Neuroendocrine System

INTROITO di CIBO e OBESITA’ : MEDIATORI NEUROENDOCRINI

Angelo Michele Carella Ospedale “T. Masselli-Mascia” – San Severo (Fg) S.C. di Medicina Interna

Caloric

Energy

Intake

Expenditure

Body Weight

SATIETY

THERMOGENESIS

HUNGER

OBESITY Obesity results from a prolonged imbalance between caloric intake and energy expenditure.

Appetite and Energy balance are regulated by several

neurochemical circuits.

The Neuroendocrine system (NES) is one of the main factors which regulates Caloric Intake

in humans. Morely JE. Endocr. Rev 1987; 8: 256-287

What is the Neuroendocrine System (NES) ?

NES is a network of cells which synthesize and secrete:

• amines • peptides • growth factors

Neurohormones

• biological mediators • neurotransmitters which modulate various biological functions by interacting with the nervous and immune system. R. Toni. J Endocrinol Invest 2004;27(6 Suppl):35-47

Neuroendocrine Cells Paracrine signailing

Autocrine signailing

Secretory Mechanisms Endocrine mechanism Neuroendocrine mechanism

Neuroendocrine Cells • amines • peptides • growth factors

Neuropeptides

• biological mediators

Neurohormones

• neurotransmitters

Neuroendocrine mediators

• citokines

R. Toni. J Endocrinol Invest 2004;27(6 Suppl):35-47

Neuroendocrine Cells Embryogenesis: • neuroectodermal (neural crest)

• endodermal

Pears AG, Takor T. Fed Proc 1979;38(9):2288-94

Pears AG, Takor T. Clin Endocrinol (Oxf) 1976;5 Suppl:229S-244S

Neuroendocrine Cells A typical morphological pattern :

• uniform nucleus • clear to granular cytoplasm • electron-dense cytoplasmic granules

Pears AG. J Histochem Cytochem 1969;17:303

Neuroendocrine Cells Neuroendocrine Cell Biomarkers: • Cytoplasmatic Biomarkers (metabolics) • Granule-associated Biomarkers (structurals)

de Herder WW. Best Pract Res Clin Endocrinol Metab 2007;21:33-41

Neuroendocrine Cells Cytoplasmatic Biomarkers

Granular Biomarkers

Neuron Specific Enolase (NSE)

Chromogranin A (CgA)

Synaptophysin (P38)

Vasostatin 1, Vasostatin 2

Synaptobrevin (VAMP-1)

Catestatin

Synapsin (1A, 1B, 2°, 2B)

Chromogranin B (Secretogranin I; CgB)

Synaptic Vesicle protein 2 (SV2)

Chromogranin C (Secretogranin II)

Protein Gene Product (PGP 9.5)

Pancreastatin (PST)

Cytokeratins

Leu-7 (HNK-1)

Vimentin

Cytochromes b561

……………………………..

……………………………..

de Herder WW. Best Pract Res Clin Endocrinol Metab 2007;21:33-41

Neuroendocrine Cells

Neuroendocrine cells are diffusely distributed

throughout the body.

Neuroendocrine Cells Topographic distribution and anatomical organization CONFINED NEUROENDOCRINE SYSTEM (CNES) • Hypophysis • Hypothalamus • Epiphysis • Adrenal gland medulla • Ganglia and Paraganglia • Carotid glomus • Parathyroid •Thyroid (C cells) DIFFUSE NEUROENDOCRINE SYSTEM (DNES) • Digestive tract (gastro-entero-pancreatic NES) • Kidney • Lung • Skin • Myocardium • Gonads

scattered neuroendocrine cells

Neuroendocrine Cells Secretory Products CONFINED NEUROENDOCRINE SYSTEM (CNES) Adenohypophysis

Corticotrope cells Somatotrope cells Thyrotrope cells Lactotrope cells Gonadotrope cells

POMC (ACTH, β-Endorphins, LPH β-γ, MSH α-β-γ) GH TSH PRL FSH, LH

Hypothalamus

Neurons in: Arcuate, Paraventricular, Periventricular, Supraoptic, and Posterior Nuclei

Somatostatin, Somatorelin, TRH, LHRH, CRH, Oxytocin, ADH, CCK, αANP, MSH, β-Endorphins, NPY, Orexin A, Met5-enkephalin

Epiphysis

Pinealocytes

Melatonin, LHRH

Ganglia / Paraganglia

Chromaffin cells

NA

Adrenal gland medulla

Chromaffin cells

NA, A, DA, NPY, Met5-enkephalin

Parathyroid

Principal cells

PTH

Thyroid

Parafollicular cells (C cells)

CT, Somatostatin, CGRP

Neuroendocrine Cells Secretory Products DIFFUSE NEUROENDOCRINE SYSTEM (DNES) Digestive tract (gastro-enteropancreatic cells)

G Cells I Cells S Cells Ecn Cells EC1 Cells EC2 Cells ECL Cells A2 Cells B Cells D, A1 Cells D1, P Cells N Cells K Cells D1, F Cells L Cells M Cells P/D1 Cells X Cells

Gastrin CCK-PZ, Gastrin Secretin Serotonin, Motilin, Enkephalins, Substance P (SP) Serotonin, Substance P (SP), Tachykinins Serotonin, Motilin Histamine Glucagon Insulin Somatostatin Bombesin, VIP Neurotensin GIP PP, NPY GLP-1, NPY, PYY, Enteroglucagon Motilin Ghrelin/Obestatin β-Endorphins, γ-MSH

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Neuroendocrine Cells Secretory Products DIFFUSE NEUROENDOCRINE SYSTEM (DNES) Central Nervous System

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Neurons and Nervous Fibers

CCK, Bombesin, VIP, NPY, SP, Gastrin, Neurotensin, Enkephalins, β-Endorphins, Serotonin, NA, SST, Galanin, Tachykinins

Peripheral Nervous Neurons and System Nervous Fibers

VIP, SP, NA, Bombesin, Somatostatin, Enkephalins, Neurotensin

Splanchnic Nervous Fibers Peripheral Nervous System

Acetylcholine, PP, CCK, Bombesin, VIP, NPY, SP, Neurotensin, Serotonin, NA, SST, Galanin, Gastrin, Tachykinins

Lung

P Cells CT Cells X Cells

Bombesin Calcitonin β-Endorphins, Met-Enk, ACTH

Heart

Myocardiocytes

ANP

Skin

Melanoblasts

Met-Enk, VIP, 2-S and 5-S-cisteinildopa

NORADRENALINE, SEROTONIN, DOPAMINE and HISTAMINE are historically considered key points

in the regulation of feeding behavior.

Morely JE. Endocr. Rev 1987; 8: 256-287

The Noradrenergic System is involved in the appetite regulation through a dual mechanism.

NORADRENALINE α1-receptors

food intake inhibition

presynaptic α2-receptors

orexigenic effect

At baseline, the anorexigenic effect of NORADRENALINE mediated by α1-receptors may be predominant. Wellman PJ, et al. Life Sci 1993;53:669-79

Several experimental studies have anorexigenic activity of SEROTONIN.

shown

the

SEROTONIN

5-HT2C receptors

food intake suppression Leibowitz SF, et al. Biol Psychiatry 1998;44:851-864

AMPHETAMINE/PHENTERMINE: • Noradrenergic agents • Work on the hypothalamus to stimulate the adrenal glands to release Noradrenaline • Appetite suppressant FENFLURAMINE/DEXFENFLURAMINE: • Serotoninergic agents • Increase the release of Serotonin and inhibit the reuptake of Serotonin from nerve terminals • Appetite suppressant Kakkar AK and Dahiya N. Eur J Intern Med. 2015;26(2):89-94

SIBUTRAMINE Mechanism of action: Sibutramine is a neurotransmitter reuptake inhibitor that reduces the reuptake of Serotonin (by 53%), Noradrenaline (by 54%) and Dopamine (by 16%) at the neuronal synapse in brain tissue.

Therapeutic effects : Sibutramine promotes a sense of satiety and decreases in appetite, reducing food intake. Sibutramine also increases energy expenditure (thermogenesis). Nisoli E. and Carruba MO. Obes Rev.2000 Oct;1(2):127-39

LORCASERIN

LORCASERIN

• serotoninergic properties • novel selective human 5-HT 2C receptor agonist

SEROTONIN

• anorexigenic drug

+ 5-HT2C receptors

food intake suppression On 27 June 2012, the FDA officially approved LORCASERIN for use in the treatment of obesity for adults. Leibowitz SF, et al. Biol Psychiatry 1998;44:851-864

Lancet 2001 Feb 3;357(9253):354-7.

Brain dopamine and obesity. Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, Netusil N, Fowler JS.

Expert Opin Ther Targets 2002 Oct;6(5):601-9.

The role of dopamine in motivation for food in humans: implications for obesity. Wang GJ, Volkow ND, Fowler JS.

ACS Chem Neurosci 2010 May 19;1(5):346-7.

Overeating, obesity, and dopamine receptors. Mahapatra A.

J Neurochem 2012 Mar;120(6):891-8.

Epigenetic dysregulation of the dopamine system in diet-induced obesity. Vucetic Z, Carlin JL, Totoki K, Reyes TM.

There are several evidences supporting the role of brain HISTAMINE in food intake regulation.

HISTAMINE +

+

H1 receptors

H3 receptors

food intake suppression

food consumption

Masaki T, et al. Diabetes 2004;53(9):2250-60 Sakata T, et al. Nutrition 1997;13:403-11

NEUROENDOCRINE MEDIATORS:

sites of action

Ventromedial Nucleus

Lateral Area Neuroendocrine Mediators

Satiety

Hunger Food intake regulation

NeuroendocrinE System: endless becoming

Food intake regulation: beyond hypothalamic dualism

Thalamus

Hypothalamus

LHA

Lateral Area DMN VMN

ARC

Dorsomedial Nucleus Ventromedial Nucleus Arcuate Nucleus

PVN

Paraventricular Nucleus

Food intake regulation: Appetite Regulation Brian Network NORADRENALINE DOPAMINE SEROTONIN HISTAMINE Neuropeptide Y (NPY) Agouti Related Protein Melanin-Concentrating Hormone (MCH) Orexins Endogenous Cannabinoids

HUNGER

Proopiomelanocortin (POMC) α-Melanocyte Stimulating Hormone (α-Melanocortin) Cocaine - and Amphetamine-Regulated Transcript (CART) ß-endorphin Corticotropin-Releasing Hormone (CRH)

SATIETY

The Melanocortin System NPY neuron GABA

Pro-opiomelanocortin (POMC) Cells

Arcuate Nucleus

α-Melanocyte Stimulating Hormone (α-MSH)

Agouti-related Peptide (AgRP)

+ appetite suppression

Agouti-related peptide (AgRP) Cells

melanocortin-4 receptor (MC4R)

appetite stimulation

The Melanocortin System BUPROPION

+ Pro-opiomelanocortin (POMC) Cells

Arcuate Nucleus

α-Melanocyte Stimulating Hormone (α-MSH)

+ appetite suppression

melanocortin-4 receptor (MC4R) Sonja K. Billes, et al. Pharmacol Res.; 2014, 84: 1-11

BUPROPION recently (2014) approved by FDA for pharmacotherapy of obesity in adults (in association with Naltrexone)

The Endogenous Opioid System

Pro-opiomelanocortin (POMC) μ-opioid receptor Cells

-

α-Melanocyte Stimulating Hormone (α-MSH) melanocortin-4 receptor (MC4R)

anorexigenic effect

Food intake

The Endogenous Opioid System

-

Pro-opiomelanocortin (POMC) μ-opioid receptor Cells

NALTREXONE

α-Melanocyte Stimulating Hormone (α-MSH) melanocortin-4 receptor (MC4R)

Food intake

anorexigenic effect Grandison L., et al. Neuropharmacology 1977; 16:533-6 Sonja K. Billes, et al. Pharmacol Res.; 2014, 84: 1-11

NALTREXONE recently (2014) approved by FDA for pharmacotherapy of obesity in adults (in association with Bupropion)

The Endocannabinoid System

CB1 receptor Δ9-tetrahydrocannabinol

Iversen L. Brain 2003;126(Pt 6):1252-70

“Effects of the cannabinoid-1 receptor blocker Rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study”. L. F. Van Gaal, et al. Lancet; 2005: 1389–97.

“Effect of Rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients— RIO-North America: a randomized controlled trial”. F. X. Pi-Sunyer, et al. Journal of the American Medical Association; 2006: 761–75.

“Perspectives of CB1 Antagonist in Treatment of Obesity: Experience of RIO-Asia”. Pan C, et al. Journal of Obesity; 2011: 957268.

Appetite and body weight regulation: is it all in the brain? Kalra SP. Neuron 1997; 19: 227-230

Gut regulation of Food intake OREXIGENIC NEUROHORMONES

ANOREXIGENIC NEUROHORMONES

Ghrelin

Insulin

Galanin

Amylin

Peptide YY (1-36)

GLP-1 Peptide YY (3-36)

Oxyntomodulin Obestatin Cholecystokinin

GHRELIN • stimulates AgRP cells

increase appetite

• the orexigenic effect of Ghrelin could be mediated by

Endocannabinoid release • exerts a potent orexigenic effect slightly lower than NPY

• reduce energy expenditure Nakazato M, et al Nature 2001;409:194-8

Glucagon Like Peptide-1 (GLP-1) Modulates Numerous Functions in Humans GLP-1: Secreted upon the ingestion of food

Hypotalamus: Promotes satiety and reduces appetite Alpha cells:

 Postprandial glucagon secretion

Liver:  hepatic glucose output

Beta cells: Enhances glucose-dependent insulin secretion

Stomach: Helps regulate gastric emptying

Flint A, et al. J Clin Invest. 1998;101:515-520; Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169

Adipose Tissue: a neuroendocrine tissue?

Anorexigenic Trayhurn P et al. Brit J Nutrit 2004;92:347-55

LEPTIN

-1-

 promotes the activation of anorexigenic pathways in the CNS: - stimulates POMC cells, producing anorexic effect - reduces Neuropeptide Y levels in the hypothalamic nuclei - interacts with many other peptide systems involved in the hypothalamic regulation of appetite (monoaminergic system, MCH , Orexins and Galanin)

Sahu A. Endocrinology 1998; 139: 795-8

LEPTIN

-2-

 in many obese patients has been observed a loss of Leptin-

induced anorexigenic effects (Leptin Resistence) probably resulting from:

- structural aberrations of Ob-Rb receptor - changes in the mechanism of post-receptorial signal transduction - receptor down-regulation

Caro JF, et al. Lancet 1996; 348: 159-61

Brain–gut–adipose tissue communication

Food intake regulation

Chun-Xia Yi, M. H. Tchöp. Dis Model Mech2012 Sep;5(5):583-7

TAKE HOME MESSAGE

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Food intake regulation: Brain–Gut–Adipose Network

Adiposity signals GLP-1

Satiety signals

CCK release

Schwartz MW et al. Nature: 2000;404:6778 modif.

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TAKE HOME MESSAGE Hedonism

Psychic

Hormonal

Socioeconomics

Environmental

Genetics

Lifestyle and Nutrients

OREXIGENIC NEUROPEPTIDES

ANOREXIGENIC NEUROPEPTIDES

Appetite and Food intake regulation

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TAKE HOME MESSAGE Neuroendocrine System Relevance to Obesity: • Genetic mechanisms

• Receptor signals • Enzymatics

• MC4R mutation • Ob-Rb mutation • other

• Genes (POMC, Leptin, other)

• Pathophysiology • Therapy

• Pharmacological • Bariatric

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TAKE HOME MESSAGE Neuroendocrine System

What to ask for the immediate future…

• May food choices affect neuroendocrine mediators? • How? • And…..which foods?

the

TAKE HOME MESSAGE

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NeuroendocrinE System

NEUROENDOCRINE SYSTEM

Obesity & Eating Disorders