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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
slide13

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
slide15

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
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
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)
slide34

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
slide39

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 hypothalamus not 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 
slide59

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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