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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