Digestive system, Metabolism

From Biol557

• started here on 04/19/10.

Contents 1 The digestive system 1.1 Functions of the digestive system 1.2 Major components 1.2.1 Oral cavity 1.2.1.1 Tongue 1.2.1.2 Salivary glands 1.2.1.3 Saliva 1.2.1.4 Mucus 1.2.1.5 Fluids 1.2.1.6 Mumps 1.2.1.7 Teeth 1.2.2 Pharynx 1.2.3 Esophagus 1.2.3.1 Barrett's esophagus 1.2.3.2 Acid reflux disease 1.2.3.3 Hiatal hernia 1.2.4 Stomach 1.2.4.1 Functions 1.2.4.2 Anatomy 1.2.4.3 HCl secretion 1.2.4.4 Gastric fingering 1.2.4.5 pH of stomach 1.2.4.6 Enterooendocrine cells 1.2.4.7 Involuntary protein spills 1.2.4.8 Pyloric problems affecting infants 1.2.4.9 Hormones involved in digestion= 1.2.5 Regulation of gastric activity 1.2.5.1 Gastric secretion: Cephalic phase 1.2.5.2 Gastric secretion: Gastric phase 1.2.5.3 Gastric secretion: Intestinal phase 1.2.6 Digestion in the stomach 1.2.6.1 Absorption in the stomach 1.2.6.2 Food propulsion and mixing 1.2.6.3 Peptic ulcers 1.2.6.4 Other contributing issues 1.3 After the stomach 1.3.1 Hepatic protal system 1.3.2 Liver, gall bladder, duodenom connections 1.3.3 Liver 1.3.3.1 Lobule organization 1.3.3.2 Bile 1.3.4 Stimulation of the gall bladder 1.3.5 Jaundice 1.3.6 Cellular structures of pancrease 1.3.6.1 Secretions of the acini cells 1.3.7 Stimulus of pancreas 1.3.8 Pancreatic problems 1.3.9 Pancreatic cancer 1.3.10 Intestingal fluid and electrolyte movement 1.3.11 Small intestine 1.3.12 Intestinal secretion 1.3.13 Small intestine wall 1.3.14 Movements of nutrients in the SI 1.3.15 Protein digestion 1.3.16 Lipids 1.3.17 Lipoproteins and lipid transport 1.3.18 Carbohydrate digestion 1.3.18.1 Problems 1.3.18.2 Lactose intolerance 1.3.19 Large intestine 1.3.20 Osmotic diarrhea 1.3.21 Secretory 1.3.22 Motility disorder diarrhea 1.3.23 Inflammation 1.3.24 Constipation 1.3.25 Defecation reflex 1.3.26 Aging 1.4 Hormonal Control of Food Intake 1.4.1 Fat cells (adipocytes) 1.4.2 Other adipocytes factors 1.4.3 Factors produces by the GI tract 1.4.4 Factors of the endocrine Pancreas 1.4.5 Summary 2 Metabolism II 2.1 Hierarchy of energy usage 2.2 Nutrient processing in the mt 2.2.1 Glycolysis 2.2.2 mt ATP production 2.2.2.1 The TCA cycle 2.2.2.2 The ETC 2.2.3 The big picture 2.3 Lypolysis 2.4 Lipoproteins 2.4.1 Chylomicrons 2.4.2 Very low density lipoproteins 2.4.3 Intermediate density lipoproteins 2.4.4 Low density lipoproteins 2.4.5 High density lipoproteins 2.4.6 Chylomicron transport 2.5 Amino acids 2.6 Metabolic components 2.6.1 Liver 2.6.2 fat cells 2.6.3 Skeletal muscle 2.6.4 Neuronal tissue 2.6.5 Other peripheral tissues 2.7 Metabolic states 2.7.1 Hormonal control of metabolic states 2.8 Food pyramid

[edit] The digestive system

• Sedentary body requireds ~30 kcal / kg body weight per day.

[edit] Functions of the digestive system

• Ingestion, getting food in.
• Secretion, we'll talk about all the secretions. (pancreas, liver, gall bladder, stomach acid, salivary glands).
• Digestion proper
  • Three different parts:
    • Mechanical: physical breakdown
    • Chemical breakdown, different than enzymes; think HCl in the stomach, not enzymes like in the small intestine.
    • Enzymatic; more specific.
• Absorption, that is how do we get the nutrients from lumen into blood.
• Defecation; getting rid of stuff that isn't useful.

• We're gong to think about microvilli to maximize absorption, peristalsis (mixing and physical breakdown).

[edit] Major components

• The tube.
• Accessory structures that protude into it or communicate with it via ducts.

[edit] Oral cavity

• There is a surface lining called the mucosa
  • There is lots of friction and abrasion so we want something that is stratified, so we have a stratified epithelial that is non-keratinized.
  • It is moist.
  • Some areas are keratinized where abrasion is occuring: surface of the tongue, hard pallat, too.

[edit] Tongue

• Intrinsic and extrinsic muscles.
• Extrinsic anchor muscle in mouth, way back to the highway bone. These are responsible for the general movement of the tongue and for formation and movement of the bolus.
• Intrinsic muscles are responsible for shaping the tongue for things like speach.
• Taste buds on the surface of the tongue has receptor cells.
  • These occur in the papillae of the tongue.

[edit] Salivary glands

• We have three major areas of where we find salivary glands: sublingual ducts, submandibular, and paraotid.
• Not all generate the same amount.
• Minor ducts are located around the lips and throat.
• Stones in the salivary glands can be very painful.
• The internal structure is similar between types.
• Along the sides of the ducts are cells that form the acinus (plural acini).
• Serous cells are watery; secrete enzymes and watery mixture. Mucous cells are thicker; secrete mainly mucin and glycoproteins.
  • These two cell types generate the saliva.
  • You can determine which type they are by histology.

[edit] Saliva

• You produce 1.5L per day (up to 2L).
• Secretions from different glands aren't necessarily of the same composition.
• Also, the ion composition will change based on the flow rate (as it goes up, NaCL release increases).
• Saliva is slightly acidic; this correlates with the preferable pH of alpha amylase.
• There is buffering, too, through bicarbonate.
• Amylase is in the secretion to break down carbohydrates.
• Lipase is also released but it is only active in the stomach.
• Lysozyme is also released.
• Antibodies like IgA are released, too, which is common around many openings.
• Lactoferrin: protein that binds iron (interferes with bacterial growth)
• Protective function

[edit] Mucus

• Lubrication is one function, also helps cause fecal material to adhere to form a stolid stool.
• Along the GI tract we need to protect the underlying epithelium, so it is interesting that the mucus helps to protect the epithelia.
• The mucus creates a physical barrier to the epithelia and also generates a microenvironment.
• Bicarbonate is found in the mucus, so we call this the neutralizing barrier.

[edit] Fluids

• We secrete about 10L of liquids into the GI tract but only excrete 100 ml / day b/c the intestine is good at reabsorbing.

[edit] Mumps

• Caused by RNA virus.
• Gets into salivary gland such that there is a huge swelling on the side of the neck.
• Can cause sterility in males through epididymysis.
• Unilateral paratoid gland swelling is generally caused by obstruction like a tumor.

[edit] Teeth

• Gingevitis is an infection of the gingeval tissue (the gum line), caused by a bacteria. Generally contributed to plaque which encourages the build up of bacteria because plaque is a biofilm (a place where bacteria can grow and hide from antibiotics).
  • Biofilms are also seen in bladder infections.
• Abscessess

[edit] Pharynx

• Divided into regions: nasal pharynx (connects GI and respiratory), oral pharynx (connects with bottom of pharynx), laryngopharynx (connects to esophagus).
• In swallowing, the soft pallate has to elevate to block off nasopharynx. AAnd the epiglottis must come down to block trachea.
• Then bolus moves to the back of the tongue / mouth where it is involuntarily swallowed.

[edit] Esophagus

• Connects pharynx to stomach.
• Has sphincter muscles: circular smooth muscles tha thelp open and close openings.
  • Some skeletal, some smooth.
• Air in the system causes noises.

[edit] Barrett's esophagus

• Can cause serious problems.
• 1% of the population.
• Reflux is coming back from the stomach.
• Acid causes irritation.
• In severe cases, epithelum of the esophagus will take on a new, more gastric-like epithelial state.
  • Not clear why, but thought to be a protective response because gastric cells can withstand acid environment more easily.
• 1-5% of patients will get esophageal cancer.

[edit] Acid reflux disease

• The cardiac sphincter fails to remain tightly closed such that stomach contents can go back into the esophagus.

[edit] Hiatal hernia

• Can live with this if not too severe.
• A portion of the stomach protrudes back through the diaphram into the hiatus yielding a hernia.

[edit] Stomach

[edit] Functions

• Storage of food.
• Mechanical breakdown of food.
• Chemical breakdown via HCl.
• Enzymatic break down via salivary lipase and pepsin.
  • Pepsin breaks down connective tissue.
• Production of intrinsic factors
  • Stimulates absorption of B12.
  • I think he called this an endocrine function.

[edit] Anatomy

• Rugae are the pleats that allow for expansion from 50mL-1L area.
• In the body of the stomach we have gastric pits.
  • Lined by different types of pits that contribute to gastric secretions.
  • Two types of cells, primarily: chief cells and parietal cells.
  • Chief cells are responsible for secreting pepsinogen (inactive).
  • Parietal cells secrete HCl and intrinsic factor.
• How does the pepsinogen get from in the pit into the lumen without getting digested by HCl?
  • Because of a process called "fingering".
• Infants secrete rennin which coagulates milk proteins and allows them to digest some fat in the stomach.

[edit] HCl secretion

• This is an active process, so we're physically moving H+ ions from the blood and putting them in the lumen.
• At the same time we're moving HCO3 into the blood.
• This process is moved by NaK atpase and requires the bicarb / Cl cotransporter.
  • Exchanged from blood into cell to maintain balance (HCO3 into blood).
• Carbonanic anyhdrase is found in the epithelial cells.
• As before, the H+ is coming from the conversion of Co2 and H20 into Hc03 and H via CA and chance.

Does K+ move?

[edit] Gastric fingering

• The acid shoots up and through the mucus layer to end up in the lumen of the stomach.
• If some of the acid lands on the mucus gel in contact with the epithelial surface, it will be neutralized by the bicarbonate that is held close to the epithelial cells. This is why we care about the chemical microenvironment.

[edit] pH of stomach

• Varies by time of day and meals.
• Most acidic between meals.
• As you eat, it changes the composition of the lumen, causing the pH to rise.
• There is also a change in the amount of somatostatin that is released. It affects gastrin secretion. Gastrin secretion affects HCl release.

[edit] Enterooendocrine cells

• G cells secrete gastrin
  • stimulates HCl secretion, pepsinogen synthesis and muscle contractions.
• D cells secrete somatostatin
  • This inhibits gastrin secretion and thus impacts the amount of HCl produced and released.
• The nervous system can affect these cells as can the consumption of food.

[edit] Involuntary protein spills

• These are severe vomiting spells.
• Tooth enamal erosion can occur.
• Can cause alkylosis and dehydration.
• Zollinger-Ellison syndrome
  • Tumor of duodenom
  • Can cause overproduction of gastrin and HCl causing a very acidic stomach.
• Several brain stem areas control vomitting.
  • Feedback to the vomitting center occurs from the intestine, the stomach, the pharynx, and esophagus.
  • The outward signals go to the abdominal muscles and diaphragm because we squeeze the stomach.
• The signal to induce this is anti-peristalsis, that is, reverse peristalsis.
  • Irritation of the stomach and duodenum can cause this reversal of peristalsis which will move food backward until the stomach is distended and stomach is squeezed.
  • Not unusual for bile to be in the vomit.
• The chemoreceptor trigger zone is found in the fourth ventrical (base of cerebellum) is also involved in vomitting.
  • Can be stimulatee by electrical or chemica signals.
  • Electrical signals come from motion sickness (sent from ears).
  • Chemicals like drugs (morphine) can directly stimulate the chemorecptor trigger zone.

[edit] Pyloric problems affecting infants

• Pylormic spasms:
  • If the pyloric sphincter doesn't relax, the stomach becomes distended and the baby has to remove food via projectile vomitting.
  • Routine projectile vomitting indicates a blockage.

[edit] Hormones involved in digestion=

• CCK = cholecystokinin
• Secretin
• gastric inhibitory peptide

[edit] Regulation of gastric activity

• Cephalic phase: prepares stomach to receive food.
• Gastric phase: while food is in stomach.
• Intestinal phase: getting rid of food

[edit] Gastric secretion: Cephalic phase

• Nerves tell G cells of the stomach to release HCl.Vagus nerve input to parietal cell is postive.
• Negative nerves activit on D cells causes release of gastrin.(somatastatin)?

[edit] Gastric secretion: Gastric phase

• Stretching causes feedback to the parietal cells, increasing HCl secretion.
• Protein begins to break down which stimulates G cells to produce gastrin.
• Gastrin feeds back to increase HCl production.
• The D cell is released from inhibition such that they stimulate (via gastrin) G cells to release HCl.

[edit] Gastric secretion: Intestinal phase

• Breakdown of carbs stimulates cells of intestine to release hormones (CCK, GIP, secretin).
• This feeds back on chief and parietal cells in the stomach to turn off whatever they produce.

[edit] Digestion in the stomach

• 10-20% of the protein is broken down.
  • Most protein being broken down by pepsin is the connective tissue.
• Some carb breakdown occurs via salivary amylase until it gets deactivated by pH.

[edit] Absorption in the stomach

• Lipids can be absorbed.
• Alcohol can be converted to acetaldehyd bye alcohol dehydrogenase.
  • Acetaldehyde is poisonous!
• Alcohol is continuously absorbed in the stomach. This explains the delay of blood alcohol level and stomach alcohol level.
• Most fat absorbed in the duodenum.

• stopped here on 04/19/10.
• started here on 04/21/10.

[edit] Food propulsion and mixing

• One of the main ideas is peristolis which is facilitated by smooth muscle contraction, some segmented, some in waves.
• Essentially, the pyloric sphincter opens to let some of the chyme into the small intestine.
• There are two different environments in the stomach: more liquid and thicker.
  • By way of the muscle contractions, the lighter fluid will come into contact with the sphincter. This causes a stirrinig that keeps the solid material on the inside and the liquid will get dumped ito the duodenom
• Not everything moves through the stomach at the same rate.
  • Carbs 3ish hours; protein about 6 hours. Recall that lipids aren't really digested in the stomach.

[edit] Peptic ulcers

• Ulcers are one of the diseases of this area of the stomach.
• It is a bacterial infection.
• It interferes with the mucosal layer including the bicarbonate barrier.
• This exposes the stomach lining to the acid and degrades the epithelium.
• This generates ulcers in several locations: cardiac end, pyloric end (more common), and even in the duodenom. So ulcers aren't usually in a particular area.
• Caused by pylori bacteria.

[edit] Other contributing issues

• Smoking stimulates secretion of gastric material like HCl.
• Alcohol leads to breakdown of mucosal barrier.
• Aspirin and NSAIDS breakdown barrier.
  • Bits make it really far down into the intestinal tract, actually. And it can generate ulcers way down in the intestine.

[edit] After the stomach

[edit] Hepatic protal system

• As we get down into the intestines, the circulation is set up such that the material is absorbed and taken directly to the liver via the portal system.
• The only exception is the breakdown of fats.
  • Short chains, carbon chains of 16 or less, will go into the blood stream to bind with albumin.
• Fatty acids and glycerides and such go straight into the portal system
• Splanchnic circulation = hepatic portal system.
• Through this system, the liver absorbs the majority of the stuff we absorb and reprocesses.

[edit] Liver, gall bladder, duodenom connections

• Liver, gall bladder, and pancreas are all in contact with the duodenum.

[edit] Liver

• Liver has four lobes with further divisions into lobules.
• Each lobule has a specific blood supply: artery and vein, and a lymphatic drainage route, too.
• There is an hexagonal pattern to the lobules.
  • The corners have the blood flow and the bile duct which runs to the gall bladder.

[edit] Lobule organization

• Here we have sinusoidal capillaries which are leaky. The openings are very important. The spaces allow for nutrients to be absorbed by the hepatocytes. This is the important part of the sinusoidal capillaries in the lobule.
• We also have kupffer cells which are like macrophages and help keep bacteria in check.
• Hepatocytes make bile which is passed down to be stored in the gall bladder.
  • So if you take out the gall bladder, the patient will have trouble braeking down fats because they don't have much stored up (only what is in the ducts).
• The liver is also used for storage.
• Toxins in the blood are purified out by the liver.
  • Alcohol, ammonia, etc.
• Hepatocytes also generate some blood components like albumin, lipoproteins, clotting factors, and angiotensinogen.

[edit] Bile

• 1 liter per day is made.
• It is alkaline.
• So bile comes in just as the acidic content of the stomach is dumped into the duodenum.
• Bile contains salts and acids. these help in physical breakdown of fat droplets but also help us with the primary absorption of fat.
• The gall bladder dehydrates the bile it stores which causes it to be more concentrated than the bile in the lobules.

[edit] Stimulation of the gall bladder

• Small intestine releases CCK when fat enters the duodenum and triggers release of CCK.

Missed some stuff here.

• Liver is involved in secreting secretin which is important in bicarb production.
• Bile is highly conserved, as it passes through the intestine about 95% is reabsorbed.
  • So we have to generate new bile salts, so we require a cholesterol level to be maintained.
  • So why fiber in the diet? It helps move the lipid biproducts (like cholesterol) out of the GI tract which means that the body will "draw down on" its cholesterol levels.
  • As cholesterol precipitates out we generate gall stones. Can be passed, can use sonification, too.
  • Bottom line: gall stones come from too-concentrated bile.

[edit] Jaundice

• The primary reason in infants is bilirubin buildup as the result of blood cell breakdown.\

I thought it was because of an underdeveloped liver?

• Hepatic jaundice
• Extrahepatic jaundice, some blockage by gallstones, or cancers or something.

[edit] Cellular structures of pancrease

• Acini cells genreate one set of compounds and the ducts another.
• Ducts: bicarb; acini cells, enzymes for pancreatic secretions.
• Pancreatic secretions are a "complete mixture".
  • Anything we haven't broken down at this point must be broken down by the enzymes of the pancrease or by ...?

[edit] Secretions of the acini cells

• Enzymes in pancreatic secretions contains all the enzymes we need for each type of molecule.

[edit] Stimulus of pancreas

• Secretin stimulates pancreas.
• HCl in the chyme is responsible stimulating release of secretin by intestinal cells.
• CCK also has an effect.
• Overall, most enzymes are released because of pancreatic activities.

[edit] Pancreatic problems

• Pancreatitis
• Really painful
• Idiopathic

[edit] Pancreatic cancer

• 4th most common cancer in the US.
• Generally over 50 and more frequent in males
• Usually when you find it you're too late.
• Very rare to treat; fatality rate is 95%.
• Removing the pancreas has its own problems with circulation and digestion; so it isn't easy.

[edit] Intestingal fluid and electrolyte movement

• Most digestion occurs in the duodenom (the digestive part).
• The rest is all about absorption.
• The SI is a major area for water reasorption with Na and K.
• We secrete some bicarb.
• Large intestine is the fine tuning of water reclaiming and secretion of K and bicarb.

[edit] Small intestine

• Duodenum (shortest), Jejunum, ilium.

[edit] Intestinal secretion

• The chloride ion is the ion responsible for fluid secretion.
• Na and bicarb are also secreted.
• CFTR is the transporter so CF affects the intestine.
• There is hypertonic material coming from the stomach (so it wants to draw water into the lumen) and <the second force that is drawing water from blood into lumen>.
• The small intestine is highly pleated and has lots of microvilli.
• There are glands associated with the intestine: the duodenal glands.
  • One thing secreted is mucus and we've talked about the need for that.
• There is also hormone production (urogastrone). It is is important in regulating the overall level of intestinal secretions.
  • Found in urine, found in gastrotract.
• Lymphoid nodules of the intestinal tract.
  • Peyer's patches are the immune environment that respondes to anything that leaves the GI tract.

[edit] Small intestine wall

• The many microvilli generate a brush boarder.
• There are also goblet cells.
• Within the folds we also have papillae which are the extension of the lymphatic and circulatory systems up into the folds.
• Note that this papillae structure generates a countercurrent structure.
  • This isn't necessarily good because some oxygen that is in the arterial side gets moved straight into the venous side.
  • So in some disease states we cannot meet the oxygen demands at the very tip of the papillae.

[edit] Movements of nutrients in the SI

• Peristalsis is a unified contraction of smooth muscle.
• It can occur in several forms.
• It can occur on a constant period such that there are segments that mixe the food up nicely thus increasing exposure to enzymes.

[edit] Protein digestion

• Though previously broken down, too, the final breakdown occurs in the intestine.
• Here we're trying to absorb the protein.
• They have to be broken down in AAs before going into the blood stream, but they can be absorbed from the GI tract in 3 or 4 aa peptides.
• In fact, immune reactions can occur when a peptide gets into the blood.

[edit] Lipids

• The liver produces bile which helps with emulsification (suspension of fat droplet in water; break large droplet into smaller ones).
• Think dish soap commercial.
• The other piece of the puzzele is colipase which is activated by trypsin such that the lipase can bind and interact with the micell and then break the fats down into three things (short chain fatty acids, amino acis, ?).
• These materials get absorbed by the epithelial cells which either use it or put it into the blood or put it into chilomicron (or something like that).
  • Don't eat just before giving blood because chilomicron will be high.

[edit] Lipoproteins and lipid transport

• HDL, LDL.
• Depositing cholesterol = bad, getting rid of cholesterol = good.
• HDL is able to pick up cholesterol and remove it from the environment.
• LDL will donate cholesterol for deposition throughout the body.

[edit] Carbohydrate digestion

• This is actually finished in the cells associated with the brushboarder.
• Material coming into the intestine is in three groups: sucrose, lactose, or maltose (ore some polymer of these).
• Sucrase, lactose, and maltase and alpha dextrinase are there to break these down.
• So glucose, galactose, and fructose are what actually gets taken into the cells.
• There is an active transport process to get them into the cells from the lumen and then from the cell into the blood. This is Na coupled.
  • Note that we are taking glucose up the concentration gradient.

[edit] Problems

• Celiac disease.
• Gluten is an additive in baked products; gives texture.
• Immune response to gluten.
• There are irritation and circulation issues.

[edit] Lactose intolerance

• Lactase deficiency.
• Not initially an issue but this is a good place for bacteria to grow and cause gas and other problems like diarrhea.

[edit] Large intestine

• Secum (appendix).
  • We weren't sure what it does but we now know that it and the appendix probably harbor cells that help activate the immune system.
• Then move on to the colon and rectom.
• Distension of the rectum stimulates deficationt.
• Mostly just secretion, not much digestion.
• We do have some good activity going on because of bacteria, though, which give us our vitamin K.
• there is some Na absorption along with Cl. This is aldosterone controled.
• Bicarb and Chloride are exchanged (bicarb out) in order to keep the ion balance.
  • This causes some obligatory water absorption to maintain osmolality.
• 800 species of bacteria in our colon.
  • Take care of vitamin synthesis.
  • Help with protein breakdown to amino acids.
  • Help breakdown bilirubin which gives tool its color.
  • Bacteria generate gas, too. ABout 500 ml / day.
  • We're looking for ways to reduce cow flatulance through diet.

[edit] Osmotic diarrhea

• We have several types.
• Osmotic diarrhea
  • When something causes water to be secreted and not reabsorbed.
  • One example is lactose intolerance, or infection and inflammation.
  • It is something in the digestive tract proper.

[edit] Secretory

• Something is secreted into the luman dand water is following.
  • Chloride is the main ion.
  • cholera toxin can cause this because it constitutively activates chlorid secretion.
    • Can cause 20 l / day to move through the tract.
    • So we ahve to think about maintaining ion composition and water when treating diarrhea.

[edit] Motility disorder diarrhea

• We can have diarrhea if we aren't moving food as we should.
• Too fast = diarrhea, too slow = constipation.

[edit] Inflammation

• Generally this type of problem comes with other issues like fever and abdominal pain or blood in the stool.

[edit] Constipation

• Water retention.
• WAter mobility decrease, fiber issues (fiber helps take chol out of the system so liver uses excess chol to produce bile salts and ythus reduce circulating levels).

[edit] Defecation reflex

• As rectum is distended, it sends a reflex response that cuases sphincter to relax.
• At some point the pressure builds up enough that voluntary inhibition cannot inhibit the sphincter.
• You can't train kids before they are able to voluntarily control if they physiologically can't control the sphincter.
• Strethc of rectom causes signal then reflexes back down to cause contraction of surrounding muscles such that poop comes out.

[edit] Aging

• The blood supply changes so absorption changes.
• Motility will become an issue so absorption and secretion will be different.
• Flavors and smells will decrease.
• Cancers increase.

• Gastric bypass skips the duodenum so we have less time to digest and resorb and thus reduce caloric intake.

• stopped here on 04/21/10.
• started here on 04/26/10.

[edit] Hormonal Control of Food Intake

• Hormones and their receptors
  • Hormones
    • Fat cells
    • Gastrointestinal tract
    • Pancreas
  • Receptors
    • Hypothalamus
    • Brain stem
    • Autonomic nervous system
• Background
  • If damage one part of the hypothalamus, caused hyperphagia (over-eating)
  • If damage a different part of the hypothalamus, severe anorexia and weight loss
  • Parabiosis experiments
    • Surgical union of two animals
    • Can determine if a component in the bloodstream of one animal is affecting the activity of another
  • Showed that a blood –borne satiety factor produced in obese animals required an intact hypothalamus
• Satiety factors
  • How does the brain know it is time to stop eating?
  • What are the shrot-term signals?
  • What are the logn-term signals?
  • One of these- discovered in the 1990s is leptin that is produced by the fat cells

[edit] Fat cells (adipocytes)

• Leptin deficiencies
  • Get fat
• Leptin receptor deficient
  • Fat
• Leptin tells the body you have plenty of adipocytes no need to produce more. Leptin made by adipocytes
• Leptin
  • Produced by adipose tissue
  • In rodents, circulating levels mirror fat stores
    • Increase with overfeeding
    • Decrease with starvation
  • There are human mutations that mirror the mice- in both leptin receptor mutations as well as leptin deficiency. However, these are very rare mutations
  • Leptin only works with patients with very rare mutations
• Where does leptin work?
  • When administered into the central nervous system of ob/ob mice- completely reverses the obese phenotype
  • Found to have a major action in the arcuate nucleus of the hypothalamus
• Leptin action in the brain
  • Opposing effects on two different types of neurons in the hypothalamus
    • Talking about picture from paper
• There is a positive and negative effect from leptin. These neurons connect to particulary type of receptor, found in the PVN(periventriculi nuclei) signaling from these receptors will reduce food intake, receptors from other parts of brain will increase energy expenditure,
• So signaling has effect on food intake and energy expenditure not just a signel factor
  • Leptin action on the arcuate nucleus of the hyptohalamus
    • Two populations of neurons which epress different peptides
• Appetite stimulating peptides
  • Melanocortin antagonish agouti- related peptide (AgRP)
  • Neuropeptide Y (NPY)
• Other types of peptides functoion is less well defined (yellow)
  • Cocaine and amphetamine related transcript (CART)
  • Precursor peptide pro-opiomelanocortin (POMC)
• Both sets of neurons project to second order, melanocortin 4 receptor (MC4R) expressing neurons in the hypothalamus and other parts of the brain
  • • What they found
• Leptin inhibits the NPY/AgRp appetite stimulating neurons
• Fasting significantly upregulates the expression of NPY and AgRP
• Loss of the NPY/AgRP neurons in adult leads to profound, life threatening hypophagia
• Leptin stimulates the POMC/CART neurons
• Fasting decreases the expression of POMC
• Loss of the PMC neurons in adults leads to hyperphagia and obesity
• MC4Rs in the paraventricular hypothalamus and elsewhere in the brain control both food intake and energy expenditure
• 5% of cases of seere childhood obesity and 0.5-2.5% of adult obesity are due to MC4R mutations.
• Serotonin will induce weight loss
• Serotonin inhibits NPY/AgRP neurons and activates the POMC neurons leading to an increase in MC4R and a reduction in food intake
• Could leptin be used to treat obesity?
  • Works in ob/ob mice
  • Works in humans with leptin deficiencies (very rare)
  • Ineffective min mice with diet-induced obesity
  • Ineffective inmost obese humans
  • Lead to hypothesis of “leptin resistance”
• Leptin resistancce
  • The clinical presentations are consistent with leptin resistance but themechanism is unknown
  • Possibilities
    • Decreased leptin receptor expression in hypothalamic neurons during agin
    • Attenuation of the intracellular leptin signaling cascade
• What regulates leptin secretion from the adipocytes
  • Insulin and glucocoritcoids psotiviely regulate leptin production
  • Beta adrenergic agonist and other agents that raise cAMP decrease leptin production
  • Androgens suppress leptin
    • Leptin higher in females (surprised her

[edit] Other adipocytes factors

• Adiponectin
  • Also produced by the adipocytes
  • Plasma levels inversely correlated with body fat
    • Decreased in obesity
    • Increases during weight loss
  • Protective against the development of insulin resistance, glucose intolerance and dislipidemia (all of these are in metabolic syndrome)
  • Regulates energy utilization rather than food intake
• Interleukins
  • Cytokines generally associated with immune response or inflammation
  • IL-6  : secreted by adipocytes
    • Independently of inflammation
    • May control energy expenditure
  • Combined loss of IL 6 and IL 1 causes hyperphagia
  • IL 18- loss of production causes hyperphagia and obesity
    • Administration of IL18 in knockout animals doesn’t alleviate the hyperphagia unless injected into the cerebral ventricles

[edit] Factors produces by the GI tract

• Cholecytokinin –CKK
  • Text book says:
    • Released into circulation by entero-endocrine cells of the duodenum and jejunum in response to fatty acids
    • Inhibits gastric secretion of acid
    • Accelerates production of pancreatic enzymes
  • Also acts as a satiety
  • CK acts at receptors on vagal afferent terminals and therby transmits signals to the briainstem
  • Also activates POMC neurons and signaling via MC4R
• Peptide YY (PYY)
  • Secreted by the enocrine L cells of the gut
  • Low in fasting state
  • Increase postprandially
  • Increase food intake if injected directly int the CSF,
  • In the bloodstream, have the opposite effect reduces food intake
  • In humans
    • Pyy levels elevated in some diseases states characterized by weight loss
    • Overweight people have a relative deficiency=reduced satiety
    • Bariatric surgery results in an exaggerated PYY surge after eating
    • Long term trials of PYY as an obesity drug are on-going
• Ghrelin
  • Secreted by the oxyntic glands of the stomach
  • Increased by weight loss, fasting and insulin- induced hypoglycemia
  • Stimulates food intake and decreases fat utilization
  • May be involved in energy homeostasis
  • Stimulates appetite
  • Mice lacking ghrelin:
    • Resistant to diet-induced obesity when fed a high fat diet
    • Preferentially utilized more stored fat
    • Regulates the disposition of the energy stores- thereby decreasing fat storage and weight gain
• Obestatin
  • Made from the same precursor as ghrelin- preproghrelin
  • Has the opposite effect sof ghrelin:
    • Suppresses food intake
    • Inhibits jejeunal contraction
    • Interesting that two opposing factors made from same precursor
• Glucagon-like peptide-1
  • GLP1- released from L cells of small intestine in response to food ingestion
  • Potent inducer of glucose independent insulin release
  • Induction of satiety via inhibition of gastric emptying
  • May also act on the brain stem to influence feeding

[edit] Factors of the endocrine Pancreas

• Insulin
  • Insulin receptors found in brain
  • Insulin appears to have an appetite suppressive role
  • Female (but not male) mice with disruption of insulin receptor gene in the CNS become hyperphagic and overweight
  • Insulin receptor ablation in just the hypothalamus resulted in hyperphagia
    • Associated with increased expression of both NPY and AgRP
• Pancreatic polypeptide (PP)
  • Released in proportion to calories ingested
  • Inhibits gastric emptying

Miscellaneous factors

• Glucocorticoids
  • Anorexia is a feature of cortisol deficiency
  • Excess glucocorticoids cause hyperphagia
  • Glucocorticoids may work via the melanocortin system
    • Adrenalectomy reverses the obese phenotype of the ob/ob mouse
    • Normalizes both the increase in AgRp and the decrease in POMC
• Steroid hormones
  • Estradiol may reduce body weight
  • Mechanism seems to be increase in POMC neuronal activity resultin in both a reduction of energy intake and ian increase in energy expenditure
  • Not an ideal target, since it’ll mess up female balance hormone system
• Thyroid hormones
  • T3- via the CNS increase food intake
  • T3 also increases basal metabolic rate
  • The increased food uptake may be secondary and compensatory to increased metabolic rate

[edit] Summary

• “the presence ofan integrated system in which adipcyte-derived signals provide tonic, long-term information to the brain about the state of nutrient stores, whereas a variety of signals triggered by ingestive status have important roles in influencing meal initiation and termination.”
• “the heritability of adiposity is very high, and the most parsimonious explanation is that genetically based variation in the homeostatic pathways controlling energy balance determines the interindividual differences in susceptibility or resistance to an environement that fosters obesity.”

• stopped here on 04/26/10.
• started here on 04/28/10.

[edit] Metabolism II

• Book chapter 25.
• Thermoregulation was covered previously and will not be part of this lecture.
• She'll try to make it clear what to memorize and what not to memorize.

• We'll talk about catabolism (breakdown of organics for use in productionof ATP by mt) and anabolism (the utilization of ATP and nutrients for cellular function).
• the nutrient pool is key to both because you need them to synthesize and as the base for making small molecular weight components for ATP production.
• The nutrient pool that can be used for mt catabolism includes fatty acids, aas, glucose (simple sugars).
• ATP is used for many other things like locomotion, contraction, etc.

• Another reminder is that the production of ATP is not very efficient.
  • 40% of energy in nutrients is used for ATP, rest is lost as heat.

[edit] Hierarchy of energy usage

• There is a hierarchy of how energy gets used.
• We call it positive energy balance (or nuetral energy balance) if you have all the energy you need.
  • In this case we'll use glucse first.
• If glucose is limited, most tissues will use lipids and proteins.
• Proteins can be used, especially in starvation, but it is not the preferred method of energy generation. It is not very efficient.

[edit] Nutrient processing in the mt

• The sources have to be broken down into molecules usable by mt.
• This breakdown is called glycolysis for carbs.
• The breakdown happens outside the mt (for all sources).
• This part of energy production does not require oxygen.
  • All other aspects do require oxygen.
  • So the breakdown is anaerobic.

[edit] Glycolysis

• Glycogen is broken down first into glucose.
• The glucose then goes through glycolysis to form two 3-carbon pyruvate molecules.
• The process uses and produces ATP.
  • There is a net generation of 2 ATP molecules.
• This all happens in the cytoplasm.
• NADH is also produced.
  • NADH is important for further ATP generation, too.
• Do we need to know all the intermediate names? No.
• We do need to understand the overall ideas of what is going on.

• Glucose comes from the blood (insulin causes uptake into cell).
• Once glucose is in, it is phosphorylated which traps it in the cytoplasm.

Is it generally true that phosed things aren't transported?

• Once this occurs, another phosphate is added to generate fructose bisphosphate.
• Now we take this 6-carbon sugar and break it into two 3-carbon compounds.
  • This generates two glyceraldehyde 3-phosphate.
• Then two NADs are converted to NADH which then moves on the mt. We'll catch up with them later.
• Then we take the bisphoshate molecules and remove a phosphate from each to generate ATP.
• Then we end up with two pyruvic acids and two more ATP.
• So there is a net 2 ATP by the conversion of a 6-carbon chain into two 3-carbon chain molecules.

• The major function of the glycolysis is to provide the mt with the pyruvate which they can use to generate ATP.
• It happens that we generate ATP and so this method can be used sometimes.
  • This is particularly helpful in the RBCs because they don't have a nucleus and they don't have mt.
  • They only need a small amount of ATP.
  • Sekeletal muscles can also use this when they are in great need of ATP.

[edit] mt ATP production

• This will include the TCA cycle, the electron transport chain.
• These are both aerobic.
• These are both in the mt.
• Again, fatty acids, glucose, and amino acids can be used to generate the small molecules for the citric acid cycle.

Get storage forms.

[edit] The TCA cycle

• This exists to take hydrogens from the small molecules to co-enzymes which lead into the electron transport chain to produce ATP.
• NAD and FAD are the coenzymes
  • Nicotinamide adenine dinucleotide
  • Flavin adenine ddinucleotide
• Each time the cycle goes around, two carbons from the organic compounds are lost as CO2.

• Diagram:
  • Pyruvic acid is in the mt and is 3 carbons long.
  • One carbon is lost and acetyl coa is formed in the presence of coenzyme A. this also transfers an hydrogen to an NAD.
  • Acetyl coa is what can enter the cycle.
  • Acetyl coa combines with a 4 carbon chain to form citric acid.
  • Citric acid undergoes chanbes.
  • 1 carbon from citric acid is lost and another NAD is converted to NADH.
  • 1 carbon is lost and anodther NAD is converted to NADH.
  • Then GDP is converted to GTP (which is used to generate an ATP) and succinic acid is generated.
  • Then two hydrogens are added onto FAD to from FADH2 and our original 4 carbon chain is generated.
  • We produced 1 ATP and 3 NADH and 1 FADH2.
  • The most important part is the production of the NADH and FADH2.
• So the goal was go produce NADH and FADH2 for the ETC.

[edit] The ETC

• This is a series of redox reactions.
• These reactions generate ATP.
• Secondarily, this process uses oxygen.
• The redox reactions transfer the electrons down their electrical gradient in steps so that the energy can be utilized (because going all the way down the gradient at once is rather explosive).
• The coenzymes are necessary as are cytochromes.
• The cytochromes include a pigment, a metal, and a protein.
  • The metal is either iron or copper.

• Diagram:
  • NADH and FADH2 are fed into the ETC.
  • First we have the coenzymes, then we have cytochromes.
  • We form water in the end, though this isn't our goal; our goal is to make ATP.

• What is really happening:
  • We move hydrogens from one side of the membrane to another.
  • As we pass the electrons down the coenzymes and cytochromes, we use the released energy to move hydrogens across the inner mt membrane.
  • The membrane provides a separation of two luminal areas so that you can generate a gradient and therefore harness the energy as the potential balances.

• Diagram 2:
  • We move the hydrogens from the matrix into the inter-membraneous space (which is pretty small).
  • There are two or three coenzynes and 3 cytochromes (b, c, a).
  • Once the gradient is generated, the hydrogens will flow through the ATP synthase which powers it to generate ATP.
  • So we call ATP being secondary because it is only through the balancing of the gradient that ATP is generated, not directly by the ETC.

• Cyanide works by arresting the ETc.

[edit] The big picture

• Energy production with one glucose:
  • We generate two ATP in glycolysis in the cytoplasm of the cell.
  • We generate thirty-four ATP in the TCA cycle and ETC.

[edit] Lypolysis

• What if glucose is limited?
• Well the next favorite energy source is triglycerides.
• When we break down a triglyceride, we have a glycerol backbone (which is a lot like glucose, and can actually be made into pyruvate for the TCA cycle), the fatty acid side chains (which will be metabolized into acetyl CoA by beta oxidation, which can be used in the TCA cycle, too).

• Diagram:
  • Starting with an 18-C fatty acid (a common length).
  • This will get broken down two carbon atoms at a time.
  • First we burn an ATP to form fatty acyl coA.
  • The fatty acyl coA has two carbons cleaved off to form a sixteen carbon fatty acid and an acetyl coA.
    • this will also give us some NADH and FADH2.
  • The acetyl coA can go into the TCA cycle.

• Lipids are pretty efficient.
  • 12 ATPs from each acetyl CoA
  • 5 ATPs from NADH and FADH2
  • Burned 1 to make acetyl coA.
  • For an 18 carbon fatty acid we get 144 ATPs.
  • Lipids are pretty good for generating energy!

• Origin:
  • Fatty acids come from metabolism of triglycerides or complex fatty acids.
  • Found in blood, bound to albumin yet still readily accessible.
  • Can diffuse across cell membrane.

[edit] Lipoproteins

• We also have lipoproteins in our body.
• These are lipid-protein complexes.
• There are generally five types, divided by how they separate out by spinning.

[edit] Chylomicrons

• These are predominantly triglycerides.
• Generated from epithelial cells from dietary fat intake.
• This is the origin of fat in our bodies.
• They carry absorbed fat form intestinal tract to the bloo.

[edit] Very low density lipoproteins

• This includes cholesterol, phospholipids, and triglycerides.
• Cholesterol
  • Comes from food sources.
  • Is also made in the body by a large process.
  • In a healthy state, the external cholesterol helps control endogenous creation.
  • Cholesterol is required for life on earth, but must be in balance.
• So these VLDLs come from the liver.
• These serve to transfer all these molecules from the liver to the peripheral tissues.

[edit] Intermediate density lipoproteins

• Less triglycerides, more phospholipids, more cholesterol.

[edit] Low density lipoproteins

• These are considered "Bad" because they are predominantly cholesterol.
• To deliver the cholesterol from the liver to peripheral tissues is their cause.
• Some of this task is good because then the cells don't have to produce as much of their own.
• When this gets too high, however, the cholesterol may be left where it shouldn't be--like on the vasculature.

[edit] High density lipoproteins

• This is the "good" cholesterol.
• These have equal amoutns of lipid and protien.
• There is choleterol and phospholipids.
• The triglycerides aren't found here because they have been used as an energy source and the HDLs are taking stuff from the peripheral cells to the liver.
  • That is, they are moving cholesterol from the peripheral cells to the liver.

[edit] Chylomicron transport

• Once down to the capillary levels, there are lipoprotein lipases which break down these complex lipids to release the fatty acids and glycerol so that they can move across the membrane and act as an energy source.
• The liver plays a major role because it controls how many of the other compoents that are found in the blood.

• The VLDL can mobilize some of the glycerol as an energy source (that is, use the triglycerides).
  • this use of triglycerides creates an intermediary lipoprotein mixture.
• This mixture will come back to the liver such that the liver generates the LDL (which has cholesterol in it). This is done so that all "these things" are loaded onto the peripheral cells.
  • So LDL is used to move stuff to the peripheral tissues.
• Excess cholesterol by the cells will be released, picked up by HDLs, move it into the liver, where it may be secreted (via bile or other mechanisms).
  • Then the HDL population that has had chol removed is put back into the blood.
  • So the more HDL you have in the blood stream, the more chol you're moving back to the liver for secretion.
• The more LDL you have the more stuff (including chol) you're moving to the peripheral cells.

[edit] Amino acids

• The last of our potential energy sources.
• We won't talk about every aa and what occurs to use it.
• Some can be readily modified to enter TCA while others need more work.
  • This can include transamination or deamination to generate keto acids.
• Only used in cases of starvation.
• Not a major energy source.
• We'll come back to keto-acids.

[edit] Metabolic components

• When we talk about compartment sof the body that are important for energy production, there are four major parts:
  • Liver
  • fat cells
  • skeletal muscle (usage and storage)
  • neuronal tissue
  • other periphral tissues

[edit] Liver

• The liver is the main organ here, really.
• It contains all the enzymes necessary to break down all the complex compounds in order to get them into the TCA cycle.
• Also, it stores lots of glucose as glycogen.
• It is also a major organ for recycling of the lipid components.

[edit] fat cells

• This is where you store lipids and lipids have lots of energy.

[edit] Skeletal muscle

• Will use lots of energy.
• Will store lots of energy via glycogen.
• Stores lots of energy in the large protein structures of the muscle, in case of starvation.

[edit] Neuronal tissue

• The brain can only use glucose as an energy source.
  • It can use some keto-acids under some circumstances but we don't want this to occur.
• Ther eare no energy reserves in the brain.
• High demand with no energy reserves in a picky organ, so we see that for the brain (and heart, actually, which also must have glucose) all the other organ systems will switch to other forms of energy in order to spare glucose for the brain and heart.

[edit] Other peripheral tissues

• The need energy and ATP.
• They are lumped, however, because ther are no large energy reserves in the other tissues.
• They can, however, use any form of energy (glucose, fatty acids, amino acids).

[edit] Metabolic states

• We have the absorptive state and post=absoprtive.

• Absorptive state lasts about 4 hours after a meal.
  • This means we are storing energy.
  • There is lots of glucose in the blood stream so it is being used and converted to glycogen and we don't have to worry about breaking down storage forms to generate glucose molecules.

• Post absorptive form:
  • When you have to break down storage forms in order go maintain the circulating glucose t a cerain level.
  • You can go above this level when eating but you cannot go below.
• Ketone bodies can be generated by lipids and amino acids.
• Ketone bodies can be turned into acetyl coA.
• Remember that we're in post=absorptive state so we see some build up of ketones.
• In the lvier you generate acetyl coa which is used to form the ketones (acetonacetate, acetone, and betahydroxobutyrate).
• This is teh way the liver generates energy for the rest of the body.
• The ketone bodies are not used by the liver and are put into the blood for use by peripheral tissues.
• Ketone bodies can be fed direclty into TCA cycle or can be modified for use in the tCA cycle.
• this is supposed to be an easy-to-use energy source for peripheral tissues.
• We gneerate this so we can have enough glucose around for the brain and heart.

• Problems:
  • If you don't eath for days, you develop ketosis, a build up of ketone bodies.
  • The problem is that when they get high enough, the blood pH starts to decrease. Thi sis called ketoacidosis.
  • If the blood pH gets low enough, you can go into coma or have cardiac arrhythmia.

[edit] Hormonal control of metabolic states

• What are the signals that control these mechanism?
• Absorptive:
  • Insulin will be released as blood glucose levels go up and thus cause:
    • peripheral glucose uptake
    • peripheral activation of glucose enzymes
    • liver generation of glycogen
    • muscular generation of glycogen
    • adipocyte generation of lipids
  • Insulin and growth hormone:
    • peripheral uptake of amino acids
    • peripheral protein synthesis
    • sekeletal fatty acid metabolism
  • Androgens and estrogens:
    • peripheral amino acid uptake and protein synthesis
    • skeletal

• Post-absorptive state:
  • Glucagon:
    • liver breaks down glycogen into glucose
  • epi:
    • liver breaks down glycogen into glucose
  • glucocorticoids:
    • released when glucose levels go down
    • cause peripheral tissues to reduce use of glucose
    • causes liver to break down glycogen into glucose
    • adipocytes breakdown lipid storage molecules
    • adipocytes generates new glucose (gluconeogenesis) from carbon sources
    • skeletal muscle breakdown if starvation is occuring so we can use the amino acids
  • growth hormones:
    • complements affects of glucocorticoids in the peripheral tissues.

[edit] Food pyramid

• Look at this if interested.
• Same with thermoneogenesis.

• You don't have to take the last exam if you're happy with your score.
  • Email her if plan not to take the exam.
  • She generally curves 3 or 4 points in the low B range.

• stopped here on 04/28/10.