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Appetite Regulation

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

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  1. Appetite Regulation Endocrinology Rounds June 1, 2011 Selina Liu PGY5 Endocrinology

  2. 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 

  3. 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

  4. 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)

  5. Forebrain Hindbrain Brainstem Neuroanatomy Review (tectum + tegmentum)

  6. 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)

  7. 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

  8. 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

  9. 1) Hypothalamus – Key Nuclei • Medial • Arcuate Nucleus (ARC) • Paraventricular Nucleus (PVN) • Ventromedial Nucleus (VMN) • Dorsomedial Nucleus (DMN) • Lateral • lateral hypothalamic area (LHA) • perifornical hypothalamus

  10. History • rat experiments (1930s-1950s): • ablation of ventromedial nucleus (VMN)  obesity • ablation of lateral hypothalamic area (LHA)  reduced feeding

  11. 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

  12. 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

  13. 2) Brainstem • Midbrain • Pons • Medulla • Dorsal Vagus Complex (DVC) • Nucleus of the Tractus Solitarius (NTS) • Area postrema - sensory CVO • Dorsal motor nucleus of vagus

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

  15. 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

  16. 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

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

  18. 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

  19. 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

  20. 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

  21. Arcuate Nucleus • ANORECTIC neuropeptides – appetite suppressing • Pro-Opiomelanocortin (POMC) • Cocaine & Amphetamine Regulated Transcript (CART) • OREXIGENICneuropeptides – appetite stimulating • Neuropeptide Y (NPY) • Agouti Related Peptide (AgRP)

  22. Pro-Opiomelanocortin (POMC) • Precursor peptide of Melanocortin system Kronenberg HM et al.Williams Textbook of Endocrinology. 11th edition. 2008 Saunders Elsevier.

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

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

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

  30. 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

  31. 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)

  32. 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

  33. 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

  34. 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

  35. 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

  36. Hypothalamus & Appetite Regulation Lateral Hypothalamic Area (LHA) • connections with nuccleus accumbens (reward centre) • ? enhance hedonistic value of food

  37. 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

  38. 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

  39. Hormonal Regulation of Brain-Gut-Adipose Axis Adipostatic factors • leptin • insulin • glucose Satiety & Hunger factors • ghrelin • cholecystokinin (CCK) • GLP-1 • PP, PYY • amylin • oxyntomodulin

  40. 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

  41. 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

  42. 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

  43. 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)

  44. 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)

  45. 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

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