example, in regulating food intake and energy homeostasis, the VMN of the hypothalamus has been pointed out.
OREXIGENIC
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7. CNS effects Memory Learning Motivation Anxiolytic Regulates mood
Alcohol and drug consumption (enhanced; blocked by GHSR1 antogonist)
NEUROPROTECTIVE
extra-hypothalamic nuclei
Concerning rewarding behavior, rodents who were given a dose of ghrelin before the experiment, were more motivated to search food even in an aversive environment
ghrelin binds to SN neurons, causing an increased production of tyrosine hydroxylase, an enzyme involved in the production of dopamine, eventually being capable of slowing down the neurodegenerative process
NAcc, amygdala, hippocampus and MPFC(-for the hyperlocomotion) through dopaminergic pathways, activating the cholinergic system and regulating hedonic behavior.
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8. ANTAGONIST HORMONES CCK Orexigenic effects of GHRELIN PYY LEPTIN
ENDO
CANNABINOIDS
Orexigenic effects of
GHRELIN
PYY
OBESTATIN

9. OBESTATIN 23 AA, Zhang et al (2005) From preproghrelin peptide
Bachem pioneering partner for peptides: Ghrelin, leptin and obestatin

10. Obestatin related disorders
Obesity
Negatively correlated with BMI, Insulin resistance Index, plasma leptin
Anorexia nervosa /
Depends on subtype
Anxiety and stress ?
A.Labarthe et al, Ghrelin-derived peptides: a link between appetite/reward, GH axis, and psychiatric disorders ? Frontiers in Endocrinology 5 (2014)

11. Discussion about ghrelin
Controversy: Anxiolytic or Anxiogenic
VTA: ventral tegmentum area : hedonic system (mood is not affected)
Amygdala: limbic system: mood
First, ghrelin increase food motivated behavior
Some data were having different conclusion about the anxiolytic or Anxiogenic effect.
Anxiety is regulated by ghrelin in the limbic system.
Some studies have shown an increasing anxiety (chronic injection of ghrelin and unstressed basal condition)
Ghrelin stimulation of amygdala depends on the available food status: if there is no food available anxiety behavior will decrease to make the animal able to find food. Where if food is available, no partular effect on anxiety behavior will occur.
This is why we can find a kind of evolutionary on this hormon
K.P. Skibicka, S.L. Dickson, Enteroendocrine hormones – central effects on behavior, Current Opinion in Pharmacology. 13 (2013)

12. Discussion about ghrelin
Important role in evolution (survival)
Diseases related to ghrelin
Anorexia
Restrictive
Binge-purging
Treatments:
Cachexia
Obesity
Connection between mood and hunger status.
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13. Discussion about obestatin
Ultradian rhythmicity
cplasma alters with nutritional status of the body
Suggested signaling pathway: GHSR

14. Obestatin influences the CNS ?
CNS effects
Mood
Memory retention
Anxiety
Obestatin influences the CNS ?
Motivation
Reward

15. CONCLUSION Obestatin: lack of knowledge ++ Ghrelin:
Agonist:
anorexia
Antagonist:
Obesity
Addiction
Medication circuit vs Discovery of Ghrelin

16. Further research needed
Ghrelin
Mechanisms of ghrelin
to modulate synapses (memory)
To sensibilize to drugs and alcohol addictions
Efficiency of the neuroprotection on diseases:
Neurodegeneration
Strokes
Obestatin
To find the receptor of obestatin
To improve the present knowledge
Z.B. Andrews, The extra-hypothalamic actions of ghrelin on neuronal function, Trends in Neurosciences (2011)

17. Thank you for your attention
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