Energy Metabolism

Energy Metabolism

• Encompasses all chemical reactions in the body for obtaining and spending energy.
• Involves nutrients which provide energy from food and how the body uses that energy for various processes.

Anabolic vs. Catabolic Processes

• Anabolic process: Building substances.
  • Example: Converting glucose to glycogen when the body doesn't immediately need the glucose from a meal.
• Catabolic process: Breaking down substances.
  • Example: Breaking down glycogen into glucose when the body needs glucose during fasting.

Oxidation and Reduction

• Oxidation: Losing electrons.
• Reduction: Gaining electrons.
• These two processes always occur together; if one molecule is oxidized, another is simultaneously reduced.
• Example:
  • Glucose is oxidized to carbon dioxide as it loses hydrogen atoms (and their electrons).
  • Oxygen is reduced to water as it accepts the hydrogen atoms (and their electrons).
• Oxidation must be tightly controlled in biological systems to prevent dangerous rates of heat production.
• Oxidation in cellular metabolism results in ATP formation (energy currency).
• Exothermic reactions release energy (heat), but the body aims to produce ATP rather than heat.
• Energy production is never 100% efficient; some energy is always wasted as heat.

Metabolic Coupling

• A metabolic reaction cannot proceed without the reactions it is linked to.
• Example: The reaction B \rightarrow C cannot proceed without ADP; it relies on the reaction 1 \rightarrow 2.
  • Enzyme converts molecule 1 to molecule 2, consuming ATP.
  • Complex reaction A \rightarrow B.
  • B and C produce ATP, taking ADP and P to produce ATP, which can then be used by reactions 1 & 2.
• These reactions happen together; neither can happen in isolation.

Energy Balance

1st Law of Thermodynamics

• Energy cannot be created nor destroyed; in a closed system, energy is constant; it can only be transformed into different types.
• For a steady state: Energy Intake (EI) = Energy Expenditure (EE) + Energy Storage
• Large EI and less EE results in a positive energy balance, leading to energy storage as adipose tissue (obesogenic state).
• EI less than EE results in a negative energy balance, where extra energy comes from storage (anorexigenic state).
• Carbohydrates, fats, and proteins are the primary sources of energy.
• Extra energy is stored, and when there's not enough energy, it is drawn from storage.
• Energy balance is crucial.

Energy Intake

• Depends on food and beverage composition.
• 1g of carbohydrate = 4 kcal or 17 kJ
  • A 70 kg body can store 700g glycogen (= 2800 kcal = 11,760 kJ).
  • If Resting Metabolic Rate (RMR) = 2100 kcal/day, the body has 1.3 days of fuel to sustain RMR.
• 1g fat = 9 kcal = 38 kJ
  • Adipose tissue is about 87% lipid or fat content.
  • 1 kg body fat = 870g of lipids, (870g x 9 kcal/g = 7830 kcal = 32,886 kJ).
  • If a 70kg person has 20% fat (14kg), they carry 12,180g lipids = 109,620 kcal.
  • If RMR = 2100 kcal/day, there are 52.2 days' worth of fuel to sustain RMR.
• 1g protein = 4 kcal = 17 kJ
  • Primarily used for structural/functional roles rather than energy provision, except during starvation (~15%).
• 1g alcohol = 7 kcal = 30 kJ

Calorimetry

• The science of measuring heat production.
  • Bomb calorimetry: Measures kcal in food.
    • Food's C and H bonds break, releasing energy as heat.
  • Direct calorimetry: Heat provides a measure of food energy composition as kcalories (units of heat energy).
  • Indirect calorimetry: measures O2 consumption and CO2 production as an indicator of heat production.
    • O2 consumption is directly proportional to heat production, which comes from cellular respiration.

Respiratory Quotient (RQ)

• Indicates what type of fuel is predominantly burned.
• Ratio of moles of CO2 produced per moles of O2 consumed at the tissue level.
  • Carbohydrate: 6O2 \rightarrow 6CO2 (1:1 ratio)
  • Fat: 23O2 \rightarrow 16CO2 (0.7 ratio)
  • Protein: 0.8 ratio

2nd Law of Thermodynamics

• Chemical transformations always result in a loss of free energy available to drive metabolic processes.
• ATP -> ADP produces a lot of energy (3 phosphates linked together).
• Gibbs Free Energy (G): Free energy available to drive metabolic processes.
• Total Internal Energy (E).
• Wasted energy (mainly lost as heat): T.S
  • Example: Consume glucose = Small increase in total internal energy (E).
    • Some of this energy is stored as glycogen (G).
    • Chemical reactions converting glucose to glycogen are inefficient.
    • Therefore, some E is wasted as heat (T.S).
• Chemical transformation will always result in a loss of free energy.
  • 1 mole glucose:
    • In bomb calorimeter: -> CO2 + H2O (completely combusts to heat, but no usable energy) = 686 kcal (heat, not conserved energy) - maximum energy in mole.
    • In the body: Mitochondria oxidise glucose -> CO2 + H2O + free energy stored (ATP) = 400 kcal of free energy; rest = 286 kcal/ mole liberated as heat energy (40% of energy is lost).
• Another way of stating the 2nd law: TS cannot = 0 (reactions are never 100% efficient).
• Therefore, if we add 0 energy, the body’s total free energy declines.

Energy Expenditure

• Burning 7830 kcal or 1 kg fat = 8 hours of running or 130.5 hours of sleep.

Metabolic Rate

• A measure of energy balance
  • Resting Metabolic Rate (RMR): Estimate of energy required while at rest.
  • Metabolism = all chemical processes involved in energy production, release, and growth.
  • A healthy young 70kg human requires 2100 kcal/day to sustain metabolism.
  • The number of calories required (i.e., RMR) can rise in response to heavy exercise, cold exposure, or illness.
  • Measured by indirect calorimetry - O2 consumed and CO2 produced.
  • Basal Metabolic Rate (BMR): Clinical measurement of metabolism, measured under several standardized conditions.
    • AM measurement after good sleep.
    • Fasted for 12 hours.
    • 1hr quiet rest.
    • 25 degree air temp. Clinical calculation of energy expended to sustain vital functions when awake – bare minimum.
    • RMR is typically higher than BMR due to the inclusion of the thermic effect of food - BMR is taken after 12 of fasting.

Energy Storage

• Balance between energy intake vs. energy expenditure.
• People are intermittent eaters (3 meals a day), but energy is used continuously.
• Humans have to store energy.

How Energy is Stored

• ATP: Adenosine Triphosphate.
  • The last 2 phosphate molecules are held by high energy bonds.
  • Adding phosphate requires a lot of energy (hydrogen gradient) so ATP synthase can produce ATP.
  • Stores energy from energy-releasing reactions (ADP -> ATP).
  • The bond is broken and it produces a lot of energy.
  • Released energy to deliver other reactions (ATP -> ADP).

Summary of Metabolic Pathways

Carbohydrates

• Cellular respiration also produces heat.
  • Glycolysis (lysis = breaking down): Breaking glucose down to pyruvic acid.
  • Glycogenesis (genesis = production): Taking glucose and forming glycogen.
  • Glycogenolysis (lysis = Break down): Breakdown of glycogen to glucose.
  • Gluconeogenesis (gluco = glucose, neo = new, genesis = creation): Creation of new glucose.
• Krebs cycle - mitochondria.
• Electron transport chain - enzymes take electrons and add them to oxygen, eventually forming oxygen and then ATP.

Lipids

• Beta Oxidation: loss of electrons.
• Lipolysis (breakdown)= taking triglyceride and breaking it down to fatty acids and glycerol.
• Lipogenesis (production): building up - whilst lipolysis is breaking down

Proteins

• Transamination
• Oxidative denomination

Distribution of Metabolic Pathways

• The liver is an important supplier.
• Muscle tends to be a consumer.
• Red blood cells only use anaerobic glycolysis.
• Consumer of products - only oxidise glucose, don't store it or produce other things

Mechanisms of Macronutrient Digestion and Absorption

• Eating a variety of foods that contain different ingredients provides a mix of substances in the intestines, which are absorbed in different ways.
  • Lumen: The section where food is floating.
  • Epithelium: Intestine absorptive cells.
  • Interstitial cells: Moving onto the rest of the body; the end product.

Absorption Processes

• Glucose: Simple sugar that doesn't need to be digested; it goes straight through the cell into the body, as it is easily absorbed.
• Protein: A bunch of amino acid monomers link together to form a polymer. The polymer is too large to move across the cell membrane. Rather than absorbing the protein, it gets broken down (lumenal - happens in lumen). Lumenal hydrolysis (break down) of polymers to monomers - monomers are absorbed and transported to the body.
• Brushborder hydrolysis: Occurs through squiggles between the lumen and epithelium, which increases the surface area for better absorption. Brushborder (location), hydrolysis (process) - very similar to luminal hydrolysis but it is happening in the cell membrane.
  • Sucrose is broken down into monomers of glucose and fructose that are easy to absorb and are transported through the body.
• Intracellular hydrolysis: Occurs inside the cell. Peptides (small portions of a protein) can be moved into the cell but need to be broken down into monomers, which are amino acids, as the body wants amino acids as building blocks, not peptides.
• Luminal hydrolysis followed by intracellular resynthesis: Triacylglycerol undergoes hydrolysis in the lumen to form glycerol and fatty acids, which are moved into the cell. Because the body wants triacylglycerol, it is reassembled - this is common.

Carbohydrates

Dietary Carbohydrate Classification

• Two groups:
  • Monosaccharides: Small molecules (monomers) directly absorbed by the intestine - Glucose, Fructose, Galactose, Deoxyribose, Ribose.
  • If you take those sugars and attach them to each other you get
    • Di (2 monomers), oligo (few) - (short polymer) and Poly-sacchardes (many) - (long polymers).
    • Some are non-digestible = fibre.
    • Non - digestible: Cannot be directly absorbed by the intestine.
    • Eg. Glucose + Galactose = di-monomer lactose - some people can break that down in intestines and absorb them both, but some people can’t do that (no longer an energy source).

Carbohydrate Absorption

• Oligo- and polysaccharide digestion:
  • Starts with salivary amylase in the mouth -> pancreatic amylase in the small intestine.
  • Products of amylase digestion are still too large to be absorbed.
  • Oligosaccharides: Enzymes on the brush border of the small intestine lumen.
    • Degrade oligomers into monomers (easier to absorb):
      • Produce glucose, galactose, and fructose.
    • The cells are very careful at what flows into the cell and they don’t want things in the cell to float out.
    • Transport across the cells is a careful process and is regulated by transporter proteins (Transport things).
    • Glucose transporter 5 and 2 (GLUT5 and GLUT2) and Na+/ glucose transporter 1 (SGLT1) transport monosaccharides across the intestinal cell into the interstitial space.
      • Glucose and sodium sit in the lumen and are transported into cells using SGLT1.
      • Fructose is transported by GLUT5.
    • Now the sugar has to be moved into the rest of the body, so it's not sitting in the intestine.
    • GLUT2 moves from inside the intestinal cells onwards.
• Food moves from the lumen, across the cell into space, and, in the case of carbs, into the bloodstream and onto the rest of the body. The blood now has a lot of energy in the form of glucose.

Lipids - Fats

• Triglycerides -> 3 free fatty acid chains + glycerol.
• FA: long carbon chains
• Oxidation of carbon to produce Hydrogen produces a lot of energy; lipids have more than twice as much energy per gram (this is why).
  • Saturated: All free C bonds occupied by H atoms (no double bonds).
  • Unsaturated: C=C double bond (mono), multiple bonds (poly).
• Undergo mechanical breakdown in GI.
• Hydrophobic - Don’t mix well with water.
• Small congregations of lipid molecules held in water = emulsion droplets -> micelle; not good as we don't want to mix in our gut -> want fat in cells

Lipid Absorption

• If someone eats a fatty meal, they will end up with a bit of fat in the intestine -> it forms a fat droplet with multiple layers of fat. All the energy in the inner layer is not accessible to the body.
• The emulsion droplet needs to be broken up using bile salt to form a mixed micelle with a single lipid layer with a much larger surface area -> something the body can work with. Fatty acids are lost during this process (which is what we want).
• Triglycerides are changed into fatty acids and absorbed at the brush border.
• Most intestines in the bulk phase are in alkaline condition -> not acidic. However, right against the brush border, it is acidic, a microclimate. This is due to the body pumping hydrogen into this area, because the acidic environment assists fatty acids to be protonated, which assists in their absorption. Lipid absorption occurs through the intestinal cell into capillaries.

*Now fatty acids are into cell, but now need to be moved onto the rest of the body

• Problem: A bunch of triglycerides together are going to form droplets, which are only good for storage -> so the body needs to move them on.
• Apolipoproteins stick to lipid droplets and form a lipid bilayer with proteins in it.
• Forming chylomicrons and very low-density lipoproteins in the Golgi apparatus (tiny yellow dot).
• Need to be moved out of the cell - wrapped up in a transport vesicle
• Booted from the cell onwards, but chylomicrons are too large to go into blood capillary -> so they go into the lymph capillaries instead.
  • (long fatty acid chains)
• Later enter the blood capillaries/ bloodstream.
  • (Short fatty acids chains) can enter the blood capillaries
• Recall: After absorption, carbs get moved into the blood capillaries, but long chain fatty acids go into the lymphatic capillary

Lymphatic Ducts

• The lymph system is a transport system within the body - it moves a variety of things, but in this case, chylomicrons upwards.
• The thoracic duct arises from the cisterna chyli and drains the rest of the body. Upwards where? Does have to end up in your blood system at some point to be used for energy.
• Moving from lymph to venous circulation at internal jugular and subclavian veins.
• Each duct empties lymph into venous circulation at the junction of the internal jugular and subclavian veins on its own side of the body; as that is what we use to transport things to different organs

Lipid Absorption - from Bloodstream to Storage

• How do we get lipids out of the bloodstream?
  • Lipoprotein Lipase (LPL) (ase = enzyme):
    • Exported from cell to endothelium - not put on cell membrane straight away but held within the plasma membrane (Stimulated by insulin) to breakdown circulating trigs for storage.
    • When the cell is treated with insulin, Lipoprotein Lipase is pushed onto the cell membrane by taking triglycerides in the chylomicron and starting to break them down into fatty acids.
    • Fats are stored as triglycerides, but when they move across a membrane, they are converted to fatty acids -> when they are back in the cell, they are stored back as triglycerides.
    • Triglyceride -> interacts with lipoprotein lipase -> gives you a fatty acid and glycerol.
    • Fatty acids are taken up by different tissues, e.g., liver hepatocyte.
      • Can be oxidised and broken down for energy or stored as a triglyceride.
    • Or can be moved through the body -> adipocyte for storage.
      • These fatty acids are being added with the glycerol to form a triglyceride.
      • These triglycerides are being moved into a lipid storage droplet - very efficient way to store fat.

Fate of Glycerol in the Liver

• Gluconeogenesis: glycerol -> glucose
• Glycolysis: glycerol -> pyruvate
• NOTE: If there is a lot of glucose, it can be converted to a triglyceride.
• Lipoprotein Lipase (LPL)
  • Exported from cells (e.g., adipocyte/ hepatocyte) to vessel endothelium, held within the plasma membrane (until needed) -> they convert triglycerides and chylomicrons to fatty acids.
  • Hydrolyses trigs in chylomicrons -> FFA + glycerol.
    • -> they can move into cells (uptake by adipocytes, muscle, hepatocytes), but not central nervous tissue as it only uses glucose.
  • Insulin promotes lipid uptake and conversion to trigs for storage.
    • I.e.; insulin induces LPL synthesis
• Why does lipid storage cease during fasting?
  • Lipids are the major source of energy storage in the body. When fasting, we have a negative intake of energy, so the body starts to move energy from storage in circulation. The first step is to prevent lipid storage, and lipid energy is liberated into the body.

Proteins:

• Proteins are folded polymers of amino acids.
• Amino acids: Same general molecular structure, but different R group.
• Uptake in all tissues.
  • Structural - proteins hold us together.
    • Skin, collagen, ligaments, tendons.
  • Functional - anything our body does uses protein enzymes to do it.
    • Enzymes, receptors, muscle filaments (actin/ myosin), hormones.
• Constant turnover (protein
• If any proteins are damaged, constantly being made by amino acids

Protein Absorption

• AAs move across the membrane, peptides broken into AAs in intestinal cells.
• Specialised transporter proteins allow peptides into intestinal cell.
  • Pep1 transporter protein moving enzyme in.
  • Co-transport: H+.
• Peptidase: enzymes within the cytoplasm of the intestinal cell degrade peptides into AAs.
• AAs exit basal membrane via AA transporter - pumped out of the cell for transport around the body

Insulin Directs Post-Absorptive Processes

• Where does insulin come from?
  • Insulin secretion from the pancreatic beta cell, stimulated by the presence of glucose and some AAs.
  • When you eat -> carbs are transformed to glucose which is floating around the body -> the pancreas detects this and starts releasing insulin.
  • Still be stimulated by AAs if you have a low-carb diet
    1. Glucose entered the via a GLUT2 transport (transports simple sugars across membrane into the cell), which mediates facilitated diffusion of glucose into the cell.
       • Glucose goes from the blood into the cell -> stimulated glucose metabolism so the pancreas starts producing ATP
    2. The increased glucose influx stimulates glucose metabolism, lading to an increase in ATP and NADH.
       • Happens in mitochondria
       • Lot of ATP floating around the cell (energy currency)
    3. The increased ATP inhibits the KATP channel (channel not working properly -> so it closes to cause positive depolarization across the channel)
    4. Closure of this K+ channel causes Vm to become more positive (depolarisation)
    5. Depolarization activates a voltage-gated Ca2+ channel in the plasma membrane
       • All of a sudden, calcium is flying in the cell -> signal and the way of the cell compensating for the depolarisation
    6. The activation of the Ca2+ channel promotes Ca2+ influx (higher concentration of calcium in the cell), thus increasing Ca2+, which also evokes Ca2+ release (the cell has more calcium that it wants to get rid of - induced Ca2+ release.
    7. The elevated Ca2+ leads to exocytosis (little vesicles of insulin are being kicked out of the cell and into the bloodstream) and release into the blood of insulin contained within the secretory granules
• When insulin is floating around the body where does it go?
  • Detected by insulin receptors - is a tyrosine kinase receptor:
    • 4 subunits bonded
      • First 2 alpha chains: extracellular (outside cell)
        • Insulin bonds to the alpha chains
          • Once insulin binds, it changes the whole structure of the receptor
      • 2 beta chains: extracellular, membrane spanning, intracellular
        • Start outside the cell, go through the membrane, then into the cell
        • Change structural formation in response to binding with insulin
        • Tyrosine kinase domains are exposed (able to activate signal cascade and react to other proteins): Phosphorylates IR and intracellular substrates = signal transmission
        • Protein changes shape and phosphorylates itself and other proteins
        • Tyrosine kinase receptors: Phosphorylate (add a phosphate group) to tyrosine residues on themselves and other proteins

In the Liver, Insulin

• The liver learns that energy is available
• Then promotes carbohydrate metabolism by hepatocytes (glycolysis, Krebs (tricarboxylic acid cycle), e-TC) and inhibits gluconeogenesis (don’t need that cause you have glucose available)
• Promotes glycogenesis (produce glycogen and not turning it into glucose) and inhibits glycogenolysis (storing the glucose)
• Promoted lipogenesis (production of lipids)
• Inhibits lipolysis (breakdown of lipids) and ketogenesis (break down proteins)
• All about accumulating energy and breaking down storage of energy (is inhibited - we want to store energy)
• Promoted protein synthesis, inhibits proteolysis
• Different sections of different tissues

Hepatocyte in Liver

1.  Promotes glycogenesis and inhibits glycogenolysis
    *   Glucose can enter the liver via GLUT2 transporter (insulin insensitive - does not need insulin to transport glucose)
        *   Glycogen synthesis - taking glucose and producing glycogen (storage trigger)
        *   Glycogenolysis - taking glycogen and producing glucose
            *   When glucose is coming in -> some will move through the process of becoming glycogen. Later down the track when there is less glucose, some of the glycogen will be broken down to glucose (glycogen = storage).
            *   At this point, we want storage (glycogen synthesis reaction)
    *   Another option is using glucose for energy - Glycolysis
        *   Feeding glycolysis into mitochondria for energy -> breaking down glucose and using it as energy
    *   Gluconeogenesis is the reaction that goes with that -> taking some energy from citric acid cycle and forming glucose (have to be low on glucose)
    *   Glucose -> G-6-P -> G-1-P -> glycogen
    *   Insulin binds to a receptor on the hepatocyte and activates transcription of enzymes:
        *   Glucokinase (1)
        *   Glycogen synthase (2)
    *   This promotes glycogen synthesis 1+2 -> Start producing glycogen (when we know we have stored energy)
    *   Insulin and glucose inhibit:
        *   Glycogen phosphorylase (3)
        *   Glucose-6-phosphatase (4)
    *   Inhibition of 3+4 prevents glycogen breakdown (glycogenolysis)
2.  Promotes carb metabolism
    *   Glucose -> G-6-P (glucose 6 phosphate) -> pyruvate
        *   Could go to citric acid cycle
    *   Insulin binds to a receptor on the hepatocyte
        *   Activates transcription of kinases / enzymes that favour glycolysis (taking glucose and burning it for energy)
        *   Glucose conversion to pyruvate - but inhibits gluconeogenesis (don’t need to make more glucose - no need to generate as we have it)
        *   Also activates enzymes that allow pyruvate -> acetyl CoA (in mitochondria) -> krebs cycle (energy production in terms of ATP)
        *   Excess stored as glycogen after requirements for carb metabolism are met
        *    Stored as glycogen or burnt -> two processes happening
3.  Insulin promotes lipogenesis
    *   More likely to store energy in lipids - a good approach to storing energy.
    *   Products of pyruvate and acetyl CoA are brought into the lipogenesis process where fatty acids are joined together to form triacylglycerols and lipid droplets
        *   Either packaged up and sent to blood as VLDLs or stored as lipid droplets
        *   Pyruvate -> acetyl CoA -> lipogenesis pathway -> FFA -> trigs
        *   Some trigs packaged into VLDL (Very low-density lipoproteins) leave liver into circulation
        *   Others remain as storage (lipid droplets)
4.  Inhibits lipolysis and ketogenesis
    *   Lipids don't want to be broken down -> if lipogenesis is underway, we want to inhibit lipolysis - no point producing a lipid and breaking it down simultaneously
    *   Insulin inhibits lipolysis
    *   Insulin inhibits the oxidation of Free Fatty Acids -> we don’t need energy for a bunch of glucose floating around the body, so rather than burning fatty acids for energy, we can burn the glucose
    *   Insulin prevents FFA carriers into mitochondria (no ketones) -> same goes for proteins (don’t make ketones when other sources of energy are available)
    *   All about using glucose, storing glucose, burning glucose and preventing anything that goes against that
    *   Explains why we can make ketones during starvation
5.  Promotes protein synthesis, inhibits proteolysis
    *   If you have a lot of energy - that is the time to start synthesising things (protein -> if protein is being synthesized, we are not breaking it down -> inhibiting lysis of protein)
    *   Insulin signals cells that it's time to store, burn and use glucose as the primary source of energy in the cell

Insulin in Muscle Cell

• Different to liver: Insulin binds to IR -> GLUT4 (instead of GLUT2)
  • GLUT4 sits in storage and does nothing until activated by the insulin receptor, then moved onto the membrane -> glucose can come into the cell
  • GLUT4 transporter incorporated in the cell wall -> glucose enters the cell
• Once glucose is in the cell, what do they do with glucose
  • Glycogen synthesis -> storage of glucose
  • Glycogenolysis -> break down of glycogen to glucose
• To produce energy, we are going to favour the synthesis pathway
  1. Insulin promotes glycogenesis and inhibits glycogenolysis (stores glucose as we are not in need)
  2. Insulin promoted carb metabolism (glycolysis, TCA, e-TC)
     • Glycolysis is stimulated and not gluconeogenesis -> extra energy is shifted into mitochondria and is available to be burnt
  3. Insulin promotes lipogenesis (storage of lipids), inhibits lipolysis (Don’t need to burn fatty acids as we have tones of glucose
  4. Insulin promotes protein synthesis, inhibits proteolysis (don’t need proteins for energy as we have enough glucose)

Insulin in an Adipocyte (Fat Tissue)

• Same as muscle, different to liver: Insulin binds to IR -> GLUT4 (not act until insulin is provided) transporter incorporated into cell wall -> glucose enters the cell
  1. Insulin promotes glycolysis (used for energy)
  2. Insulin promotes lipogenesis:
     • Pyruvate -> acetyl CoA -> fatty acids (Shuttled into lipogenesis pathway) -> trigs = lipid droplet
       • Fatty acids are being stored and converted to triglycerides and being stored as lipid droplets
       • Fatty acids are coming from the free fatty acids outside (chylomicrons and VLDL)
       • How does the cell know when to do this?
       • Because it has insulin floating around -> triggers glucose to come in -> allows more lipids to be synthesised
  3. Insulin Inhibits hormone-sensitive lipase (3) - (HSL initiates lipolysis)
     • (insulin inhibits lipolysis -> preventing the burning/breaking down of lipids as we are trying to build them up
  4. Promotes synthesis of lipoprotein lipase (Protein that is required to bring fatty acids into adipose tissue), exported to the endothelial cell to break down trigs in chylomicrons = free FA -> into adipocyte (lipogenesis)
• Without insulin, cells won’t be activated -> really powerful hormone

Lipoprotein Metabolism

• Insulin activates lipoprotein lipase (LPL) enzyme:
  • Breaks FFA from chylomicrons -> storage/ fuel
  • LPL activate after food intake
  • LPL inhibited when fasting

Hormone-Sensitive Lipase (HSL)

• HSL converts stored trigs (fatty acids) -> FFAs for export (for fuel)
• Insulin inhibits HSL -> Don't need fatty acids for energy
• LPL facilitates the uptake of dietary lipids into cells, while HSL promotes the breakdown of stored fat in adipocytes

Insulin Mechanism for Action

• How do we get insulin from outside the cell to the final outcomes><- outcomes of three different sections

  1. Insulin binds to the receptor -> activates tyrosine kinase (TK) on intracellular beta chains (2)
  2. It is phosphorylated and requires ATP -> ADP, extra phosphate going to TK
     • That goes down to section 3
  3. Pi = energy to activate receptor and insulin-receptor substrate family (IRS) (3)
  4. Whole bunch of proteins sitting together and activated by this process -> insulin arrives, activates protein -> activates these proteins in 3 = called signal cascade as one protein activates another
  5. IRS activates phosphatidylinositol (PI) pathway -> 2nd messengers in the lipid membrane of the cell
     • Activates GLUT4 transporter from vesicles in the cell membrane (5)
  6. Telling the body or cell that glucose is available and time to bring it into the cell -> start with insulin and end up with glucose being transported using GLUT4

Outcomes

• When glucose comes in it is either stored or oxidised -> glucose is being bought into the body to be burnt for energy or stored as glycogen
  7. Protein kinases activated by the PI pathway induce translation of mRNA
     • We activated GLUT4 and other kinase that promote protein synthesis
     • Cascade that activates protein synthesis -> we do this when there is a lot of energy to spare as it is a good time to produce proteins
  8. Back is step 3, IRS activates MAP kinase (MAPK) pathway, leading to DNA transcription
     • End up in the nucleus and doing DNA growth and repair

Why do we wait for insulin signals to do these

• Because they take a lot of energy to repair DNA, don’t want to bring energy out of storage to do this - we might as well wait
  9. The body has started to produce DNA, but there is extra energy floating around -> extra glucose (we make glycogen for storage)
     • MAPK + PI pathways lead to glycogen synthase activation = glucose -> glycogen (storage)
  10. All about triglycerides -> We have extra energy floating around so we from Fatty acids and triglycerides
      • IRS-1 -> lipogenesis and lipid storage

NEED TO KNOW THE OUTCOMES

Insulin Function Outcomes

• What happens when we are fasting and need to use energy?
  • Energy liberation instead of energy storage.
  • Glycogenolysis (break down) in the Skeletal Muscle: Glucose Liberation (get glucose into the body)
  • Happens when we have low blood glucose levels -> need to signal that we need glucose from other sources
  • Neurotransmitter epinephrine (adrenaline) released during low blood glucose levels (BGL)
  • Released from the adrenal medulla
  • Binds to beta-adrenergic receptors (G protein-coupled receptors (GPCRS)) expressed on muscle cell wall
  • Stimulates protein cascade
  • G-protein complex stimulates adenylyl cyclase/ cAMP/ protein kinase (PK) pathway
  • Point: Glycogenolysis: Glycogen -> glucose-1-phosphate -> G-6-P -> glycolysis
  • Breaking down glycogen into glucose
  • Epinephrine (not moving to the cell but binding to the receptor) flows through extracellular space and binds to the receptor
  • Once binded, the receptor will have a physical change - sites on the inside of the cell will become active
  • Activating G-protein complex - activates protein kinase A
  • Protein cascade -> activates protein kinase A that prevents glycogen synthase (as we want to break it down)
  • Also activates phosphorylase kinase - activates additional proteins such as phosphorylase
    • Phosphorylates glycogen to break off a glucose molecule and forming glucose 1P
    • Then becomes glucose 6P (What we want) and then form glycolysis (end product)
  • This can go both ways! Insulin is about syntheses - but now we are doing the opposite and looking for lysis
  • The pathways activates glycogen phosphorylase and inhibits glycogen synthase enzyme (cannot create glycogen)

Glycogenolysis in the Liver

• Everything downstream is the same as the muscle.
• Except for glucagon receptor kicks off the process.
• Glycogenolysis in the liver: Glucose Liberation
  • In the liver (also kidney and intestine):
    • G-6-P -> glucose (directly) via glucose-6-phosphatase (G6Pase)
    • Glucose released into the bloodstream
    • Source of energy from those tissue to other tissues
• What are the implications of glucose in the bloodstream?
  • Glycogenolysis - Breaking down and storage of glucose
  • Gluconeogenesis (De Novo = from new) - Making glucose
• What are we creating glucose from?
  • After an overnight fast, hepatic glucose output derived from:
    • 50% glycogenolysis,