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Appetite Regulation. Endocrinology Rounds June 1, 2011 Selina Liu PGY5 Endocrinology. Objectives. To review the key neuroanatomical areas involved in central appetite regulation To provide an overview of the major signalling circuits involved in appetite regulation

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Appetite regulation

Appetite Regulation

Endocrinology Rounds

June 1, 2011

Selina Liu

PGY5 Endocrinology


Objectives

Objectives

  • To review the key neuroanatomical areas involved in central appetite regulation

  • To provide an overview of the major signalling circuits involved in appetite regulation

  • To appreciate the cross-talk between central and peripheral mechanisms involved in appetite regulation

  • To highlight key hormones involved in central appetite regulation 


Conceptual levels of appetite regulation

Conceptual Levels of Appetite Regulation

Central Neurotransmitter & Metabolic Events

Peripheral Physiology & Metabolic Events

Psychological Events & Behavioural Operations

http://www.endotext.org/obesity/obesity7.3/obesityframe7-3.htm


Central nervous system key areas

Central Nervous System - Key Areas

1) Hypothalamus

  • Medial

  • Lateral

    2) Brainstem

  • Midbrain

  • Pons

  • Medulla

    3) Circumventricular Organs (CVO)

  • Median Eminence

  • Subfornical Organ (SFO)

  • Organum Vasculosum of Lamina Terminalis (OVLT)

1) Hypothalamus

2) Brainstem

3) Circumventricular Organs (CVO)


Neuroanatomy review

Forebrain

Hindbrain

Brainstem

Neuroanatomy Review

(tectum + tegmentum)


Central nervous system key areas1

Central Nervous System – Key Areas

1) Hypothalamus

  • Medial

  • Lateral

    2) Brainstem

  • Midbrain

  • Pons

  • Medulla

    3) Circumventricular Organs (CVO)

  • Median Eminence

  • Subfornical Organ (SFO)

  • Organum Vasculosum of Lamina Terminalis (OVLT)


1 hypothalamus

1) Hypothalamus

  • essential, evolutionarily highly conserved region of mammalian brain

  • ultimate structure that allows for maintenance of homeostasis

  • destruction is incompatible with life

  • coordinates endocrine, autonomic and behavioural responses


1 hypothalamus1

1) Hypothalamus

  • receives:

    • sensory input from external environment (i.e. light)

    • input from internal environment (i.e. blood glucose levels, hormones involved in food intake/energy metabolism)

  • provides output to:

    • pituitary gland

    • cerebral cortex

    • premotor & motor neurons in brainstem, spinal cord

    • autonomic preganglionic neurons


1 hypothalamus key nuclei

1) Hypothalamus – Key Nuclei

  • Medial

    • Arcuate Nucleus (ARC)

    • Paraventricular Nucleus (PVN)

    • Ventromedial Nucleus (VMN)

    • Dorsomedial Nucleus (DMN)

  • Lateral

    • lateral hypothalamic area (LHA)

    • perifornical hypothalamus


History

History

  • rat experiments (1930s-1950s):

    • ablation of ventromedial nucleus (VMN)  obesity

    • ablation of lateral hypothalamic area (LHA)  reduced feeding


History1

History

  • dual centre model of feeding proposed:

    • satiety centre: ventromedial nucleus

    • feeding centre: lateral hypothalamus

      HOWEVER – much more complex!

  • involves multiple nuclei and signaling pathways


Appetite regulation

AC – anterior commissure

OC – optic chiasm

Medial Hypothalamus:

ARC – arcuate nucleus

PVN – paraventricular nucleus

VMH – ventromedial nucleus

DMH – dorsomedial nucleus

Lateral Hypothalamus:

LH – lateral hypothalamic area

Kalra SP et al. 1999. Endocr Rev. 20(1):68-100


2 brainstem

2) Brainstem

  • Midbrain

  • Pons

  • Medulla

    • Dorsal Vagus Complex (DVC)

      • Nucleus of the Tractus Solitarius (NTS)

      • Area postrema - sensory CVO

      • Dorsal motor nucleus of vagus


Appetite regulation

MEDULLA

Bloom SR et al. 2008 Mol Interv 8(2):82-98


2 brainstem1

2) Brainstem

  • sensory visceral afferents from GI tract, hepatoportal regions are stimulated by:

    • gastric stretch

    • taste, chemical stimulation

    • local production of gut hormones

  • carried via vagus and glossopharyngeal nerves

  • signals terminate in the NTS of DVC – integrated with parasympathetic nervous system input, and relayed to the hypothalamus


3 circumventricular organs cvo

3) Circumventricular Organs - CVO

  • areas adjacent to hypothalamus which lack the blood-brain-barrier (BBB)

  • contain neuronal cell bodies – “sensory”

  • uniquely placed to detect peripheral signals in blood and transmit to hypothalamus


Appetite regulation

http://www.nibb.ac.jp/annual_report/2001/html/ann501.html


Peptide hormones

Peptide Hormones

  • thus 2 main mechanisms of peptide hormone communication between periphery and brain:

    • via stimulation of vagal afferents

       transfer between NTS (in DVC in medulla of brainstem) and ARC (in hypothalamus)

    • via CVO to the hypothalamic nuclei


Hypothalamus appetite regulation

Hypothalamus & Appetite Regulation

  • the hypothalamus regulates appetite and metabolism by detecting peripheral signals

    i.e. nutrients within blood hormones from gut, adipose tissue

  • integrates all signals together to maintain homeostatic balance between energy intake and energy expenditure


Hypothalamus appetite regulation1

Hypothalamus & Appetite Regulation

Arcuate nucleus (ARC) – at base of hypothalamus

  • 2 distinct neuronal populations:

    • neurons that express OREXIGENICneuropeptides

    • neurons that express ANORECTIC neuropeptides

  • relays signals to downstream effector neurons

  • also expresses insulin and leptin receptors


Arcuate nucleus

Arcuate Nucleus

  • ANORECTIC neuropeptides – appetite suppressing

    • Pro-Opiomelanocortin (POMC)

    • Cocaine & Amphetamine Regulated Transcript (CART)

  • OREXIGENICneuropeptides – appetite stimulating

    • Neuropeptide Y (NPY)

    • Agouti Related Peptide (AgRP)


Pro opiomelanocortin pomc

Pro-Opiomelanocortin (POMC)

  • Precursor peptide of Melanocortin system

Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.


Melanocortin system

POMC

(pro-opiomelanocortin)

PC1

PC2

a-melanocyte stimulating hormone

(a-MSH)

Melanocortin System

PC1 and PC2 = prohormone convertase 1 and 2

a-MSH

  • agonist at melanocortin receptors MC3R, MC4R

    • inhibition of food intake – ANORECTIC effect

    • MC3R, MC4R abundant in ARC, PVN, VMN

    • MC4R mutation – most common single gene cause of human obesity


Cocaine amphetamine regulated transcript

Cocaine & Amphetamine Regulated Transcript

  • CART neurons expressed throughout CNS

    • abundant in hypothalamus, almost exclusively co-expressed with POMC

  • first sequenced in 1980 (? function), then found to be upregulated after cocaine and amphetamine administration

  • intracerebral CART administration – either inhibits or stimulates feeding depending on location

  • role not totally elucidated


Neuropeptide y npy

Neuropeptide Y (NPY)

  • most abundant peptide in CNS

  • most orexigenic peptide within hypothalamus

  • induces food intake – especially CHO-rich foods

  • also:  energy expenditure  thermogenesis  sedation anticonvulsant effect on mood/memory stimulates LH release

  • hypothalamic NPY levels correlate with food intake

    • expression increases with fasting, decreases with food intake

  • leptin, insulin have negative feedback on NPY expression


Neuropeptide y npy1

Neuropeptide Y (NPY)

  • endogenous ligand for 4 known receptors (GPCRs) in humans:

    • Y1R

    • Y5R

    • Y2R

      • predominant NPY receptor in brain

    • Y4R

  • these receptors also bind PP, PYY

  • Y1R

    mediate orexigenic actions

    Y5R

    Y2R

    - autoinhibitory presynaptic receptor

    mediate anorectic actions

    Y4R


    Agouti related peptide

    Agouti-Related Peptide

    • related to agouti protein

    • agouti – in mice, expressed in skin & hair follicles

      • endogenous melanocortin receptor antagonist (MC1R, MC4R)

      • induces pheomelanin production (yellow pigment)

      • Agouti AY mice – model of obesity - ectopic expression of agouti - MC1R antagonism  yellow colour - MC4R antagonism  obesity


    Appetite regulation

    Barsh GS & Schwartz MW. 2002. Nat Rev Genet. 3;589-600


    Appetite regulation

    www.chem.ufl.edu/~richards/members.htm


    Agouti related peptide1

    Agouti-Related Peptide

    • endogenous melanocortin receptor (MC4R) antagonist

    • recall: melanocortin neurons within ARC have inhibitory effect on feeding

    • therefore, MC4R antagonism:

      • inhibits inhibition of food intake

         stimulates food intake

        i.e. OREXIGENIC effects


    Summary arcuate nucleus

    Summary - Arcuate Nucleus

    • ANORECTIC neuropeptides – appetite suppressing

      • Pro-Opiomelanocortin (POMC)

      • Cocaine & Amphetamine Regulated Transcript (CART)

    • OREXIGENICneuropeptides – appetite stimulating

      • Neuropeptide Y (NPY)

      • Agouti Related Peptide (AgRP)


    Appetite regulation

    AC – anterior commissure

    OC – optic chiasm

    Medial Hypothalamus:

    ARC – arcuate nucleus

    PVN – paraventricular nucleus

    VMH – ventromedial nucleus

    DMH – dorsomedial nucleus

    Lateral Hypothalamus:

    LH – lateral hypothalamic area

    Kalra SP et al. 1999. Endocr Rev. 20(1):68-100


    Hypothalamus appetite regulation2

    Hypothalamus & Appetite Regulation

    Paraventricular Nucleus (PVN) – base of 3rd ventricle

    • divisions:

      • medial parvocellular - TRH, CRH, somatostatin, VIP, enkephalin

      • lateral magnocellular - vasopressin, oxytocin

    • important in energy balance

      • role in thyroid and adrenal axes

    • site of integration with ARC and NTS


    Hypothalamus appetite regulation3

    Hypothalamus & Appetite Regulation

    Dorsomedial Nucleus (DMN)

    • role in coordinating circadian rhythm with feeding and energy expenditure

      Ventromedial Nucleus (VMN)

    • previously “satiety centre”

    • contains neurons expressing brain-derived neurotrophic factor (BDNF) – ANORECTIC effects


    Hypothalamus appetite regulation4

    Hypothalamus & Appetite Regulation

    Lateral Hypothalamic Area (LHA)

    • previously “feeding centre”

    • very sensitive to NPY

    • also contains neurons releasing:

      • orexin A

      • orexin B

      • melanin concentrating hormone – ↑ food intake

    aka “hypocretins” – OREXIGENIC ↑ appetite, ↑ arousal, may initiate food-seeking behaviour in starvation


    Hypothalamus appetite regulation5

    Hypothalamus & Appetite Regulation

    Lateral Hypothalamic Area (LHA)

    • connections with nuccleus accumbens (reward centre)

      • ? enhance hedonistic value of food


    Appetite regulation

    AC – anterior commissure

    OC – optic chiasm

    Medial Hypothalamus:

    ARC – arcuate nucleus

    PVN – paraventricular nucleus

    VMH – ventromedial nucleus

    DMH – dorsomedial nucleus

    Lateral Hypothalamus:

    LH – lateral hypothalamic area

    Kalra SP et al. 1999. Endocr Rev. 20(1):68-100


    Brain gut adipose axis

    Brain-Gut-Adipose Axis

    • cross-talk between brain, gut and adiposse tissue is essential for regulation of energy homeostasis

    • complex interplay of neuronal and endocrine signals


    Hormonal regulation of brain gut adipose axis

    Hormonal Regulation of Brain-Gut-Adipose Axis

    Adipostatic factors

    • leptin

    • insulin

    • glucose

      Satiety & Hunger factors

    • ghrelin

    • cholecystokinin (CCK)

    • GLP-1

    • PP, PYY

    • amylin

    • oxyntomodulin


    Leptin

    Leptin

    • product of ob gene

    • produced by white adipose tissue – in proportion to total body fat content

      • minor sites: skeletal muscle, placenta, stomach

    • leptin-R on hypothalamic neurons: inhibits NPY/AgRP, stimulates POMC/CART neurons

    • fasting decreases leptin levels  stimulates food intake and reduces energy expenditure

      • leptin deficiency (or leptin-R deficiency) – obesity


    Leptin1

    Leptin

    • previously thought that leptin was ANORECTIC

    • but in common human obesity, increased leptin levels do not suppress appetite

      • due to leptin resistance?

    • role of leptin: signal that energy stores are sufficient

      i.e. acts as a permissive hormone allowing energy requiring processes to occur


    Insulin

    Insulin

    • not produced by adipose tissue, but levels correlate with body adipose tissue mass

      • “adipostat” hormone

    • contrasting role in peripheral tissues (anabolic) vs central (catabolic)

    • insulin-R in brain – intracerebral injection of insulin decreased food intake (baboons, rodents)

    • deletion of insulin-R from neurons – mild obesity (mice)

    • overall – central effect is ANORECTIC


    Ghrelin

    Ghrelin

    • only peripheral OREXIGENIC hormone

    • secreted from X/A-like endocrine cells in stomach oxyntic (parietal) cell glands

    • endogenous ligand at the GHS-R1a(growth hormone secretagogue receptor 1a) – hypothalamus & brainstem

    • increases with fasting, decreases after food intake

      • role in meal initiation?

    • stimulates NPY and AgRP neurons in ARC

    • ghrelin administration – stimulates feeding (rodents, humans)


    Ghrelin1

    Ghrelin

    • levels are highest in cachetic subjects, reduced in lean subjects, and lowest in obese subjects

      • adaptive response – attempt to stimulate or suppress appetite according to energy imbalance

    • however – obese subjects more sensitive to effects of ghrelin

    • ? role of ghrelin antagonist to treat obesity

    • ? role of ghrelin treatment as appetite stimulant (i.e. cancer-related cachexia)


    Cholecystokinin cck

    Cholecystokinin (CCK)

    • produced by GI tract – enteroendocrine I cells in duodenum, jejunum

    • released post-prandially in response to fat, protein

    • actions:  food intake  delay gastric emptying stimulates pancreatic enzyme secretion stimulates gallbladder contraction

    • mediated via binding to CCKA R on vagus nerve – activates neurons in NTS and AP (in dorsal vagal complex)

    • CCK administration – inhibits food intake meal size,  meal duration

    • ANORECTIC effects


    Glucagon like peptide 1 glp 1

    Glucagon Like Peptide-1 (GLP-1)

    • produced via post-translational modification of pre-proglucagon

    • incretin effects:

      stimulates insulin release, inhibits glucagon release

      • upper GI motility, gastric emptying, gastric acid secretion

    • central effects:

      • in hypothalamusnot totally clear, but GLP-1 R found on POMC neurons in ARC

      • signal via vagus nerve to NTS and ARC

      • in brainstem


    Pancreatic polypeptide pp

    Pancreatic Polypeptide (PP)

    • same family as NPY, peptide tyrosine tyrosine (PYY)

    • secreted from pancreas, distal gut in response to meals via vagus nerve stimulation

    • act via Y4R – in dorsal vagus complex of medulla

    • ANORECTICeffects


    Peptide tyrosine tyrosine pyy

    Peptide Tyrosine Tyrosine (PYY)

    • found in pancreas and small intestine

    • released post-prandially

    • act via binding to Y2R on NPY in ARC

      • recall: Y2R – autoinhibitory  decrease NPY signaling decreased appetite - ANORECTIC

    • also via signaling through vagus nerve to NTS to hypothalamus

    • reduced by fasting – likely a satiety factor

      • levels lower in obese subjects

      • PYY response to nutrient ingestion is reduced in obesity


    Amylin

    Amylin

    • co-secreted with insulin – in response to nutrient ingestion

    • amylin readily enters brain

    • high-affinity amylin binding sites – in hypothalamus (ARC)

    • peripheral & intracerebral amylin infusions: (rodents)

      • acute – inhibit food intake

      • chronic – sustained weight loss


    Oxyntomodulin oxm

    Oxyntomodulin (OXM)

    • 37 a.a. peptide – contains entire sequence of glucagon and a C-terminal extension

    • binds to GLP-1 R (but  affinity)

    • released post-prandially (co-secreted with GLP-1, PYY)

    • shares ANORECTIC effets

    • OXM administration in humans over 4 weeks  weight loss

      • due to  energy intake and  energy expenditure


    Hormonal regulation of brain gut adipose axis1

    Hormonal Regulation of Brain-Gut-Adipose Axis

    Adipostatic factors

    • leptin

    • insulin

    • glucose

      Satiety & Hunger factors

    • ghrelin

    • cholecystokinin (CCK)

    • GLP-1

    • PP, PYY

    • amylin

    • oxyntomodulin


    Objectives1

    Objectives

    • To review the key neuroanatomical areas involved in central appetite regulation

    • To provide an overview of the major signalling circuits involved in appetite regulation

    • To appreciate the cross-talk between central and peripheral mechanisms involved in appetite regulation

    • To highlight key hormones involved in central appetite regulation 


    Appetite regulation

    References

    • Barsh GS & Schwartz MW. 2002. Nat Rev Genet. 3:589-600

    • Bloom SR et al. 2008. Mol Interv. 8(2):82-98

    • Kalra SP et al. 1999. Endocr Rev. 20(1):68-100

    • Zac-Varghese S et al. 2010. Discov Med 10(55):543-52

    • Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

    • www.endotext.org

    • www.medscape.com

    • http://www.nibb.ac.jp/annual_report/2001/html/ann501.html

    • www.chem.ufl.edu/~richards/members.htm


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