Post on 16-Aug-2015
transcript
Appetite Regulation
Presented by: Alden ParkerBS – 860: Endocrinology
3/9/2015
http://www.grubgrade.com/2009/02/23/celebrity-grubbers-homer-simpson/
Appetite Regulation Overview• Introduction/Background
– Organs/Systems• Purpose, Initiation, Regulation
– Hormones & Other Players• Synthesis Sites & Targets
– Effects• Gene Activation/Repression • 2nd Messenger Systems/Signal Transduction• Receptor modification
• Regulation, Crosstalk, Psychology and Treatment– Opposing Systems, Concerted Systems– Location Dependence– Gray Areas– Psychology/Behavior– Consequences of Dysfunction/Behavioral Excess– Treatment/Beating the system
• Case Studies
• Summary
https://robliano.files.wordpress.com/2011/12/food_for_thought1.jpg
Purpose
• Control of Food Intake to replenish depleted nutrients (i.e. glucose and FAs)
• Maintain energy homeostasis for proper function of ALL systems
• In other words, to avoid malnutrition (under OR over nutrition) and obesity
Organs
(Zheng & Berthoud, 2007)
Regulation/Modulation: “the appestat”
Appetite Initiation:
http://xernt.com/DIRECT-SALE-Direct-Sell-Sell-Tips-Duble-Priced-Method
http://guardianlv.com/2013/11/male-and-female-nose-size-related-to-oxygen-demand/
http://www.forbes.com/sites/pauljankowski/2013/02/27/quick-what-are-they-saying-about-your-brand/
http://doctorstevenpark.com/earremedies
→
Central Melanocortin System• Involved in pigmentation, appetite regulation, energy expenditure, cardiovascular function, inflammation, and
sexual function. (Gantz & Fong, 2003)
• Made up of 3 peptides (α-, β-, γ-MSH) and ACTH, 5 GPC melanocortin receptors, and endogenous melanocortin antagonists Agouti – related Protein (AgRP) and Neuropeptide Y (NPY). (Gantz & Fong, 2003)
(Greenwood et al., 2011)
Hormones – Major Players
• Leptin (↓ appetite, adipose cells CNS receptors)
• Ghrelin(↑ appetite, stomach CNS receptors)
• α-Melanocyte-Stimulating Hormone (↓ appetite, hypotalamus many downstream targets, neurons and tissues)
• Insulin (↓ appetite)
• Thyroid Hormone (↑ appetite)
Other orexigens (some major, some minor)
• Neurotransmitters– Dopamine (↑ appetite, ventral tegmenal areareleased in Pre-frontal cortex) (Schultz,
2007)– Orexin/Hypocretin (Hcrt is precursor) (↑ appetite, hypothalamusCNS)
• Hypothalamic Neuropeptides– Agouti-related Protein (AgRP, ↑ appetite, hypothalamusCNS) – Neuropeptide Y (NPY, ↑ appetite, hypothalamusCNS)– Melainin concentrating hormone (MCH, hypotalamusCNS)
• Ancillary molecules– Glutamate/GABA/Galanin/Cerebellin1(↑ appetite, hypothalamic signaling)
• Glucagon/TH/Cortisol/ACTH/GH (↑ appetite) Kim et al., 2014; Crespo et al., 2014
Other anorexigens (some major, some minor)
• Neurotransmitters– Seratonin (↓ appetite, ~90% made and stored in enterochromaffin cells in small intestine,
~10% made in Raphe Nuclei throughout whole brain) (Berger et al., 2009)
• Hypothalamic Neuropeptides– Pro-opiomelanocortin (POMC, ↓ appetite, hypothalamusCNS)
• Ancillary peptides– Cholecystokinin (CCK) (↓ appetite, duodenum/jejunumhypothalamus)– Cocaine/Amphetamine – Related Transcript (CART) (↓ appetite, widely expressed in
CNS/PNS, concentrated in hypothalamus, receptors not ID’d yet(Lin et al., 2011)) – Peptide YY (PYY) (↓ appetite, ileum/colonhypotalamus, ↑POMC/↓NPY)– Ciliary Neurotrophic Factor (CNTF) (↓ appetite, olfactory bulb?)– Glucagon-like peptides (GLP) (↓ appetite, pancreas, gut, brainstemCNS)– Vassopressin (↓ appetite, HPA BV and kidneys)
• Insulin/Amylin, Glucagon, TRH, TSH, Adiponectin(↓ appetite)
Kim et al., 2014; Crespo et al., 2014
Brain “Appetite Active” Sites
• Hypothalamus (GHSR1aNPY, AgRP, LepRbPOMCα-MSH), Pituitary
• Brainstem (POMC neurons in commisural nucleus of solitary tract, NT synthesis)
• Downstream targets expressing Melanocortin -3 or -4 receptors (i.e. target neurons throughout CNS/Cortex)
• Regulation: BBB, receptor expression, peptide production, activation/repression, etc.
Vagus Nerve• Gut hormones
– Leptin– CCK– PP– GLP-1– Ghrelin
• Adiposity Signals– Leptin
Bloodstream• Gut Hormones
– PYY– Oxyntomodulin
• Adiposity Signals – Adiponectin– Leptin
• Insulin
Transportation of Peripheral Signals to ARC
Complexity in the Brain
(Horvath & Diano, 2004)
Leptin• Greek “lepto” means thin
• Produced in WAT, 16kDa protein of 167 AA’s.
• Interacts with 6 receptors derived from alternative splicing of Ob-R gene, but anorexigenic effects only on long form of leptin receptor
http://thenaturalhistorian.com/2014/04/04/elusive-bird-leptin-finding-missing-hormone/Kim et al., 2014; Crespo et al., 2014
Leptin Regulation (long term)
Flier, 2004
CB1 – cannabinoid receptor 1MCH – melanin concentrating hormoneBDNF – brain derived neurotrophic factor
Leptin Signaling (long term)
Ahima & Antwi, 2008
PIP – Phosphatidylinositol bi/tri PhosphateSOCS3 – Suppressor of Cytokine Signaling 3JAK – Janus KinaseSTAT- Signal Transducer and Activator of T(x)IRS – Insulin Receptor SubstratePI3K - Phosphoinositide 3 - Kinase
JAK/STATPI3KMAPK
Leptin Effects
• Upon binding to LepRb neurons in arcuate nucleus: – ↑POMC mRNA, ↓NPY/AgRP mRNA
– Depolarizes (activates) POMC neurons, hyperpolarizes (deactivates) NPY/AgRP neurons
– Mediates synaptic input organization in hypothalamus (POMC upregulated, NPY/AgRP downregulated)
Kim et al., 2014; Crespo et al., 2014
Ghrelin• Growth Hormone Release-Inducing = Ghrelin
• Produced in ghrelin cells in GI (Sakata & Sakai, 2010)
• 28 aa acylated peptide, cleavage product of preproghrelinproghrelinghrelin
• Orexigenic effect through GHSR
http://www.chemblink.com/products/304853-26-7.htm
Kim et al., 2014; Crespo et al., 2014
Ghrelin Regulation (short & long term)
CCK – CholecystokininGLP1 – Glucagon-like peptide 1PYY – Peptide YY
http://www.nutridesk.com.au/stomach-intestine-ghrelin-cck-glp-1-gut-hormones.phtml
Primarily regulated by feeding
(Crespo et al., 2014)
Ghrelin Signaling (short & long term)
(St. Pierre et al., 2003)
Ghrelin Effects
• Upon binding to GHSR neurons in arcuate nucleus: – ↓ POMC mRNA, ↑NPY/AgRP mRNA, ↑electrical activity in
NPY/AgRP neurons
– Activates NPY/AgRP neurons
– Activates prolyl carboxypeptidase (enzyme for α-MSH degradation), inhibits MC4 activation
– Mediates synaptic input organization in hypothalamus (POMC upregulated, NPY/AgRP downregulated)
Kim et al., 2014; Crespo et al., 2014
α – Melanocyte Stimulating Hormone
• Acetylated, 13aa peptide produced in POMC neurons of the hypothalamus from cleavage of POMC
POMCACTHα - MSH
• Anorexigenic effect mediated via MC3 and MC4 receptors
http://www.chemblink.com/products/75921-69-6.htm
NPY/AgRP + α – MSH Signaling/Effects
(Cyr et al., 2013)
Insulin• Insulin signaling in AgRP neurons = ↓ hepatic glucose production
• Insulin signaling in POMC neurons = ↑ hepatic glucose production and energy expenditure (Lin et al., 2010)
• Insulin & Leptin signaling have opposing effect on POMC for body weight regulation, but concerted effect on glucose homeostasis
• Thus IR and LepRb may be differentially expressed in POMC neurons Insulin and Leptin activate separate subsets of POMC neurons (Williams et al., 2010)
• Amylin – co-released, decreases appetite by slowing gastric emptying (Crespo et al., 2014)
Thyroid Hormone
• T3 in hypothalamus↑UCP2 ↑NPY/AgRP mRNA, ↓POMC mRNA ↑ appetite
• fasting-induced suppression of TRH(↓appetite) mRNA in PVN
(Kim et al., 2014)
Others • Adrenals
– Cortisol/ACTH - ↑appetite, regulates POMC production (Kim et al., 2014) (Cushing’s obese, Addison’s thin)
• Gut – PYY, CCK, GLP-1, PP - ↓appetite, released as stomach stretches
and glucose levels rise. Takes some time (eat slowly, small plates, etc.). Downregulated as stomach shrinks and glucose levels fall
• CNS – Orexin (Hcrt) - ↑appetite, neurotransmitter inhibited by Leptin,
activated by Ghrelin– Oxyntomodulin - ↓ appetite, reduces neuronal activity in ARC
Crespo et al., 2014
Concerted Sytsems vs. Opposing Systems
Concerted• Ghrelin, AgRP/NPY, TH,
cortisol, glucagon• Leptin/POMCα-MSH• Leptin/Insulin• Leptin/gut hormones
Opposing• Leptin+gut
hormones+insulin vs. Ghrelin, etc.
• POMC vs. AgRP+NPY
Regulation – Location & Temporal dependence• Leptin must make it into the brain to exert its effect because Hepatocyte-specific
leptin-deficient mice have a normal phenotype (Cohen et al., 2001; De Luca et al., 2005)
• bIR deficient mice are obese, but bIR specific to arcuate melanocortin neurons have no alteration in energy homeostasis and only a dysfunction in hepatic glucose suppression (Konner et al., 2007)
• Central POMC’s role is not replaced by peripheral POMC (Kim et al., 2014)
• POMC KO in pre-natal early onset obesity+hyperphagia, POMC KO post-natal decreased energy expenditure, but no hyperphagia (Kim et al., 2014).
• “Different receptor expression in different tissues for different effects”
Gray Areas• Insulin & Leptin signaling have opposing effect on POMC for body weight regulation, but
concerted effect on glucose homeostasis (Williams et al., 2010)
• Leptin inhibits AgRP synthesis while Insulin stimulates it (Crespo et al., 2014)
• Evidence for both insulin and glucagon to be appetite inhibitors (Kim et al., 2014; Parker et al., 2013)
• Peripheral administration does not equal Central administration (likely due to BBB)
• TRH and TSH decrease appetite, TH increases it (Amin et al., 2011)
• Foods that smell/look bad but taste good and vice versa
• Cravings for particular foods (pregnancy)
• Food “addiction”
Psychology: Thought for Food?
https://pmg503.wordpress.com/tag/psychology/
http://www.marathontalk.com/boyontherun/tag/donkey/
Dysfunction
• Hyperphagia/ overnutrition– Obesity– Overweight– Hypertension– Hyperglycemia– Mineral imbalance
↘
• Hypophagia/ undernutrition– Emaciated– Underweight– Hypotension– Hypoglycemia– Mineral imbalance
↙
Organ/Systems FailureHealth Problems DEATH
Treatment• Caloric limitation (diet) + increase in energy expenditure (exercise)
• Ghrelin receptor antagonists to block orexigenic signals from the gut to the brain or ghrelin receptor inverse agonists that would block constitutive activity of the ghrelin receptor, thereby increasing the response to inhibitory signals to block “between-meals" food intake (Holst & Schwartz, 2004)
• Bombesin Treatment (SNS activation, Crespo et al., 2014)
• Drugs– Metreleptin – Leptin analog (Chou & Perry, 2013)– Orlistat (aka Alli GSK) – lipase inhibitor reduces fat breakdown and caloric absorption (O’Meara et
al., 2004)– Rimonabant (Acomplia) – CB1 receptor antagonist, may increase thermogenesis and energy
expenditure (Akbas et al., 2009)– Many many others
• Gastric Balloon/Bypass in severe cases of obesity
Treatment
http://www.bmb.leeds.ac.uk/illingworth/metabol/2120lec4.htm
Case Studies – Ghrelin KO
Wortley et al., 2005
Taste Discrimination in drosophila
Masek & Scott, 2010
Leptin Deficiency (ob/ob)
Leibel RL, 2008
Leptin and Mood
Yamanada et al., 2011
High fiber, more soup, fruits, and veggies more satiety “Volumetric Diet” (Barbara Rolls, Ph.D Penn State)
http://howtostoyno.altervista.org/volumetrics-diet-plan/
Volumetric Diet
Flood-Obaggy & Rolls, 2009
Prader-Willi syndrome• Elevated plasma Ghrelin
• Low muscle tone, short stature, incomplete sexual development, cognitive disabilities, problem behaviors, and a chronic feeling of hunger that can lead to excessive eating and life-threatening obesity (Cassidy et al., 2011)
VAS = “how much could you eat now?” visual analog score
(Purtell et al., 2011)
Effect of Adequate Rest
→
Morselli et al., 2011
Flaw in circadian rhythm of obese people?
(Yildiz et al., 2004)
Summary of Hunger Regulators
(Austin & Marks, 2009)
Summary of Satiety Regulators
(Austin & Marks, 2009)
Summary of Peripheral Signaling
Stanley et al., 2005
Summary of Peripheral Signaling
(Zheng & Berthoud, 2007)
CNS Integration Site – ARC Summary
Stanley et al., 2005
CNS summary
(Zheng & Berthoud, 2007)
Summary of Melanocortin system• Peripheral signals (hormones, glucose, lipids, peptides, and AA’s) act on
the melanocortin system in the CNS, where there are intra and extracellular mechanisms that create changes in peptide and receptor expression levels
– Change synaptic output/organization
– Change intracellular organelle organization/function
– Dysfunction can cause serious systems issues leading to significant health problems and even death
– GeneticChemical basis for dysfunction, but functional system can be over-ridden by psychological inputs (mood, emotional state, sensory input, memory, etc.)
Kim et al., 2014
References• Kim JD, Leyva S, & Diano S. (2014). Hormonal regulation of the hypothalamic melanocortin system. Front Physiol. 5; 480.• Crespo CS, Cachero AP, Jimenez LP, Barrios V, & Ferreiro EA. (2014). Peptides and food intake. Front Endocrinol. 5; 58.• Zheng H & Berthoud H. (2007). Neural systems controlling the drive to eat: mind versus metabolism. Physiol. 23; 75 – 83.• Greenwood HC, Bloom ST, & Murphy KG. (2011). Peptides and their potential role in the treatment of diabetes and obesity. Rev Diabet Stud. 8; 355 – 368. • Schultz W. (2007). Multiple dopamine functions at different time courses. Ann Rev Neurosci. 30; 259 – 288. • Berger M, Gray JA, & Roth BL. (2009). The expanded biology of seratonin. Ann Rev Med. 60; 355 – 366. • Lin Y, Hall HA, & Kuhar MJ. (2011). CART peptide stimulation of G protein-mediated signaling in differentiated PC12 cells: identification of PACAP6-38 as a CART receptor antagonist.
Neuropeptides. 45; 351 – 358. • Gantz I & Fong TM. (2003). The melanocortin system. AJP Endocrinol and Metab. 284; 468 – 474. • Horvath TL & Diano S. (2004). The floating blueprint of hypothalamic feeding circuits. Nat Rev Neurosci. 5; 662 – 667. • Flier, JS. (2004). Obesity wars: molecular progress confronts an expanding epidemic. Cell. 116; 337 – 350. • Ahima RS & Antwi DA. (2008). Brain regulation of appetite and satiety. Endocrinol Metab Clin North Am. 37; 811 – 823. • Sakata I & Sakai T. (2010) Ghrelin cells in the gastrointestinal tract. Int J Peptid. 2010; 945056. • St. Pierre DH, Wang L, & Tache Y. (2003). Ghrelin: a novel player in the gut-brain regulation of growth hormone and energy balance. Physiol. 18; 242 – 246. • Cyr NE, Toorie AM, Steger JS, Sochat MM, et al. (2013). Mechanisms by which the orexigen NPY regulates anorexigenic α-MSH and TRH. Am J Physiol Endocinol Metab. 304; E640 – E650.• Lin HV, Plum L, Ono H, Gutierrez-Juarez R, et al. (2010).Divergent regulation of energy expenditure and hepatic glucose production by insulin receptor in agouti-related protein and POMC
neurons. Diabetes. 59; 337 – 346.• Williams KW, Margatho LO, Lee CE, Choi M, et al. (2010).Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J Neurosci. 30; 2472
– 2479.• Parker JA, McCullough KA, Field BC, Minnion JS, et al. (2013). Glucagon and GLP-1 inhibit food intake and increase c-fos expression in similar appetite regulating centers in the brainstem
and amygdala. Int J Obes (Lond). 37; 1391 – 1398. • Amin A, Dhillo WS, & Murphy KG. (2011). The central effects of thyroid hormones on appetite. J Thyroid Res. 2011; 1 – 7. • Cohen P, Zhao C, Cai X, Montez JM, et al. (2001). Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest. 108; 1113 – 1121. • De Luca C, Kowalski TJ, Zhang Y, Elmquist JK, et al. (2005).Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. J Clin Invest. 115; 3484 –
3493.• Konner AC, Janoschek R, Plum L, Jordan SD, et al.(2007). Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 5; 438 – 449.• Moreselli L, Leproult R, Balbo M, & Speigel K. (2010). Role of sleep duration in the regulation of glucose metabolism and appetite. Best Prac Res Clin Endocrinol Metab. 24; 687 – 702. • Yildiz BO, Suchard MA, Wong M, McCann SM, et al. (2004). Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity. Proc Natl Acad Sci. 101; 10434 –
10439. • Purtell L, Sze L, Loughnan G, Smith E, et al. (2011). In adults with Prader-Willi syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and GLP-1 levels.
Neuropeptides. 45; 301 – 307. • Cassidy SD, Schwartz S, Miller JL, & Driscoll DJ. (2011). Prader-Willi syndrome. Genet in Med. 14; 10 – 26. • Holst B & Schwartz TW. (2004). Constitutive ghrelin receptor activity as a signaling set-point in appetite regulation. Trends Pharmacol Sci. 25; 133 – 147. • Chou K & Perry CM. (2013). Metreleptin: first global approval. Drugs. 73; 989 – 997. • O’Meara S, Reimsma R, Shirran L, Mather L, et al. (2004). A systematic review of the clinical effectiveness of orlistat used for the management of obesity. Obes Rev. 5; 51 – 68. • Akbas F, Gasteyger C, Sjodin A, Astrup A et al. (2009). A critical review of the cannabinoid receptor as a drug target for obesity management. Obes Rev. 10; 58 – 67. • Wortley KE, Rincon J, Murray JD, Garcia K, et al. (2005). Absence of ghrelin protects against early-onset obesity. J Clin Invest. 115; 3573 – 3578. • Masek P & Scott K. (2010). Limited taste discrimination in Drosophila. Proc Natl Acad Sci USA. 107; 14833 – 14838. • Leibel RL. (2008). Molecular physiology of weight regulation in mice and humans. Int J Obes. 32; S98 – S108. • Yamanada N, Katsuura G, Ochi Y, Ebihara K, et al. (2011). Impaired CNS leptin action is implicated in depression associated with obesity. Endocrinol. 152; 2634 – 2643. • Flood-Obaggy JE & Rolls BJ. (2009). The effect of fruit in different forms on energy intake and satiety at a meal. Appetite. 52; 416 – 422. • Austin J & Marks D. (2009). Hormonal regulators of appetite. Int J Pediatr Endocrinol. 2009; 141753. • Stanley S, Wynne K, McGowan B, & Bloom S. (2005). Hormonal regulation of food intake. Physiol Rev. 85; 1131 – 1158.