Lecture #10 - Integrative metabolism

Question 1

Why is metabolism important to know

Answer 1

1. It touches all of biology and science (Ex. Epigenetics is affected by Actly coA metabolism)
2. There is a revolution in the feild
   
   • Occured due to technology + Many things are related to metabolsim (Diabeties + obsetity + Cancer metabolsim + aging + immunology + Alzheimers)
3. There is a not eanough of qualified metabolic scientists
4. Some of the most important discoveries were made in metabolsim reserach (Ex. 2nd messengers)

Question 2

How much ATP do we make and break in 1 Day

Answer 2

We make and break down A TON of ATP every day

Chart – Shows tasks done during the day and how much energy (ATP) each tasks exerts (Energy expenditure in kj/min)
- To maintain sitting - Need to make and burn 80 lbs of ATP per day
- To maintain working – 800 Lbs per day

There are many regulatory mechanisms to take the food we eat and gernate work

Question 3

Catagories of metabolism

Answer 3

1. Catabolism
2. Anabolism

Question 4

Catabolism

Answer 4

Catabolism - breakdown of large macromolecules into smaller molecules (Energy containing nutrients –> energy depleted end products)
- Exergonic reaction (-dG)
- Catobolic processes oxidzies things we eat –> makes CO2 and Water ; ALSO makes amonia

Directly or indirectly coupled to ATP productions and reducing equivilents (NADH and FADH2)
- ATP and GTP can be derived directely (Ex. Glycoslysis)
- NADH and FADH2 are used to push reactions foward OR to generate ATP (Ex. make ATP by driving the ETC or powering Oxphos)
- ATP is used for many things (Ex. Used in gluconeogensis)

Question 5

Anabolism

Answer 5

Anabolsim – Syntehsis of large moelcules from smaller buidling blocks (making complex lipids + nucleotides + proteins)
- Endergonic reaction (+dG)

Directely or indirectely consumes ATP (uses energy made in catabolic processes)
- Can require ATP (Ex. Gluconeogensis)
- Can utilize reducing reagents (Ex. Use NADH in fatty acid/lipid synthesis)

Question 6

Energy density of metabolic substrates (fatty acids and glucose)

Answer 6

Fatty acids (9.31 Kcal/g) are more energy dense than Carbohydrtates (glucose is 3.72) –> makes fatty acids good stroage vessels
- If we only stored carbohydrates for energy humans would be very large because carbs are less energy dense
- Easier to pack FA than carbs = can store more energy in less space using fatty acids (water needs water Vs. FA are stored in lipid droplet as triglycerides w/o water)

During starvation body uses the high-density energy storage to maintain life

Question 7

Study starvation in lab

Answer 7

IF grow cells in culture and remove all nutrients you are NOT studying starvation because under staravtion cells release Fatty acids and beta hydroxy-butarte and ketone bodies (STILL have nutrients around in stravation)

Stravtaion in humans = difefrent utilization of nutrients/change in the type of macronutrients

Question 8

Metabolic pathways segregation

Answer 8

Metabolic pathways segregation:
1. Physical segregation - Segreates processes so don’t competing with one another
- Ex 1– FA synthesis in the cytioplasm Vs. Fatty acid oxidation (break down of fatty acids) is in the mitochondrial
- Ex 2 – Liver - Glucose kinase is in the cytoplasm (glycolysis using carbs) Vs. Glucose-6-phosphatase is in the ER (break down glycogen to release glucose)

2. Intrinsic limitations on substrate access

I THINK - both are forms of regulatiion

Question 9

Metabolic pathways segregation - Intrinsic limitations on substrate access

Answer 9

Ex 1 - Preventing glucose entry and therefore glycoslysis under low glucose concentration by expresisng only transportes/glucokinases with high Km

Ex 2 - Ketone bodies are made in he liver BUT made from FA in Adipose –> ability to make ketone bodies is not regulated by the amount of substarte that is available (Regulate access to the substarte by keeping the substrate in the adipose tissue = can only make ketones when FA is released from adipose to liver)

Done by inhibting entry of fatty acids into the mitcodnira by an intermediate of fatty acid syntehsis (maol coA)

Done by insulin simulated diaply of glucose transports on teh surface of muscle and fat cells

Question 10

Way to regulate metabolic pathways

Answer 10

Form of regulation - competing pathways are segregated

Reactions occur in different places in the cell:
Example 1 - Glycolysis and Glucogoneogensis
Example 2 - Glycogen breakdown and glycogen synthesis
Example 3 - Fatty acid oxidation & synthesis
Example 4 – Triglyceride synthesis/breakdown
Example 5 – ketone synthesis and breakdwn

Question 11

Why is bioenergetics complex

Answer 11

OVERALL – bioenergetic is complex because we need to maintain homeostasis –> Blood glucose must be maintained within a narrow range (3.5-7mM) because of metabolic limitaions of the brain and physiologic concerns
- If glucose drops too low body goes into coma
- Brain uses glucose in restrictive manner
- Maintaining blood glucose levles is complicated because huamans have a complicated life style

Question 12

Complications of lifestyle that makes maintaining blood glucose complicated

Answer 12

1. We consume large amounts of sugar/lipids/proteins –> excess glucose must be cleared from the blood quickly (need to maintain glucose levels even when eat different diets)
   
   • Sugars – Stores as glycogen in liver and muscles
   • Lipids – Stored as fat in adipose and liver
   • Proteins – Stored in mucle
2. Energy intake falls during fasting and starvation –> need a mechanisms for metbolizing energy reserves/stored glucose and maintaining blood glucose while fasting
   
   • Done using Glyconenolysis + Liposlysis + protein catabolism/Urea cycle + Glyconeogensis
3. Excersize can create large energy demands –> need to make sure that tehse energy demads do not deplete blood glucose (maintain glucose during exercise)

Question 13

Example of glucose homeostasis

Answer 13

Example 1 - Humans can maintain blood glucose even during a hunger strike (survive 2 months without any food)
- People were cognizant until they died
- Did not die even though were not taking in nutrients because they stored enough glucose to maintain blood glucose

Example 2 – obese people can starve for a year and maintain normal blood glucose concentration

Shows homeostasis regulation allows people to survive during starvation

Question 14

Source of blood glucose in extended fast

Answer 14

Chart – Shows where blood glucose comes from (subsrates that are used to mainatin blood glucose)

Example – Person eat a carb -> body immeidatley uses the crab as the main source of glucose to mianatin blood glucose levels –> when stop eating body uses Glycogen (short term carbohydrarte source) –> After time need crabs (glucose) from other substartes so the liver will make glucose from proteins (breaks down of muscle –> proteins go to the liver and the amino acids is used by the liver to make glucose in gluconeogenesis) (THIS IS mainatins blood glucose for long term)
- Gluconeogensis = making new glucsoe

Question 15

Glycogen

Answer 15

Glycogen – polymer of glucose stored in the liver
- Glycogen = short term carbohydrates

When blood glucose drops – Put gluose from glycogen into the blood

Glycogen is in Muscle and Liver
- IN liver - Glucose can be released in response to low blood glucose
- IN muscle - muscle does not care about blood glucose levels (won’t release gluclse if starving); the glycogen is only used for fight or flight (reason why eating carbs before marathon does not help)

Question 16

Fat associated diseases

Answer 16

Issue in medicine = increase in obesity (60% of americans are overwieght ; 30% of americans are obese)

Issue with being overweight –> being overweight is involoved with things that kill us
- Example – Coranary artery diseases is linked to body weight (affects risk of stroke)
- Example 2 – cancer can be associated with obesity

Losing weight has health beneifts (Ex. cardio vasuclar benefits)

Question 17

Fed + fasted + starved state

Answer 17

Fed + fasted + starved state requires intimate coordination among tissues

Question 18

Divison of bioenergtic labor in the body

Answer 18

Systems responsible for hemeostatic regulation:
1. Pancreas - islets sense glucose and release insulin/glucagon according to dietary intake
2. Liver - center hub of metabolsim (easy for liver because of anatomical position)
3. Muscle - removes glucose from the blood in response to insulin
4. Adipose tissue
5. Brain - draws glucose (requires constant on demand source of blood glucose)
6. Red blood cells: Utilize glucose by glycolysis only

Question 19

Liver - Overall

Answer 19

Functions as a glucose buffer - removes excess blood glucose (stores it as glycogen) and removes excess fat and sterols (sends it to other tissues)
- Liver can do FA oxidation and synthesis
- Liver regulates amonia by making urea

When low glcuose - generating glucose (via gluconeogenesis) using fat as the power and amino acids as the building blocks

If there are too many lipids in liver –> get lipid droplets –> get liver failure

Question 20

Muscle - Overall

Answer 20

Removes glucose from the blood in response to insulin (converts it to glycogen)

Can do long-term store of protein –> protein in muscles can be broken down to amino acids –> Amino Acids can be delivered to the liver during periods of fasting/starvation/lo carb –> liver uses amino acids for gluconeogensis
- Amino acids = carbon substrate used to make glucose during fasting

Muscle uses fatty acids as an energy source

Muscle is the largest insulin sensitive tissue

Question 21

Adipose Tissue - Overall

Answer 21

Adipose: removes glucose from blood in response to insulin –> converts glucose to fat –> releases fat to the liver during periods of fasting/starvation/lo carb diet
- Adipose tissue = stores high density energetic fatty acids + can make endocrine molecules to communicate with the brain and the liver

Runs on fatty acids under all conditions

Question 22

What happens during Fasting

Answer 22

1. Adpiose tissue releases triglycerisdes (FA) –> triglycerides are used by muscle (heart + skeletal muscle) as the main energy source AND gives FA to liver
   
   • Ex - wave of energy = muscle is switching from carbs to using FA as energy source
2. Need to make glucose - Done by using Amino Acids from break down of muscle as the substrates for gluconeogensis
   
   • Done in the liver and some in the kidneys)
     - Alanaine = substrate for gluconeogenesis in Liver ; Glutamte = substrate in the kidney
3. Fatty acids are broken down to make ketone bodies (in liver)
   
   • Ketones are used in starved state (can be used by brain and other tissues in starvation)
     - Ketone bodies can pass BBB

Question 23

Pancreus - Overall

Answer 23

Mostly made up of acinar cells (secrete digestive enzymes)

Has endocrine cells (release insulin and glucagon)
- Inculin is made in proportion to the amount of crabohydrates that are taken in (Pancreus senses the concetration of extracellular glucose and releases the right amount of insulin to maintain glucose homeostasis)
- Alpha cells make glucagon (starvation hormone)

Question 24

Types of Diabetes

Answer 24

T1D - Autoimmune disease –> pencreatic beta cells are detsroyed –> can’t control blood glucose
- Given pateints insulin to decrease glucose (have many ways to make insulin and modify it)
- Don’t want to give too much insulin (become hypoglycemic because take too much glucose out of blood) or too little (become hyperglycemic)
- Get uncontrolled lipolysis

T2D - insulin is made BUT the muscle/liver are resistent to insulin (insulin does not lead to the uptake of glucose)
- Beta cells can due after resistence
- Loss of extremities + vision

Question 25

What happens when have no Insulin

Answer 25

If there is no insulin then can’t control lipolisis --> can’t stop fatty acids being released from adipose stores --> body thinks it is in a constant state of starvation --> Free fatty acids go to the liver and make ketone bodies Issue if have too much beta-hydroxy butarate (type of ketone) - Ketone bodies are acideic = chnage the blood pH --> When change blood pH the hemoglobin can’t interact with oxygen --> get ketpacidosis (accute issue in T1D)

Question 26

Inuslin

Answer 26

Insulin is secreted in response to an increase in glucose concetration (in fed state) - Function - Insulin receptor regulates glucose uptake in skeatal muscle and adipose tissue Insulin receptor is a tyrosin Kinase (RTK) Tissues that insulin acts on: 1. Liver --> promote FA/glycogen deposition + inhibits gluconeogesis (don;t want to make glucose if have high glucose and wnat to put glucise into glycoen stores to lower blood glucose) 2. Muscle --> promotes glucose by casuing GLUT4 to go to surface of muscle cells (GLUT4 bring glucose into cells) 3. Adipose --> promotes glucose by casuing GLUT4 to go to surface of adipose cells

Question 27

Glucagon

Answer 27

Glucagon is secerted during glucose deprication (in fasted state) Glucacon receptor is a GPCR Tissues glucagon acts on: 1. Liver --> promotes gluconeogensis and glycogen break down (want to release glucose and make new glucose when have low blood glucose) 2. Adipse tissues --> causes lipolysis in adpisoes --> cause release fatty acids from --> fatty acids go to liver --> liver can use to do gluconeogensis 3. Muscle --> muscle does NOT respond to glucagon (Because glucagon is a starvation horomone and mucsle doesn't care it you are starving)

Question 28

How do you release glycogen in muscles

Answer 28

Muscles do NOT use glucagon to release glycogen INSTEAD use epinephrine to release glycogen in muscles - Epinerprin – causes breakdown of glycogen in muscles (only used in fight/flight NOT used in starvation)

Question 29

Regulation between the amount of carbohydrates in circulation and the secretion of insulin

Answer 29

Regulation between the amount of carbs in circulation and the amount of insulin secreted is connected How does the endocrine cells in the pancreus secerete the right amount of insulin in respose to the amount of glucose in the extracellular space: 1. Pancreotic cells take in glucose through a 1 glucose transported (GLUT2) 2. Glucokinase Km 3. ATP concentration signals to channels to change insulin secretion

Question 30

How does the endocrine cells in the pancreus secerete the right amount of insulin in respose to the amount of glucose in the extracellular space -GLUT2

Answer 30

Pancreatic cells take in glucose through GLUT2 -> Km of GLUT2 is the physiological conetration of glucose Because of Km GLUT2 only binds to and brings in glucose when glucose is at/above correct glucose concentration

Question 31

How does the endocrine cells in the pancreus secerete the right amount of insulin in respose to the amount of glucose in the extracellular space - Glucokinase

Answer 31

When glucose goes into cells it is phosphorylated by Glucokinase to Glucose-6-Phosphatse (traps glucose in cells and primes it for glycolysis) Pancreus releases right amount of insulin because the Km of Glucokinase is the physiological conetration of glucose (only trapping glucose in cells at the right concetration of glucose) - Glucokinase is able to to interpret the extracellular glucose concetartiion because it only works homeostatic concetration of glucose

Question 32

Regulation of Glucokinase

Answer 32

Gluckinase is not feedback inhibited by product = it will keep phosphorylating glucose until the concentration of glucose goes below homeostasis (below Km) NOTE - Don't want the brain to regulate carb intake based on the concetration of glucose in circulation beause need to think at low and high conceyraion of glucose - If want neuron to go through glycolysis faster need to get rid of glucose-6-p

Question 33

How does the endocrine cells in the pancreus secerete the right amount of insulin in respose to the amount of glucose in the extracellular space - ATP concetration signals to channels to change insulin secretion

Answer 33

Overall - ATP concentration signals to channels to change insulin secretion Metabolism of glucose generates ATP --> ATP inhibits K channels in the membrane --> closing K channels changing the voltage across the membrane --> change in voltage actiavtes voltage Gates Calcium chanels --> Calcium goes into the cell which causes insulin granuals to fuse with the membrane --> get exocytosis of insulin granuals - SulfonyUrea inhibits the Katp chanel to increase insulin secretion (used to treat T2D)

Question 34

Free fatty acids During fasting

Answer 34

Free Fatty acids are released during fasting If release insulin during fasting – person dies because remove all of the glucose from circulation To not die during stravtion - beta cells won't break down fatty acids for energy --> release of fatty acids won’t trigger beta cells to release insulin = won’t get insulin during fasting

Question 35

Why do animals that dont need crabohydtrates (Ex. Cats) still need insulin and how do they regulate insulin secretion of they are not eating crabohydrates

Answer 35

To regulare insulin secretion - use amino acids - When eat --> Insulin is released so that the Amino acid are placed in adipose tissues - Can have fed and fast responses

Question 36

Metabolic functions of liver

Answer 36

Liver can take in carbs and make Lipids OR can take in lipids and make ketone bodies AND can make glucose de novo in gluconeogensis 1. Liver receives fat/choletraol from gut in the form of chylomicrons and repackages them in VLDL partciles 2. Dipsoses of choletraol via bile 3. Liver serves as a biffer for blood glucose 4. Liver gelps get rid of nitrogen - In fasting state – when use Amino acids to make glucose --> releases amino groups --> liver gets rid of the amino groups using the Urea cycle

Question 37

Metabolic functions of liver - Liver receives fat/choletraol from gut in the form of chylomicrons and repackages them in VLDL partciles

Answer 37

If consume a lot of carbs --> need to place the carbs in long term storage Carbs left over after glycogen is made (in the muscle and the liver) --> liver takes the excess carbs (carbon in glucose) and make them into long chain fatty acids (lipids) To avoid fatty liver --> the liver transports the lipids to the adipose tissue to be stored - Transport lipids to the adipose tissue in a lipoprotein particle (phospholipid monolayer surrounds neutral lipids triglycerides and cholesterol esters)

Question 38

Metabolic functions of liver - Liver serves as a buffer for blood glucose

Answer 38

Liver can buffer for blood glucose by: 1. Taking carbon skeletons from glucose and make fatty acids 2. By oxidizing fatty acids to fuel gluconeogensis 3. By making ketone bodies during fasting (takes in carbs and makes lipids)

Question 39

What happens when eat a fatty meal

Answer 39

Fats are digested into their components (fatty acids and monoacyl glycerol) and packed into lipoprotein particles in the gut (chylomicron) --> chylomicron are exported into lymphatics - Exported into lymphatics because want peripheral tissue to have access to digested fats before the liver

Question 40

Lipids exiting the inestial epithelia

Answer 40

In the lumen of the gut – digestes fats (triglycerols) to make Free fatty acids and monoglycerols - Chylomicros are made in the gut In the intestinal epitethelial cells --> fatty acids and monoglycerols are made into triglycerols which combine with other lipids and proteins --> makes a chylomicron --> chylomicron exit epthelia and goes to the lymphatic system (goes to periphery)

Question 41

How is cholestrol transported in the blood

Answer 41

Choletrol is transported in the blood as an ester that has been incorporated into Lipoprotein particles (chylomicrons) Chylomicron particle structure: 1. Phospholipid monolayer - Phospholipid FA tails stick inside (head is outside) and interact with the neutral lipid in Triglycerols and fatty acids 2. Center - Triglycerols + choletrol esters (attatched to FA) + free unestrified cholestrol - ALL lipids have no charge = can be packed tight in particle

Question 42

What happens when chylomicrons enters circulation

Answer 42

Chylomicron leave the lymphatics --> go into circulation --> go into capilary beds in the muscle or adpiose tissue When on the surface of endothelial cels in capilary bed - lipoprotein lipase attatched to surface of endothelial cells hydrolyzes the triglycerides (break them down) --> allows tissues to take up the fatty acids for storage or for energy - Chylomicron reminants are taken up by the liver and reproccessed

Question 43

Making Fat de novo

Answer 43

Liver can make fats Ex - Liver makes low density lipoparticles (has a lot of cholestrol ester) - Low density liporpartciels is exported --> goes to capilary beds and peripheral tissue --> tissues can extract and use fatty acids - LDL delivers cholesterol to target tissues (VLDL --> IDL --> LDL --> Tissues) Can’t break down cholestrol --> need to send cholestrol back to liver (uses HDL)--> in liver it is conjugates it to bile and put into feces - HDL - delivers choelstrol from tissues to liver (LDL in tissues --> HDL --> Liver)

Question 44

Liproprotein variety

Answer 44

Multiple types of lipoprotein particles participate in lipid transport through the bloodstream - Types - vary in size, lipid composition, and protein composition Example - LDL Vs. HDL - different because of size + have different proteins on the surface - LDL is asscoiated with cardiovascular disease (bad cholestrol) - HDL (good cholstrol)

Question 45

Issue with LDL

Answer 45

LDL can lead to formation of a Fatty streak in the coronary artery Fatty streak can have macrophages (phagocytosed oxidized LDL) that try and help with the fatty streak BUT they get traped and the tissue becomes fibrotic (have fibrotic area in the vessel wall) --> fibrotic plaque can break off --> jams the coronary artery --> get a blockage of artery --> get a heart attack

Question 46

Liver and pancreus exposure to glucose concentrations

Answer 46

Liver and pancreus are exposed to large changes in glucose concetraions (5-25 mM) Chart – shows hexokinase and Glucokinase levels Vs. Glucose concetration - Hexokinase and Glucokinase are in the beta cells in pancreus --> shows how cells interpret extraellualr glucose signals for insulin secretion - Glucokinase is ALSO in the liver

Question 47

How does liver manage metabolsim of glucose

Answer 47

Liver has glucokinase - Liver manages metabolism of glucose through glucokinase Because liver does Glyconegsis and glucosneogensis (BOTH release glucose into circulation) --> liver does not always want to take up glcuose Liver only wnats to take up glcusoe when the blood glucose is higher than homoestasis (higher than Km for glucokinase) - Below Km want to make glucose in the liver (NOT take up glucose)

Question 48

Muscle Glycogen

Answer 48

Muscle stores glycogen BU it only uses it for its own use (selfish) - Does not use the glycogen to maintain blood glucose levels There is no way to get glucose out of stored glycogen out of the muscle (can't do gluconeogensis/not release glucose from glycogen) - Glucogenogensis specifc step uses glucose-6-phosphatase -->  Glucose-6-phosphatase is expressied in the liver + kidney + gut but NOT in the mucle --> there is no way to get glucose out of glycogen out of the muscle - NOTE - gut can do gluconeogensis BUT most is done in the liver and the kidney

Question 49

How does Liver Stave off Muscle wasting

Answer 49

Liver gives ketones to the muscle to stave off muscle wasting Why does the liver make ketone bodies: - Brain can use ketone bodies instead of glucose when in a straved state --> Using ketone bodies – lowers the blood glucose level that the body needs to make in order to mainatin brain function (because the brain is able to use an alternative substrate and does not need glucose) Because can use ketone bodies and therefore can have lower blood glucose – the body can does not need to break down as much mucle to make more glucose --> shows use of ketone bodies can starve off muscle wasting (not breaking down as much protein)

Question 50

Effect of Excersize

Answer 50

Exercise is linked to metabolic health in many ways - Can make people smarter --> more BDNF made in the brain during exercise Experiment - Patients got lipsuction (removed 10% of body weight) Vs. Pateints excersized and lost 10% of body fat - Liposuction groups had no metabolic imporvement - People that excersize had metabolic imporvmnet - MEANS Excersize causes a signal that leads to health benfites beyond losing wieght

Question 51

White Adipose Tissue (WAT)

Answer 51

Thought WAT was an inert tissue (storage for triglycerides) until they found leptin WAT has endocrine funcation that secretes hormones to communicates with the nervous system - Function - Suppresses eating using hormones (Ex. WAT secretes Leptin) - To communicate with the nervous system – WAT expressed leptin + Adiponectin + IL-6 + TNFa

Question 52

What do we know about genetics of weight

Answer 52

Know a lot about weight/genetics of weight in mice because wieght is a visible phenotyoe Example – ob/ob mice have mutated gene and are 2X in size - Positionally cloned the gene and found mutations in a gene that is only expressed in WAT(Leptin gene) Now know humans can have mutations in leptin (mutation is found in very overweight people)

Question 53

Does giving leptin to pateints help with weight loss

Answer 53

Giving Leptin to people with mutation in the leptin gene does NOT help with weight loss - NOTE - Give Leptin to ob/ob mouse = they lose weight People with polygenic obesity don't lose weight because there can be a small amount of leptin throughout person's life (not enough to actually work but enough to make the receotors ressitnt to leptin) - Want to receptors sensative to leptin (would be able to use natural amount of leptin)

Question 54

Mutation in leptin itself Vs. Mutation that causes small amount of leptin to be made

Answer 54

Humans with mutation in leptin itself = are sensitive to leptin (giving healthy leptin helps) Vs. Muatiion so that only a very small amount of leptin is made = not sensative to leptin because receptors are resistant to it

Question 55

Function of WAT

Answer 55

Function – Triglyceride strorage Adipose tissue is a good place to store triglycerides BUT there is a limit to how much adipose tissue we can make --> once reach that limit the trigycerides spill out and the triglycerides are stored in the muscle and the liver --> When the triglycerides spill out get insulin resistnce IF you could increase the amount if triglycerides in WAT/increase amount of WAT) would not have insulin resistance --> made mice that can have more adipose tissue and store all of the triglycerides in adipose tissue -- they fat but metabolically healthy because expansed adipose tissue (can store all triglucerids in right place)

Question 56

Brown Adipose Tissue (BAT)

Answer 56

BAT is sensative to insulin Function – burn energy and makes heat (uses an uncoupling protein that uses ATP synthesis proteins BUT does not make ATP and instead makes heat) - Ex – When a bear wakes up from hibernation it uses BAT which uses fatty acids to burn energy In humans - Babies have BAT (used in perinatal period) AND adults have some (know from PET scans - background is activated BAT)

Question 57

Insulin resistence in High Vs. Low Fat

Answer 57

To much fat (WAT) – can lead to insulin and leptin resistnce and Type 2 diabetes (High glucose) - Obesity can lead to insulin resistnce and expansion of adipose tissue To little fat (WAT) – can lead to insulin resistance and Type 2 diabetes (High glucose) - Can be treated by giving patients leptin

Question 57

Insulin Sensitive Tissues

Answer 57

Muscle and Adipose are insulin sensative tissues --> MEANs that insulin stimulates glucose uptake via GLUT4 (insulin sensative glucose transporter) in adipose and muscle cells How are cells sensative to insulinn --> Insulin is linked to GLUT4 mediated translocation to the membrane

Question 58

How does insulin mediate uptake of glucose

Answer 58

GLUT2 in panecraitic beta cells is ALWAYS on the surface allowing beta cells to take up glucose/always be monitoring blood glucose - GLUT2 is regulated by the Km (regulated by its enzymatic properties) GLUT4 (on muscle and adipose cells) – Mediates insulin’s effect on blood glucose - Normally (no insulin) --> GLUT4 is in the cytoplasm of the cell in vesicles - When beta cells secrete insulin --> insulin mediates fusion of the vesciles containing the GLUT4 receptor with the membrane --> NOW GLUT4 goes to the surface of the cell and GLUT4 allows cells to take in glucose from circulation (ONLY occurs when inculin is released = glucose levels are high)

Question 59

How is GLUT4/Glucose levels regulated in Muscle and adipose cells (regulating glcuose uptake in general in muscle and adpiose cells)

Answer 59

Regulation – done by limiting subrate from its transporter Becaue GLUT4 does not ind to glucose until there is high glucose and insulin is secreted and GLUT4 goes to the plasma membrane)

Question 60

What happens if give too much insulin

Answer 60

If give someone too much insulin they die because all of the GLUT4 receptors go to the plasma membrane --> receptors take all of the glucose out of the blood -> person becomes hypoglycemic --> go into coma

Question 61

Brain - Overall Energy

Answer 61

Brain mainly utilizes Glucose BUT it can switch to use ketone bodies during fasting - Brain uses uses 20% of the fasting blood glucose Nervous system needs energy on demand - nervous system wants to quickly take up energy to fuel processes that are happening in the neuron - Mutation in mitocindria/ATP generation can cause nuerologic impairments (energy is important in brain)

Question 62

Brain fuel source

Answer 62

Chart - shows where all of the fuel the brain uses is coming from - In well fed state – Almost all of the fuel used by the brain comes from glucose (Crab) - In Starved state – Brain can use Ketone bodies (hydroxy butarate and Acetoacetate) as fuel Keto diet – used for people with epilepsy (suppresses seizure frequency and severity) because of the restriction of carbs - Keto diet mimics the fasting state

Question 63

Fasting Effect on Ketone concentration in Blood

Answer 63

Fasting increases ketone concentration in blood Chart – shows the amount of ketone bodies in criculation after fasting (# of days of fasting on X-Axis) - Top metabolite made = Ketone - beta-hydroxybutarate (6nM) --> beta hydroxybutarate would be taken up by the brain and used as an alterantive oxidative metabolite in other oxdative tissues Shows effect of keto on epilepsy could be due to change in beta hydrxy butarate (has a 1000X change in concetartion in the blood during fasting)

Question 64

MRI of 2-deoxyglucose

Answer 64

Question 65

Red Blood cells

Answer 65

RBCs do not have a nucelus or mitocondira RBCs can’t use fatty acids or ketone bodies as an energy source Reaction in RBCs – Glucose --> Pyruvate --> lactate - Lactate keeps glycolysis going OR can be used by the liver as a gluconeogenic substrate (to make glucose) - If have mutations in Glucose metabolsim --> get lactic acidosis --> toxic

Question 66

What happens during short fast

Answer 66

During a short fast (ex. sleep) blood glucose drops below ~5.5 mM What happens: The pancreas stops production of Insulin and begins secreting glucagon --> change in the insulin/glucagon ratio tells the liver to breakdown glycogen to buffer blood glucose

Question 67

What happens during refeeding

Answer 67

During feeding - blood glucose rises above ~5.5 mM What happens in body during refeeding: 1. The pancreas starts production of Insulin and stops secreting glucagon --> change in the insulin/glucagon ratio tells the liver to store glycogen and stop gluconeogensis 2. Insulin also inhibits lipolysis in adipose and amino acid breakdown in muscle, while promoting the storage of fuels 3. Decreased lipolysis and increased fatty acid production in the liver lead to a cessation of ketone body production

Question 68

What happens during longer fast

Answer 68

1. Gluconeogenesis begins in the liver (and somewhat in kidney) 2. Adipose tissue hydrolyzes triglyceride to provide the liver with glycerol for gluconeogenic carbon skeletons and fatty acids to “power” gluconeogenesis (via NADH and ATP) 3. Muscle provides protein for gluconeogenic carbon skeletons for liver to gluconeogensis - Crabon is from muscle and the fatty acids from adioise power gluconeogensis 4. Liver also produces ketone bodies from fatty acids for use by brain and muscle

Question 69

Adrenal Gland

Answer 69

Overall - makes epinephrin and cortisol hormones Epinephrin goes to mucle --> causes glycogen to become Glucose-6-phosphate --> can use glucose) Cortisol – communicate with muscle in stravation AND can promote gluconeogensis in the liver during starvation

Question 70

Cortisol Vs. Epinephrin

Answer 70

Cortisol - Production is controlled at the level of the hypothalamic/pituitary axis - Function: stimulates gluconeogenesis + promotes breakdown of muscle proteins + stimulates ketogenesis in liver and utilization elsewhere. Epinephrine - Production is controlled at the level of the sympathetic nervous system - Function - stimulate glycogenolysis + stimulates lipolysis from adipose

Question 71

What does the Gut express

Answer 71

Gut expresses many endocrine molecules (part of incretin response) 1. ghrelin --> inrecases food intak 2. PPY and GLP (GLP1 = active ingrediant in ozempic) - GLP1 = insulin agonist --> increases insulin secretion

Question 72

Use of GLP1 for treatments

Answer 72

Past treated T2D - Gave people GLP1 that was made as a product of Hela monster to increase insulin secretion OR gave inhibitor of the peptidates that cleaves GLP1 - Dis not affect body weight NOW - have ozempic (New GLP1) Ozemic GLP1 Vs. Hela monster GLP1 --> GLP1 now is able to pentrate the brain --> it can access the CNS --> get increase in weight loss - Ozemepic is an anti diabetic drug – wight loss is an off target effect

Question 73

Ways to do a glucose tolerance test in mice

Answer 73

1. Inject glucose into the peritenieum --> can see an increase in blood glucose THEN once insulin is secreted the glucose level decreases in the plasma 2. Give Mice glucose orally - Get a different curve than when inject glucose due to the due to incretrin repsonse (due to hormones in gut) NOTE - Gastric bypass surgery enhances insulin sensitivity well before weight loss ensues