Digestion and Weight Regulation Flashcards
What are the main features of the anatomical layers of the gut?
- Epithelium: specialised for absorption (fast turnover)
- Mucosa: protects gut as immune cells contained
- Submucosa: contains secretory glands (E.g. Brunner’s glands in duodenum) and submucosal plexus (nervous control)
- Muscularis externa: muscular wall (circular and longitudinal) and myenteric plexus to control them
- Serosa: suspends gut in mesentery (prevents tangling)
What are the inputs for the enteric nervous system?
Input from CNS – coordinates to outside world
Parasympathetic promotes mobility:
- Vagus nerve (long preganglionic neuron)
- ACh released on enteric nerves
Sympathetic:
- Preganglionic release of ACh in prevertebral ganglion
- Postganglionic releases NA on myenteric/submucosal plexus
- NA inhibits gut digestion
What afferents from the enteric nervous system exist?
Intrinsic primary afferent neuron (IPAN):
- Intrinsic reflexes
- Cell body in submucosal plexus
Intrinsic fugal afferent neuron (IFAN):
- Long distance reflexes
- Cell body in mucosal plexus synapsing on preganglionic SNS synapse.
- Short circuits the ENS in long-distance reflexes (e.g. for pain) reducing number of synapses and time.
General visceral afferent = ‘normal’ sensory fibre (innervates gut epithelium to CNS)
- Vagus nerve: can allow for vasovagal reflexes (entirely carried in Vagus nerve)
- Important in nociception (can lead to referred pain)
Describe the structure of smooth muscle and how it is adapted for a large SA:
Cytoplasmic dense bodies anchor cells with actin/myosin running at different directions:
- Relies on Ca2+ coming in across membrane (through VG channels) NOT internal stores.
- Therefore high Ca2+ accessibility required
Large SA (for high Ca2+ diffusion rates)
- Caveolae indentations to increase SA
- Calcium induced calcium release (from SR)Electrical and physical coupling (similar idea to heart)
- Smaller than skeletal muscle cells
Electrical and physical coupling(similar idea to heart)
- Forming functional syncytium
- Gap junctions between muscle fibres
How does smooth muscle contract? How does this compare to skeletal muscle contraction?
Contraction mechanisms:
- Ca2+ bind calmodulin
- Activates MLCK which phosphorylates myosin causing contraction
- Contraction stopped by MLCP (phosphatase)
- Peristalsis = waves of circular and longitudinal contraction/relaxation to move food along gut.
Differences from skeletal muscle:
- No troponin involved
- Enzymes used instead (slower)
- Slower contraction but more contraction
Describe peristalsis and the local mechanisms which control it:
Waves of circular and longitudinal contraction/relaxation to move food along gut.
Local control mechanisms:
- Peristaltic reflex (Starling): stretch due to bolus causes relaxation and contraction
- Local stretch causes 5-HT release by enterochromaffin cells (in mucosa)
- IPANs stimulated in myenteric plexus
Oral side neurons release ACh = contraction
Anal side neurons release NO = relaxation
- Serotonin must be removed to prevent +ve feedback of this process
What are slow waves? How do they cause movement?
Slow waves = fluctuating membrane potentials (from -50 to -20mv) over several seconds
- Due to interstitial cells of Cajal (ICCs) (generate slow waves and coordinate other cells through gap junctions)
- Innervated by ENS to cause modulation
- Spikes (Ca2+ based action potentials through L-type VG Ca2+ channels) can be overlayed on top to cause a coordinated contraction
- Isolated gut cells do not show this)
How are slow waves modulates by the ENS?
Modulated by ENS:
- Suppressed by NA or excited by ACh
- Excitatory transmitters ➡ increase Na+/Ca2+ ➡ depolarise cells (stronger and longer contraction)
- Controls amplitude of contraction without controlling frequency to stop peristalsis
- Inhibitory transmitter ➡ increase K+ ➡ hyperpolarise cells
Which peptide hormones control acid secretion and protection?
- Secretin: produced by S cell (duodenum) to protect from acid: stimulates bicarbonate rich solution from pancreas and constriction of pyloric sphincter
- Gastrin: promotes acid release
Which hormones are responsible for appetite regulation?
- Ghrelin: promotes appetite
- Incretins (GIP/GLP-1): promote insulin release (suppress appetite)
Which hormones are involved in movement of the gut and Gaul bladder?
Neurocrine:
- ACh (excitatory)
- NA (inhibitory)
- NO and VIP
Paracrine: do not travel in blood
- 5-HT and HA
Endocrine:
- Motilin: initiates migrating myoelectric complex
- CCK: produced by I cells of small intestine stimulates Gaul bladder contraction - relaxation of sphincter of Oddi (leads to removal of fatty products).
What is potentiation? Give an example of occurance in the digestive system:
When response of cell to a combination for messengers exceed sum of response to same messengers delivered individually (synergism)
- Often due to activation of two different intracellular pathways
- E.g. SNS (raised cAMP) and PNS (raised Ca2+) stimulated together = large increase in amylase
What are the functions of saliva?
- Lubrication
- Defence (lysozyme, lactoferrin, IgA, proline-rich proteins to reduce tannin toxicity)
- Buffering (HCO3- combats acid)
- Digestion (amylase)
How is saliva produced and modified?
Primary secretion:
- Na+ actively secreted; water follows into acinus
Secretion modified through intercalated duct:
- Active movement and ion composition
- Na+ replaced with K+
- Cl- replaced with HCO3-
Shown by saliva composition against flow rate experimentation – also showed that process is active (not ultrafiltration like kidney)
What are the mechanisms behind PNS and SNS control of salivary secretion? How does this exhibit synergism?
Anticipatory response (Pavlov’s dogs)
Parasympathetic activation:
- Produce ACh and VIP
- ACh binds M1/2 receptors to increase Ca2+ and therefore secretory volume
- VIP promotes vasodilatation and myoepithelial contraction
Sympathetic activation:
- NA binds β1 receptors increasing cAMP levels and exocytosis
- NA produced promoting myoepithelial contraction
- Secretory enzyme content increased
How is motility of the oesophagus achieved? Why might it fail? How can movement be detected?
Top 2/3rds:
- Due to skeletal muscle
- Requires external neuronal stimulation to sequentially stimulate muscle regions
Bottom 2/3rds
- Smooth muscle
Ends:
- Upper and lower oesophageal sphincter
- Lower sphincter requires extrinsic innervation from Vagus nerve
Movement can be seen by internal pressure changes within oesophagus.
Failure = achalasia (sphincter contracted and not responsive to enteric nervous system)
- E.g. caused by trypanosoma cruzi in Chagas’ disease
How is emesis stimulated; prepared for and consequences?
Stimulated by:
- Stretch of GI tract to vomiting centre in medulla (via vagus nerve)
- Emetic drugs
Prepared for by:
- Increased salivation
- Reverse peristalsis and lowering intrathoracic pressure/raising abdominal pressure
- Sphincter opening
Consequences:
- Damage (tp oesophagus and teeth)
- Ion imbalances (metabolic alkalosis; hypokalaemia)
- Hypovolaemia
How does the stomach move?
Retropulsion due to slow waves:
- Muscle contraction towards pylorus and forcing antrum through (grinding effect)
- Pylorus diameter controls emptying rate
Migrating myoelectric complex:
- To empty stomach
- Controlled by motilin
Enterogastric reflex: Keeps stomach full:
- Reduce stomach motility/tighten sphincter
- Stimulated by CCK (fat and acid in duodenum)
- Stimulated by duodenal stretch
- E.g. Ileal brake (food products detected in ileum
How can the size of the stomach sphincter be experimentally measured?
- Use of radiolabelled glucose solution and radio-opaque plastic spheres
- Measure time between intake and stomach emptying.
How is the anus controlled? Give an example of when this control goes wrong:
Skeletal muscle which responds to stretch of the colon (internal anal sphincter):
- Activation of autonomic fibres from the spinal cord
- Activation of intrinsic nerves to release NO/VIP
- Relaxation
- External sphincter: spontaneously contracts on stretch (relaxed voluntarily to defecate)
- Defecation increased by valvasa manoeuvre (increasing pressure in abdominal library)
Hirschsprung’s disease results in missing communication of myenteric neurons to sphincter = problems passing stool
What are the secretory glands of the stomach? What do they produce?
Top of stomach: Cardiac glands = Mucus
- Mucus traps HCO3- as protective layer
Majority: Oxyntic glands = acid/enzymes
- Zymogens (inactive enzymes E.g. pepsinogens; chymosin (=rennin) for milk digestion)
- Intrinsic factor: binds to B12 to protect it (allows ileal endocytosis)
Bottom 1/3: Pyloric glands = mucus and gastrin
- Gastric acid: delays stomach emptying, solubilises and improves ion absorption (Fe, Ca) and kills microbes
Parietal cells = gastric acid
How might stomach acid composition state change in a fasted/fed state?
Fasted state:
- Mainly NaCl
- Lower acid concentration
- Protects stomach and reduces metabolic cost of gastric juice production
How is stomach acid secretion controlled?
Promoting secretion:
- Gastrin (G cells): promotes parietal and ECL cell action by raising Ca2+
- HA (from enterochromaffin-like cells): binds H2 to increases cAMP levels in parietal cells
- ACh: increases Ca2+ levels in parietal cells
Inhibiting secretion:
- Secretin
- Somatostatin (produced by D cells): reduces cAMP levels in parietal cells
- Prostaglandin
Describe synergism between different stimulants of: gastrin and stomach secretion generally:
Gastrin secretion (from G cells) stimulated by:
- Nervous stimulation (ACh)
- Hormonal stimulation (gastrin releasing peptide (GRP))
- Paracrine signals (digestion products E.g. amino acids)
Acid secretion:
- Hormonal stimulation = gastrin
- Nervous (neurocrine) = ACh
- Paracrine = HA
All three gives maximal affect as both Ca2+ and cAMP increased – increases proton pump activity and opens K+ channels
What are the exo and endocrine secretions of the pancreas?
Endocrine:
- Insulin
- Glucagon
- Somatostatin
Exocrine: THINK SALIVARY GLAND
- Primary secretion is NaCl
- Enzymes (zymogens added containing pancreatic secretory inhibitors to prevent damage)
- HCO3- swapped for Cl- (more HCO3- at higher flow rates
How is secretion from the pancreas controlled? How is secretion achieved?
Secretion: no myogenic control - liquid moves out as pressure increases
Control:
- Secretin and VIP increase cAMP and therefore permeability of Cl- channels and increases flow rate
- CCK and ACh (on M3) increases Ca2+ to increase K+ leakage out of cells
- Synergism between two signals for maximum effect.
How is the gut adapted for absorption? What does coeliac disease cause?
Surface area:
- Folds of Kerckring
- Villi and microvilli (brush border)
Capillary
lacteal
Coeliac disease causes destruction of microvilli = malabsorption
How are carbohydrates digested in the small intestine?
- Amylase turns Amylopectin to oligosaccharides
- Glucoamylase/α-dextrinase: Oligosaccharides to glucose (branching degraded)
- Disaccharide specific: sucrase; lactase
- Absorption: using SGLT; GLUT5; GLUT2
How are proteins and amino acids digested and absorbed in stomach? What are the feedback loops between enzymes?
Protein digestion:
- Proteases need to be activated
- Pepsins activated in stomach by low pH
- Trypsinogen –> trypsin by enteropeptidase
Amino acid digestion:
- Amino acids transported across luminal membrane
- Glutamine kept and metabolised by lining cells – good N donor which is used in high turnover rate of cells
Feedback loops:
- Trypsin stimulates trypsinogen conversion (+ve feedback loop)
- Trypsin activates other peptidase (e.g. elastase; chymotrypsin)
How are ions (Ca2+ and FeII and III) absorbed? How is over-absorption of Fe preveted?
Ca2+ absorption:
- TRPV5 + calbindin + NCX transporter out
- Increased by calcitriol
- Can be transepithelial at high concentration
Fe absorption:
1. Fe III reduced to Fe II
2. DMT1 used to transport into cell (haem passes through directly)
3. Binds to ferritin to store in cell
4. OR transported out by ferroportin
Once outside: Fe II oxidised back to Fe III to bind transferrin for blood transport
Over absorption of Fe prevented by:
- Trapping of Fe in epithelial cells (ferritin bound) then lost when cells die
- Ferroportin action reduced by hepcidin from liver (when stores high)
How are vitamins absorbed?
- Water-soluble: taken up by diffusion (active transport)
- Fat-soluble (A/D3/E/K): enter micelles and are absorbed with fat
- B12 bound to intrinsic factor and taken up in ileum –> transported bound to transcobalamin II in blood
What is the structure of a hepatic unit?
Hexagonal structure with portal triad at each vertex containing:
- Bile duct branch
- Hepatic portal vein capillary
- Hepatic artery
- Drain into central hepatic vein
What are the carbohydrate/lipid/protein metabolism functions of the liver?
Carbohydrates:
- Glycogenesis and glycogenolysis (through GLUT2 glucose movement)
- Gluconeogenesis
Lipids:
- Triglyceride metabolism: vLDLs produced
- Production of ketone bodies for brain metabolism
- Hormone sensitive lipase produced
- Cholesterol synthesis
Protein:
- Non-essential amino acids made (urea/glutamine exported)
What are some general functions of the liver?
- Carbohydrate/lipid/protein metabolism
- Cholesterol synthesis
- Destruction and detoxification (by Kupffer cells)
- Filtration and storage of blood, vitamins and Fe
- Formation of bile
How does the liver form bile? What is bile made of?
Constituents:
- Bile acids = fat absorption (including phospholipids)
- Waste removal: cholesterol (can form gaul stones); bilirubin; heavy metals
- Protection: IgA; tocopherol; mucus
Formation:
- Counter current flow between blood and bile for maximum diffusion
What are the actions of bile salts?
Increases surface area:
- Amphipathic molecule causing micelles formation
- Allows lipase (and colipase action) to breakdown fat
- Fat digestion products with FA binding protein –> chylomicrons –> lacteal
What are the functions of the gut flora?
- Digests products currently undigested (E.g. raffinose)
- Produce vitamins (E.g. vit K)
- Colonisation resistance
- Immune system stimulation
Why is potentiation important for acid secretion?
All signals released under different conditions – only when all are met will there be acid secretion:
- ACh: CNS allowing digestion
- Gastrin: suggests there is food in the stomach = produce HA (from ECL cells)
- Somatostatin: low levels suggest there is no (“too high acidity”) signal
Parietal cell effectively working as a ‘coincidence detector’
- Some factors (stress, H.Pylori, Zollinger-Ellison syndrome, NSAID) unbalance mucus/acid secretion
How could you suppress gastric secretion?
- Proton pump inhibitors (omeprazole)
- H2 (HA type 2) receptor agonists (e.g. some types of antihistamines)
How do artiodactyls (ungulates) use contractions and rumination to mix their food?
Contractions:
- Regulated vasovagal reflexes: triggered by stomach stretch, touch, chemo-sensation
- Primary contractions of rumen mix contents
- Secondary contractions control gas (belching)
- Causes movement of digesta into omasum (faster for liquid)
Rumination (chewing the cud):
- Reverse peristalsis delivers food bolus to mouth
- Oesophagus relaxes (lowers pressure)
- Remastication
- Abolished by vagotomy (cutting Vagus nerve)
How are monosaccharides used as a fuel source for ruminants?
Production of VFAs:
- Sugars made into pyruvate by bacteria (in anaerobic environments)
- Allows NAD+ regeneration
- VFAs produced as waste products by bacteria (acetate/propionate)
Ruminants can further oxidise VFAs as they have access to oxygen
How do ruminants use different VFAs?
VFAs acts as majority of daily ruminant energy source:
- Acetate: respired directly or converted to fatty acids in adipose tissue
- Propionate (short chain FFA): travels to liver to be used in gluconeogenesis (exception to rule that fatty acids can’t be converted to glucose)
- Butyrate: converted to β-hydroxybutyrate to be absorbed for metabolism
How do ruminants get protein?
Urea currency used:
- Urea produced in host and swallowed (in saliva) from ammonia
- Urea hydrolysed by microflora to produce ammonia
- Ammonia converted to protein
- Excess NH3 taken up by host
- Digested bacteria provide protein substrates for host
How are fats and vitamins gained by ruminants?
Fats:
- Polyunsaturated fats hydrolysed in rumen by microbial lipases
- Fermented into propionate
- Saturated fats absorbed in intestine
- Polyunsaturated fat can be absorbed by bypassing reticulorumen (using pellet)
- Long chain FFAs emulsified and absorbed directly in small intestine
Vitamins:
- Microbes synthesise K and B vitamins
What are the advantages of foregut over hindgut fermentation? What about hindgut over foregut fermentation?
Foregut over hindgut:
- Fibre digestion more thorough
- Food can be stored for later mastication
- Toxins consumed can be dealt with microbes (not host directly)
- Nitrogen recycling more efficient
Hindgut over foregut:
- Faster transit time (more food can be ingested)
- Easily digestible food processed directly
- Smaller energy loses (as methane in ruminants)
How can measurements of metabolism/weight be made?
- Indirect calorimetry
- Respiratory quotient (RQ) = rate of CO2/rate of O2 consumption
- Double labelled water: urine collected (higher metabolic rate leads to decreased 18O:2H ratio)
- Measuring body fat (BMI; underwater weighing using body fat volume; bioelectrical impedance; dual X-ray absorptiometry)
How do you calculate body fat using underwater weighing? What about using respiratory quotient?
Body fat volume:
- 5.5(Vt -Vr) - 5M
- Vt = total body volume
- Vr = residual volume in lungs
Respiratory Quotient (RQ):
- Rate of CO2 production/O2 consumption
- Must be steady state measurement
- May exceed 1.0 is fat synthesis from glucose unusually high
What are the endocrine responses to starvation?
Reactive changes:
Glucagon:
- Stimulated by hypoglycaemia and low insulin levels
- SNS and PNS stimulation and high amino acid concentration
- Stimulates liver to undergo glycogenolysis/neogenesis/ketogenesis
Adrenaline.
Longer term:
- GH
- Cortisol
- FGF-21
What are the metabolic phases which occur during starvation and their hallmarks:
First few days:
- Glucagon high; insulin low
- GH rising
- Plasma glucose drops and compensated for by gluconeogenesis/lipolysis
- Metabolic rate drops (T3 reduced)
Week –>
- Metabolic swap to ketone bodies
- FGF21 and GH important
Last days before death:
- Fat reserves exhausted
- Protein metabolism forced
- RQ rises
What are the major anorexigenic hormones?
- CCK (from fat products in duodenum)
- GLP-1 (from L cells of jejunum): under feedforward control
- PYY (form L cells of jejunum): for medium meal control
- Gastric leptin, amylin, GRP…
What are the Hervey and Coleman experiments and how did they lead to leptin discovery?
Hervey experiments:
- Effect of parabiosis: lesion VMN in one rat causes weight gain but other rat becomes anorexic
- Implied signal carried in blood
Coleman experiments:
- Ob/ob mouse is unable to produce satiety factor (leptin)
- Db/db mouse produces leptin but can’t respond to it due to defective leptin receptor
Leptin discovery:
- Ob/ob mouse discovered with congenital leptin deficiency
Which molecules are produced by the arcuate nucleus to control appetite?
Appetite suppression:
- Upregulate POMC neuron production of α-MSH (binds MC4 receptors)
Appetite stimulation:
- NPY upregulation (by ghrelin)
- AgRP neurons respond to NPY inhibition and suppress the appetite suppressing pathway (inhibit MC4 receptors in hypothalamus)
What does the PVN do in response to increased NPY? (reverse true for POMC stimulation)
- Increases food intake (via nucleus tractus solitarius)
- Controls sympathetic output to brown fat (how much fat is burned off?)
- Control of hypothalamic-pituitary-thyroid axis
- Short term blood glucose control
What are some ways to treat obesity?
- Diet and exercise
- Non exercise thermogenesis (NEAT)
- Pancreatic lipase inhibitor (E.g. orlistat) to lose fat in faeces = steatorrhea (can result in fat soluble vitamin deficiency (b12))
- Surgery (gastric bypass)
- GLP-1 receptor agonists to suppress appetite (incretin injection)
- Upregulation of UCP3
- Leptin or CCK injection (short term so not feasible)
Which aspects of cow metabolism mirror human metabolism?
Human metabolism WHEN FASTED:
- Gluconeogenesis
- Fatty acid oxidation
- Ketone body production
Which feedback loops os CCK controlled by?
Positive feedback (digestion is not homeostatic!):
- Long chain FFAs stimulate CCK from I cells
- Causes increased pancreatic secretion, including lipase
- Increases triglyceride digestion in duodenum
Negative feedback (later following digestion):
- CCK stimulated from I cells by FFAs
- Increases GB contraction
- Bile released to increase absorption for digestion
- Absorption reduces triglyceride concentration
Compare and contrast ICC and SAN pacemaker cells:
Both generate spontaneous contraction:
- SAN produces true APs (K+ modulated)
- ICCs produce slow waves (not all-or-none; smaller amplitude and Ca2+ modulated)
Both modulated by extrinsic nerves:
- SAN by cardiac accelerator nerves from medulla
- PNS has effect of decreasing HR but upregulating digestion (increase slow waves)
How is smooth and cardiac muscle similar?
Anatomically:
- Small
- Connected cells (chemically and electrical gap junctions)
- Form syncytium
- Extracellular Ca2+ contributes to excitation-contraction coupling (plus CICR)
Activity:
- Mechanically and electrically coupled for coordinated contractions
- Since both moving fluid
Why is extrinsic nervous control necessary for the digestive system?
- Feedforward mechanisms (emesis; cephalic digestion)
- Striated muscle control (anus)
- Vasovagal long distance reflexes (gastro-colic/ileal brake)
- Communicate external circumstances (emotional state/danger?)