Marie Nováková, spring 20211 GASTROINTESTINAL TRACT Marie Nováková, spring 20212 serosis (adventicia) epithelium muscularis mucosae longitudinal layer circular layer plexus submucosus (Meissner) plexus myentericus (Auerbach) ENS muscularisexterna submucosa Modified according to: J. Švíglerová: Fyziologie gastrointestinálního traktu, LF UK Plzeň, 2012 coordination of motility secretion and absorption + glands + lymphatic tissue Marie Nováková, spring 20213 Circular muscle layer: inhibitory fibers, contraction – gut is longer and smaller in diameter Longitudinal muscle layer : no inhibitory fibers, contraction – gut is shorter and bigger in diameter GIT motility – mainly nervous control Secretion in GIT – mainly humoral control + PARASYMPATICUS (preganglionic cholinergic fibres) n.VII, n.IX, n.X, nn.pelvici (S2-S4) - SYMPATICUS (postganglionic adrenergic fibres) Th5-L2 (tonus and motility –) (vasoconstriction) (musc.mucosae, sphincters +) Marie Nováková, spring 20214 GIT INNERVATION ENTERIC NERVOUS SYSTEM SYMPATICUS PARASYMPATICUS Local (short) reflex Central (long) reflex CNS +- mechanoreceptors chemoreceptors osmoreceptors thermoreceptors Vagovagal reflex Marie Nováková, spring 20215 ENTERIC NERVOUS SYSTEM (plexuses + endings of sympathetic and parasympathetic nervous system + other GIT neurons) Local (short) reflexes Mediators and modulators: Ach, peptides and bioactive amines Ach, VIP, NOR, DOPA, serotonin, histamine, AT II, PG somatostatin, enkephalin, GABA, TRH, neuropeptide Y, substance P secretin, GIP, glucagon, gastrin, CCK, G-releasing peptide (Secretin group) (Gastrin group) Chemoreceptors, mechanoreceptors, thermoreceptors… (mucosa, musc. externa) Central (long) reflexes Marie Nováková, spring 20216 Continuous tonus of S, PS FORWARD SIGNALS: SPEED UP, OPEN THE WAY BACKWARD SIGNALS: SLOW DOWN, CLOSE THE WAY Marie Nováková, spring 20217 CONTRACTIONS tonic (stomach, colon) rhythmic MOVEMENTS propulsive (peristalsis, myenteric reflex) mixing Receptive relaxation. These contractions and movements are responsible for churning, peristalsis and reservoir action in GIT. GIT MOTILITY Marie Nováková, spring 20218 ELECTROPHYSIOLOGY OF GI SMOOTH MUSCLE Resting potential: from - 40 to - 80mV ( gNa : gK) Lower activity of Na+/K+-ATPase Slow waves (oscillation of rest.MP) 3 (stomach) – 12(duodenum)/min – basal electric rhythm Spike (AP) low voltage, depolarisation – Na+ and Ca2+, 1-10/sec Pacemaker cells in ENS automacy Variability neurohumoural regulation Innervations: nexus, innervations of circular muscle >> longitudinal muscle No motor endplate Ach, ENS, exceptions 0 -40 ICa direct activation of contraction (binding to calmodulin) 0 -40 5s Basal muscle tonus, basal rhythm (time summation) Spike -10 -20ms F E 5s Contractions triggered by slow waves (no AP!!!) F E Stomach Modulation of slow waves – amplitude (less by frequency) Marie Nováková, spring 20219 SWALLOWING • Oral phase (voluntary) • Pharyngeal phase (reflex)<1s • Oesophageal phase (peristaltic) Food – chewing (voluntary and reflex) Frequency of swallowing – approx. 600x / day Saliva (1.5 litres / day) SWALLOWING CENTRE (oblongata, pons) X., …. REC (touch) Plexus myentericus Parasympathetic NS (VIP) Sympathetic NS V.X. Proximal sphincter (somat.motoneurons – X. striated muscles) Peristalsis – 3-5cm/s (primary - swallowing centre, secondary - ENS) Mouth Pharynx Central reflexes Junction Distal sphincter (cardia) (smooth muscle) – opened by secondary peristalsis Local reflexes Reflex relaxation of cardia (PS) Achalasia (cardiospasmus) Gastrooesophageal reflux IX. Oesophagus Marie Nováková, spring 202110 GASTRIC MOTILITY Reflex relaxation of distal oesophageal sphincter (cardia) Receptive relaxation of fundus and body (X. – VIP) (Laplace: P = T . R) Pacemaker zone (3/min) Motoric gradient (F <<< A) Chyme stratification 1,5 l A B F D P C O Migrating myoelectric complex („hungry“ contractions) Reservoir Mixer (3/min) 1-2 hour: rest 10-20 min: activity, during fasting is stronger PYLORUS = sphincter ??? Common ENS with bulbus duodeni Smooth muscle sympaticus +++, n.X. --- (VIP) N. vagus + Plexus cealicus prominent circular layer Marie Nováková, spring 202111 EMPTYING OF STOMACH CNS PACEMAKER CONTRACTIONS OF ANTRUM CONTRACTIONS OF PYLORUS DUODENUM: pH < 3,5 Lipids Peptides secretin CCK, GIP gastrin Oddi gastrin chemoreceptors osmoreceptors slowed emptying (entorogastric reflex) Symp. Paras. FA, H+, osmotically active substances, tryptophan Modulation: •Peristaltic movements •Continuous tonus (summation of contractions of antrum – relaxation) pressure, distension, pH, pain VIP Ach SYMP. x. Coordination of contractions of antrum and relaxation of bulbus Duodenogastric reflux A/D reciprocal activity - Marie Nováková, spring 202112 VOMITING (PROTECTION) HIGHER CENTRES CENTRE FOR VOMITING IN MEDULLA OBLONGATA Afferentation: X., symp. Taste Smell Vision Labyrinths Central Mechanoreceptors of pharynx Peripheral Mechano- a chemoreceptors of stomach and duodenum Peripheral Trigger zone – bottom of 4.chamber Area postrema – circ. ventric. organisation • Antiperistalsis in jejunum and duodenum • Relaxation of pylorus and antrum • Contractions of diaphragm (increased intraabdominal pressure) • Inverse Valsalva manoeuvre (decreased intrathoracal pressure) • Contractions of pylorus and antrum • Relaxation of cardia • Relaxation of upper pharyngeal sphincter Emetics: central peripheral Antiemetics Marie Nováková, spring 202113 MOTILITY OF SMALL INTESTINE • Slow waves – approx.11-13/min in duodenum, 8-9 - ileum • „Minute“ rhythm (jejunum) – salvos approx. every minute • Hour rhythm (migrating myoelectric complex, MOTILIN) hours 100% 1 2 3 fasting food 5 10 12/min duodenum jejunum ileum Distance from pylorus in vitro 7/min in situ Segmentation >>> peristalsis (up to 10 cm) LAW OF INTESTINE INTESTINO-INTESTINAL REFLEX GASTRO-ILEAL R. GASTRO-COLIC R. Marie Nováková, spring 202114 MOTILITY OF COLON • Slow waves with frequency 4 – 6 / min • Segmentation = haustra; 5-10 cm/hour– pendulum movements • Mass peristalsis; 1-3/day – „sweeping“ • Reverse peristalsis – in proximal colon („delay“ – absorption of water and ions) • Control of anal sphincter: int. – reflex, ext. – voluntary (+reflex) • Defecation: abdominal muscles +++, muscles of pelvic bottom – • Reflex: colono-colonic, gastro-colic • Parasympaticus + (X. till FL) • Sympaticus – (L2 – L4) 4-8 hod 12-72 hod VIC parasympaticus. sacral sympaticus Int. Ext. sphincter Marie Nováková, spring 202115 GIT REFLEXES SYMP. Voluntary control Voluntary control pharynx oesophagus stomach small intestine colon rectum A Superimposed on continuous basal tonus PS and S (sphincters S PS ) a1 10´´ 2-3 hrs 2-4 hrs 10-20 hrs Signalling: relax, move on! slow down! PARASYMP. VI P Achswallowing lower oesophagus local pyloric gastroileal enterogastric internal anal sphincter gastrocolic receptive relaxation of fundus colonoileal colonocolonic Marie Nováková, spring 202116 SECRETION in GIT GIT glands: • Salivary glands • Gastric glands • Small glands of esophagus and intestine • Exocrine pancreas • Liver Stimulation of secretory functions in GIT: 1. Neurocrine 2. Endocrine 3. Paracrine Function of GIT secretion: • Lubrication of food • Swallowing • Mechanical protection of GIT • Chemical protection of GIT • Enzymes • Immune function(s) • Articulation Common features of GIT secretion: water, ions, HCO3-, mucin Marie Nováková, spring 202117 PRODUCTION OF SALIVA • Mucinous vs. serous secretion • Gl. parotis, gl. submandibularis, gl. sublingualis, small salivary glands in mouth • 1 liter / day ( 1ml/min/g ) • High resting blood flow – 10 x contracting muscle, high metabolic exchange • pH: 7 – 8 (at rest rather acidic, increase in HCO3- - alkalization) • Parasympathetic stimulation – Ach, VIP, VII. and IX.n.; vasodilatation ACINES Serous secretion (H2O, ions; isotonic)(gl. parotis) Salivary amylase (zymogenic granules – exocytosis) Over pH 4!!! PRIMARY SALIVA Mucinous secretion (glycoproteins) (gll. submandibularis and sublingualis) Resembles exocrine pancreas DUCTUS Na+ Cl- HCO3- K+ SECONDARY SALIVA (hypotonic, after stimulation – increased tonus) pH ~ 8 Xerostomia Trophic influence of PS Marie Nováková, spring 202118 REGULATION OF SALIVA PRODUCTION Transmitter 2. messenger Final secretion SYMPATHETIC NS Only transient effect !!! amylase vasoconstriction secretion of K+, HCO3- Na+ ClH2O volume PARASYMPATHETIC NS (dominant) - n.fac., n. glossoph. amylase, mucin vasodilatation VIP cAMP NOR b a IP3Ach Subst.P K+ Na+ Na+ (antiport) Ca2+ Ca2+ amylase = + amylase Marie Nováková, spring 202119 SECRETION OF GASTRIC JUICE Mucus (pH 7-8) Gastric pits (glands) pH 2, high concentration of K+ (vomiting) a ClSurface epithelia Lamina propria Mucous neck cells Parietal cells (HCl, intrinsic factor) Main cells - zymogenic granules (pepsinogen) G cells (gastrin) Area: • Subcardial (mucus) • Fundus (HCl) • Pyloric (mucin, G) Gastric juice: water, salts, HCl, pepsin, intrinsic factor, mucus Production increases after meal Higher secretion – lower pH, lower secretion – more Na+, (always more K+ than in plasma) pepsinogen pepsin HCl Gastric mucinous barrier Gastric ulcers Stimulation of a-receptors – decreased secretion of HCO3 NSA – decreased secretion of HCO3 - and mucus Ach, G, CCK, secretin + (individual number!!!) Marie Nováková, spring 202120 HCl PRODUCTION IN PARIETAL CELL AP SP SP H2O+CO2=HCO3-+ H+ (CA) Cl- Cl- Na+ Na+ K+ K+ H+ K+ Cl- HCl Tubulovesicular system (rest, 10% – secretion) Proton pump Basolateral membrane Apical membrane blood „alkaline tide“ (1 000 000 : 1 ) Marie Nováková, spring 202121 CONTROL OF HCl PRODUCTION IN PARIETAL CELL H+K+ (cholinergic fibres) Ach H G (antrum, duodenum) (mast cells) PK IP3 cAMP ? Ca2+ Potentiation of stimulation!!! muscarin rec H2 Phases of gastric secretion: • Cephalic (vision, smell, taste)(X.)(directly, G, H) • Gastric (distension of stomach; peptides, AA)(mechanorec.-local and central reflexes; tryptophan, phenylalanine, caffeine, alcohol – G) • Intestinal (distension of duodenum, peptides, AA)(G from duodenum and jejunum) Inhibition of gastric secretion: Low pH, FA, hypertonia v duodenum and jejunum; secretin, bulbogastron, GIP, CCK PGE, somatostatin – inhibition of HCl secretion Marie Nováková, spring 202122 CONTROL OF PANCREATIC JUICE SECRETION PANCREAS: 100 gr Exocrine and endocrine part n. X. Acinus Ductus (epithelium) Proteins Proenzymes Digestion products (lipids, peptides) Na+ K+ HCO3- Cl- H2O CCK Ach G Subst. P ISOTONIC HCO3 - Cl- HCO3 - Na+ K+ Cl- H2O Decrease of pH Secretion of VIP 1. Trypsinogen (trypsin activates 1, 2, 3) 2. Chymotrypsinogen 3. Prokarboxypeptidase 4. Trypsin-inhibitor 5. a-amylase 6. Pancreatic lipases • Enterokinase – activates trypsinogen PANCREATIC JUICE: approx. 1 l/day 1. Water phase (HCO3 -) – secretin; ductal cells 2. Enzymatic phase - CCK Oddi sphincter (X. – relaxation, secretin - contraction) Regulation of secretion 1. Phase cephalic (n.X. – gastrin) 2. Phase gastric (distension of stomach – gastrin) 3. Phase intestinal (acid in duodenum and jejunum – secretin; peptides, AA = tryptophan., phenylalanine, FA – CCK) Acute pancreatitis Marie Nováková, spring 202123 LIVER FUNCTION • Regulation of metabolism (saccharides – glycogenolysis, gluconeogenesis; lipids – chylomicrons, lipoprotein lipase, VLDL, cholesterol and triglycerides; ketone bodies; proteins – synthesis of urea) • Proteosynthesis (non-essential AA, lipoproteins, albumins, globulins, fibrinogen and other proteins of blood clotting cascade) • Storage (glycogen, vitamins – A, D, B12, iron) • Degradation (hormones – epinephrine, norepinephrine, steroids, polypeptide hormones) • Inactivation and excretion (remedies, toxins) – detoxication by conjugation with glucuronic acid, glycine and glutathione Marie Nováková, spring 202124 BILE PRODUCTION LOBULUS hepatocytes (1-2 layers), fenestration v. portae bile ductus sinusoides a. hepatica Bile • 250-1500ml/day, isotonic, primary secretion – resembles plasma, CCK; modification - secretin • bile acids (salts – Na+) – conjugated (glycin, taurin) – soluble in H2O, 50% of dry, micels • cholesterol (crystals, lithiasis) • lecithins • bile pigments (bilirubin – glucuronid) – yellow colour of bile (lithiasis) • Na+, K+, Cl• H2O, HCO3 - (secretin) Secretion resembles exocrine pancreas Marie Nováková, spring 202125 ENTEROHEPATIC CIRCULATION of BILE ACIDS CCK X. (G) D IJ 20% conjugated bile acids secretion HCO3 - H2O 35ml portal circulation G, CCK, S G, CCK X. Intestinal phase bile acids Na+ Cl- HCO3 - H2O Between meals – thickening up to 5-20x Active transport – other ions keep electroneutrality Oddi Cephalic phase Gastric phase Intestinal phase deconjugated bile acids Marie Nováková, spring 202126 REGULATION OF SECRETORY FUNCTIONS IN GIT HCl G Ach H peptides H2 receptors (mast cells) GRP subst.P (axon. reflex) (motility) ENS VIP GIP glucose lipids INSULIN (b-cells, endocrine pancreas) enzymes HCO3 - CCK,GIP peptides AA, FA HCl SS (d-cells) motility electrolytes H2O exocrine pancreas * CEPHALIC PHASE (taste, smell…) * GASTRIC PHASE (Ach, H, S, G, CCK stimulation of production INTESTINAL PHASE OF SECRETION * mediated by gastrin Marie Nováková, spring 202127 SELECTED QUESTIONS – related to ABSORPTION, IONS AND WATER Marie Nováková, spring 202128 • Both active and passive mechanisms participate in GIT absorption • Both paracellular and transcellular movements are involved • Absorption area is enlarged by folds, villi and microvilli (mostly in small intestine) • Absorption of water and electrolytes occurs in both small and large intestine, absorption of nutrients occurs only in small intestine • Small intestine absorbs water and electrolytes and secretes HCO3 -, large intestine absorbs water and electrolytes and secretes potassium and HCO3 • Water „follows“ electrolytes, eventually is „drafted“ by osmotically active substances • Numerous absorption mechanisms depend on sodium gradient Marie Nováková, spring 202129 TRANSPORT MECHANISMS in GIT Diffusion Facilitated diffusion Co-transport Active transport Marie Nováková, spring 202130 DAILY WATER BALANCE INTAKE OUTPUT saliva gastric juice pancreatic juice bile small intestine colon ~ 2 - 3 ~ 1,5 ~ 1 - 2 ~ 1,5 ~ 0,5 ~ 1,5 ~ 0,4 ~ 0,2 (~7,5) (~1,3) (~0,2) Marie Nováková, spring 202131 WATER ABSORPTION (small intestine, gallbladder, stomach, colon) (duodenum – osmotic draft of H2O) Continuous osmotic gradient brush border H2O H2O FILTRATION Na+ Na+, K+, Cl- +10m V Na+ K+ Cl- TRANSPORT •Transcellular •Paracellular Brush border Tight junctions Basal membrane Lateral membrane F STIMULATION: digestion products (AA, sugars) Marie Nováková, spring 202132 TRANSPORT OF IONS K + Na+ K + K + Na+ Na+ IL IL glucose, galactose, AA Cl- H2O+CO2 H+ HCO3 - H2CO3 H2O + CO2 ClLieberkühn cryptes: matured cells – absorption, immature cells – secretion of Na+, Cl- a H2O JEJUNUM ILEUM brush border basolateral membrane J glucose, galactose, AA Marie Nováková, spring 202133 TRANSPORT OF IONS K+ Na+ (120mM/l) K+ Na+ Na+(25mM/l)+H2O Cl- H2O+CO2 H+ HCO3 - H2CO3 H2O + CO2 COLON K+ ClALDOSTERONE ALDOSTERONE ALDOSTERONE – synthesis of transport systems (as in proximal tubule) basolateral membrane brush border K+ Marie Nováková, spring 202134 REGULATION OF TRANSPORT OF WATER AND IONS 1. Autonomous nervous system: SYMP (noradrenaline, enkefalins) + somatostatin – increase of absorption of water, sodium and chlorine 2. Aldosterone: colon – stimulation of secretion of potassium and absorption of sodium and water (up-regulation of Na/K-ATPase, Na-channel) 3. Glucocorticoids: small intestine and colon - absorption of sodium, chlorine and water (up-regulation of Na/K-ATPase) Marie Nováková, spring 202135 ABSORPTION OF Ca2+ INTAKE: 1000mg/day ABSORPTION: 350mg/day Absorption against concentration gradient (1:10) in all GIT (D, J), 50x slower than absorption of Na+ Ca2+ Ca BP Ca2+-ATPase Na+/Ca2+-antiporter VIT.D ER Mch 1,25-dihydrocholecalciferol Calbindin – prevention of formation of insoluble salts (phosphates, oxalates) [Ca2+]pl. Basolateral membrane brush border TRPV6Ca2+ K+ Na+ Marie Nováková, spring 202136 RACHITIS (rickets) Marie Nováková, spring 202137 ABSORPTION OF Fe2+ endocytosis 2 Fe2+ TRANSFERIN INTAKE: 15-20mg/day ABSORPTION: Men: 0,5 - 1mg/day Women: 1 – 1,5mg/day D, J pH: Fe3+ Fe2+ 70% - Hb 25% - F Insoluble salts and complexes (20:1) – limitation of absorption Decrease of pH Fe – up-regulation Fe2+ stimulates synthesis of TF – regulation! Hemosiderin – deposits of Fe in desmosomes PLAZMATIC TRANSFERIN (Apo)-Feritin Excess of Fe2+ – loss with epithelium Fe2+ stimulates synthesis of apoferitin (translation) – regulation! basolateral membrane brush border Marie Nováková, spring 202138 VITAMIN B12 • Daily need is close to its absorption capacity • Synthesised by bacteria in colon – BUT there is not absorption mechanism • Store in liver (2-5mg) • In bile 0.5-5mg / day, reabsorbed • Daily loss – 0.1% of stores stores will last for 3-6 years ABSORPTION 1. Gastric phase: B12 is bound to proteins, low pH and pepsin release it; bound to glycoproteins – R-proteins (saliva, gastric juice), almost pH-undependable; intrinsic factor (IF) – parietal cells of gastric mucosa; most of vitamin bound to R-proteins 2. Intestinal phase: pancreatic proteases, cleavage of R-B12, bound to IF (resistant to pancreatic proteases) Marie Nováková, spring 202139 ABSORPTION OF B12 VITAMIN IF B12 B12 B12 IF IF Intrinsic Factor IF-B12 receptor complex ? B12 B12 B12 v.portae ILEUM B12 transcobalamin II Marie Nováková, spring 202140 Pernicious anaemia (megaloblastic) Marie Nováková, spring 202141 DIGESTION AND ABSORPTION OF SACCHARIDES POLYSACHARIDES (a-glycosyled s.) OLIGOSACCHARIDES MONOSACHARIDES FRUCTOSE GLUCOSE GALACTOSE AMYLOPECTIN GLYCOGENa-amylase DEXTRIN TRICHACHARIDES DISACHARIDES: SACCHAROSE MALTOSE LACTOSE isomaltase maltase saccharase lactase Saliva Pancreatic juice Na+ Epithelium of duodenum and jejunum • Lactase intolerance • Diarrhoea salivary amylase 2 binding sites for Na+ 1 binding site for saccharide facilitated transport + diffusion GLUT-5 SGLT-1 GLUT-2 Marie Nováková, spring 202142 DIGESTION AND ABSORPTION OF PROTEINS STOMACH Pepsin DUODENUM Trypsin Chymotrypsin Carboxypeptidase JEJUNUM Membrane peptidases (brush border) CYTOPLASM of epithelial cell di-, tri-peptidases PEPTIDES > 4 AA DI-, TRI-PEPTIDES AA AA PROTEASES 15% 50% PEPTIDASES (exo-, endo-) NUCLEASES Na+-cotransport Diffusion Purine, pyrimidine bases – active transport 100g food + 30g GIT juices + epithelial cells enterokinase Marie Nováková, spring 202143 DIGESTION AND ABSORPTION OF LIPIDS Triglycerides (TAG) Sterols (-esters) Phospholipids (lecithin) LIPID DROPS EMULSIFICATION (+lecithin, +monoglycides) Ø 1mm BILE ACIDS SALTS DEESTHERIFICATION PANCREATIC LIPASE (colipase) CHOLESTEROL-ESTHERASE PHOSPHOLIPASE A2 ENTERIC LIPASE Glycerol FA MAG CH LFL MICELLES Ø 5nm, 20-30 molecules polar stratification, hydrophilic disintegration of micelles TAG unstirred water layer 200-500mm bile acids resorption (diffusion) reesterification (FA >12c, in endopl.retic.) CHE PL PROT. EXOCYTOSIS CHYLOMICRA Ø 10nm LYMPHATIC CIRCULATION NEFA (<12c) GLYCEROL capillaries (fenestration) Na+ Marie Nováková, spring 202144 ABSORPTION IN COLON • Na+ (active transport, aldosteron) H2O (90% water in colon) • ClREST OF CHYME 1. Cellulose, collagen 2. Bile acids, epithelia, mucin, leucocytes • Bacteria fermenting: fibre (pectin, cellulose) – lactate, alcohol, acetate, CO2, methane • Bacteria putrescent: residues of AA – NH3, SH2, phenol, indole, solatol (carcinogenic) Production of vitamin K and vitamins of B group – BUT NO ABSORPTION MECHANISMS NUTRITION PASSAGE EUMICROBIA Marie Nováková, spring 202145 REGULATION OF FOOD INTAKE AND NUTRITIONAL STATE Marie Nováková, spring 202146 INTAKE OUTPUT CENTER OF SATIETY CENTER OF HUNGER (permanently active) ncl. ventromedialis in hypothalamus lateral hypothalamus (nucleus under fasciculus telencephalicus medialis) Marie Nováková, spring 202147 FEELING OF SATIETY FOOD INTAKE Chewing movements Receptors in nose, mouth, oesophagus, intestine Mechanoreceptors in stomach GIT chemoreceptor s SATIETY PRERESORPTIVE FEEDING Central gluco- thermo- lipo- receptors COMPILING THE INFORMATION IN CNS (CENTER OF SATIETY = ncl. ventromedial in hypothalamus) RESORPTIVE FEEDING Marie Nováková, spring 202148 FEELING OF HUNGER LACK OF FOOD Hungry contractions of stomach Decreased glucose availability Decreased heat production Changes of lipid metabolism Mechanoreceptors Glucoreceptors Internal termoreceptors (hypothalamus) „Liporeceptors“ HUNGER SHORT-TERMED REGULATION LONG-TERMED REGULATION Compensation of dietary mistakes Marie Nováková, spring 202149 HYPOTHESIS: 1. Lipostatic 2. GIT peptides 3. Glucostatic 4. Thermostatic REGULATION OF FOOD INTAKE Marie Nováková, spring 202150 OREXIGENIC FACTORS • Neuropeptide Y • Orexin A and B (hypocretin 1 and 2) • ARP (agouti-related peptide) • Ghrelin (lenomorelin) – s.-c. hormone of hunger (released from „empty“ stomach) • Motilin • Sugars (fructose) ANOREXIGENIC FACTORS • Leptin - – s.-c. hormone of satiety • POMC – derivative MC4-R • CRH (corticoliberin) • CART (cocaine- and amphetamine-regulated transcript) • Peptide YY (pankreatic peptide; L-cells in ileum and colon, suppresses gastric motility, increases absorption) • CCK (cholecystokinin) • glucagon MEDICAMENTS !!! Marie Nováková, spring 202151 LEPTIN (ob-protein) Secreted by adipocytes into the blood Binding proteins Effect on CNS (regulation of body mass and stability of adipose tissue) • Pulsatile and diurnal character of plasmatic levels • Free and bound form (in serum) • SLIM PEOPLE HAVE 2x MORE OF BOND FORM THAN OBESE PEOPLE • LEPTIN REZISTANCE: often in obese patient with insulin resistance RECEPTORS from cytokine family • Peripheral (gonads) • Central (hypothalamus, pituitary) Modulates expression of genes for oestrogens. Regulation of obesity by leptin mediated by NPY and MSH. Leptin controls adipose tissue by coordination of food intake, metabolism, autonomous nervous system and energy balance. Marie Nováková, spring 202152 ADIPOSE TISSUE INCREASE OF BODY MASSLOSS OF BODY MASS - LEPTIN +LEPTIN HYPOTHALAMUS HYPOTHALAMUS NPY RESPONSE TO FASTING MSH RESPONSE TO OBESITY NPY RECEPTOR MSH RECEPTOR + Food intake - Reproduction - Temperature - Energy expenditure - Food intake + Energy expenditure PARASYMPATHETIC ACTIVITY SYMPATHETIC ACTIVITY POMC derivatives LEPTIN RESISTANCE (MC4-R)(Y1, Y2, Y5)