Metabolism - Exam#4, Part One Flashcards
What are the 5 stages of glucose homeostasis?
I – Absorptive → FED II – Post-absorptive → IN-BETWEEN MEALS III – Early Fast IV – Intermediate Starvation V – Long-term Starvation **We usually spend all of our time in Phase 1 (fed) and Phase 2 (in-between meals) as long as we eat breakfast
When is metabolic fuel provided to cells?
ALL the metabolic states → Fed (absorptive), in between meals (post absorptive) and the other three.
What fuel is used for energy in Stages 1 and 2?
GLUCOSE is always required by the central nervous system for 100% of the energy;
Other tissues include: erythrocytes (red blood cells), gastrointestinal tract (smooth muscle cells?), renal medulla, retina, and skin.
What is metaboliccaly different about mature RBCs?
Mature red blood cells DO NOT have mitochondria and thus produce lactate → No TCA or ETC cycle to produce other energy metabolites
What happens during Phase 2, or between meals?
- Metabolic changes that occur in b/w meals are the consequences of the need to PRESERVE GLUCOSE and the limited reserves of glycogen in liver for use by tissues that burn ONLY GLUCOSE;
- Ensure the provision of alternative fuels for other tissues.
- *Remember that skeletal muscle DOES NOT have the glucose 6-phosphatase enzyme so glycogen in muscle cannot leave as glucose, but as lactate.
What happens during Phase 4, or ~2 days without food?
- As body reaches state IV, intermediate starvation, the central nervous system uses KETONE BODIES, which are derived from fatty acids and ketogenic amino acids;
- Ketone bodies can meet about 20% of central nervous system’s energy needs, but the other source states 50%
What metabolic changes regarding glucose take place during PREGNANCY?
- Fetus requires a significant amount of glucose (possibly exclusively)
- =Mother’s hormone secretions during pregnancy promote LOWER INSULIN SENSITIVITY to spare glucose for the fetus; also spares protein (amino acids) and fat for structural and functional development in the fetus. → Mother gives up her affinity for storage to provide for the fetus FIRST - Lower insulin sensitivity allows greater glucose for mammary glands for synthesis of lactose for breast milk
What is the difference between Fed (1) and Fasted (2) states?
FED = metabolic fuel reserves are laid down;
FASTED (in-between meal) = metabolic fuel reserves are mobilized.
How are fats catabolized?
- Lipolysis of TAGs in a fat droplet ;
- Beta-oxidation of fatty aicds = fatty acyl → acetyl-CoA
What are the roles of the two types of adipocytes?
- White adipocyte store TAGs.
- Brown adipocyte undergo thermogenesis – production of heat in organisms, particularly warm-blooded animals → Loaded with mitochondria and maintains body temperature → Goes through beta-oxidation but it NOT coupled with TCA, so it just produces heat.
Where are fatty acids synthesized and stored?
- Much of the fatty acid synthesis goes on in HEPATOCYTES (liver cells);
- In contrast, Adipocytes then store TAGs arriving from the GI tract (DIETART fat) as part of chylomicrons and from the liver as part of VLDL = Fatty acids and glycerol put back together, but very little synthesis of fatty acids. → Just preformed, not totally synthesized as within the liver.
How do tissues use fatty acids BETWEEN meals?
- In BETWEEN MEALS, when many tissues need for oxidation of fatty acids is high, LIPASES in adipocytes hydrolyze stored TAGs to release free fatty acids into the bloodstream;
- Beta-oxidation of stored fats is catalyzed by lipoprotein lipase to release the fatty acids to be oxidized to generate energy when glucose is not present.
How is Glycerol-3-PO4 made for TAG synthesis?
- Glycerol is released from adipose tissue as a result of lipolysis, and only tissues such as liver and kidney that possess glycerol kinase, can convert to glycerol 3-phosphate;
- Glycerol 3-phosphate may be oxidized to dihydroxyacetone phosphate by NAD+ catalyzed by glycerol-3-phosphate dehydrogenase.”
→ Glycerol-3-phosphate in adipose tissue produced via glycolysis
What are the steps in Glycerol Utilization?
-Glycerol Kinase is found in the LIVER and KIDNEY → Can use glycerol to create TAGs = Catalyzes Glycerol to L-Glycerol 3-Phosphate so it can be used for TAG synthesis;
If reactions continue, in the adipose tissue, D-glyceraldehyde can be generated and used for Glycolysis
What hormones regulate the body’s response to food consumption or lack of?
- Insulin (lower blood glucose)
2. Glucagon (raise blood glucose)!
What cells make insulin?
-Insulin is secreted by the β-islet cells of the pancreas in the fed state in response to nutrients (primarily glucose) absorbed into the portal blood.
What are the Islets of Langerhans?
- Endocrine cells of the pancreas;
- Contains alpha, beta, and delta (A, B and D cells) that secrete peptide hormones
How is glucose regulated by actions of the Pancreas?
- Pancreas is a lot like liver in that it has GLUT 2 and cytoplasm has same glucose concentration as blood;
- Glucose is trapped in cell by phosphorylation by Glucokinase then catabolized; - Increased ATP causes CLOSING of K+ channels. Reduced efflux of K+ causes…
- DEPOLARIZTION of the membrane which causes opening of voltage gated Ca2+ channels.
- The resulting increase in cytosolic [Ca2+] triggers
- insulin release by EXOCYTOSIS;.
* *Note that K+ efflux through a channel HYPERPOLARIZES a membrane.
* *From portal blood glucose: Direct effect on membrane by Nervous System
How does Insulin affect Glucose UPTAKE in Phase 1?
- Into muscle and adipose tissue.;
- Insulin causes the migration of glucose transporter vesicles to the cell surface, exposing active glucose transporters, GLUT 4.;
- Muscle and adipose will only take up glucose from the blood stream to any significant extent in the PRESENCE OF INSULIN. (Recall though muscle and exercise)
What happens when Insulin levels falls?
-Insulin drops as blood glucose drops, the GLUT 4 transporters are internalized again, reducing further glucose uptake by muscle and adipose;
What are the different circumstances that drive glucose uptake?
- Remember is that there is glucose uptake driven by insulin and glucose uptake driven by a high glucose level in the blood stream.;
- And also remember the effect of exercise INDEPENDENT of insulin
How do MOST tissues uptake glucose?
- Glucose uptake by most other tissues is INDEPENDENT of INSULIN;
- So in the case of Diabetes, when blood glucose stays high longer than in healthy condition, more glucose gets into tissues in higher amounts than is healthy.
- *One of the keys to a healthy life is to remain INSULIN SENSITIVE.
How does the concentration of glucose in the LIVER compare to the blood?
Hepatocyte (liver) glucose concentration (cytoplasm) is essentially the same as blood serum;
-One of the isoforms of HEXOKINASE (the first enzyme in glycolysis pathway) is GLUCOKINASE (hexokinase IV);
How does Glucokinase regulate glucose in the liver?
-Glucokinase acts at levels BEYOND the LIVER’s energy requirement to convert glucose to glucose 6-phosphate. → Will only allow storage in the liver AFTER the rest of the body is well supplied. Would be pointless to stored in the liver and have to waste energy to pump out and supply the other tissues
What opposing reactions are stimulated by Insulin?
- Both liver and muscle;
- STIMULATE glycogen synthase → synthesis of glycogen);
- INHIBIT glycogen phosphorylase → glycogen breakdown;
- Much of control of enzymes is driven by OPPOSING phophorylations and dephosphorylations = Pairs of enzymes have opposite activities depending on their phosphorylation states:
- *This control is driven by PREDOMIANT hormone, e.g. insulin to glucagon ratio.
How else can the Liver use glucose?
- Liver;
- Lipogenesis – production of glycerol and fatty acids → and synthesis of triacylglycerol (triglycerides);
- If glucose is available and stimulating the release of insulin, glucose will be used FIRST to supply energy; ONLY when there is excess glucose after all cells have been supplied through glycolysis and glycogen stores are resupplied in the liver, then EXCESS glucose can be converted to fatty acids in the liver once insulin is not longer secreted.
What oppositions does Insulin stimulate in ADIPOSE?
- In ADIPOSE tissue, insulin STIMULATES conversion of glucose to glycerol 3-phosphate (liver as well) and maybe conversion of glucose to fatty acids;
- In ADIPOSE, insulin INHIBITS intracellular lipolysis and release of free fatty acids
How does Insulin affect the products of LIPID digestion?
- On the surface of CAPILLARIES near adipose tissue and skeletal muscle, LIPOPROTEIN LIPASE IS activated in response to INSULIN;
- Lipoprotein Lipase – enzyme REMOVES fatty acids from glycerol in chylomicrons (lipoprotein of FED state), and the fatty acids enter the adipose cells and to some extent muscle cells;
- Glycerol remains in the and is taken up by the liver and used for glycogen synthesis or lipogenesis;
- *Muscle and adipose CANNOT phosphorylate glycerol to use;
- Liver takes up chylomicron remnants, repackages and ships out as VLDL.
What are the different effects on WHERE fat is stored?
- Trained athletes have some fat stores in muscle tissue. It appears to be IN THE CELLS because electron micrographs show small fat droplets surrounded by mitochondria in athletes;
- However, some people develop too much fat in NON-ADIPOSE tissue that is large fat droplets and this makes them prone to develop T2DM
How does Insulin affect proteins in Phase 1?
- INCREASE in protein synthesis in the ABSORPTIVE phase in response to insulin;
- Increased 20-25%;
- Balanced by a net protein catabolism in the post-absorptive phase so that under normal feeding patterns the rate of tissue protein catabolism, no net gain or loss of body protein.
When would protein balance not be equal?
- Athletes would be different. → More synthesis and net gain;
- A starvation diet would be different. → More breakdown and catabolism
What is the overall condition of the Fed State, or Phase 1?
In the FED state (absorptive phase), under the control of insulin, metabolic fuels are laid down and EXOGENOUS (dietary) glucose is the major fuel.
How does insulin affect signaling in brain when FED?
Insulin goes to the BRAIN;
- Sends signal to the liver to STOP glucose production via gluconeogenesis;
- Also a satiety effect
What ratio defines Phase 2?
LOW insulin to glucagon ratio:
- FED stated ENDS, POST-absorptive = in-between meal = fasted state or phase
- Conc. of glucose in the portal BLOOD drops and so INSULIN drops. (No glucose, No insulin needed);
- With the drop in insulin, muscle and adipose DON’T take up much glucose and glycogen synthase in liver and muscle is no longer stimulated;
- Muscle and adipose use GLUT4 and are DEPENDENT upon insulin glucose uptake!!
What is now secreted by the Pancreas when glucose is LOW?
- Pancreas responds to the lack of exogenous glucose and fall in blood glucose by secretion of GLUCAGON by APLPHA cells;
- Glycogen Synthase is INHIBITED;
- Glycogen PHOSPHORYLASE is ACTIVATED by Glucagon.
- *Remember that the RATIO is the real key: insulin/glucagon.
Where do the glucose regulators come from in the pancreas?
- Pancreas secretes INSULIN from the beta cells → Uptake glucose;
- Pancreas secretes GLUCAGON from the alpha cells → Release glycogen
How does GLUCAGON stimulate the release of stored glycogen?
- Glucose 6-phosphate from GLYCOGEN in the LIVER is converted to FREE glucose by glucose 6-phosphatase.;
- Glucose can then leave the cells and circulate in the blood for use;
- Muscle glycogen does NOT contribute directly to blood glucose because muscle LACKS glucose 6-phosphatase = keeps for its own energy;
- POST-absorptive, muscle and adipose are using glucose for energy, but at a much REDUCED rate.
What happens in ADIPOSE in response to GLUCAGON?
In adipose tissue, the effect of decreased insulin and increased glucagon results in:
- inhibition of lipogenesis;
- inactivation of lipoprotein lipase;
- activation of hormone-sensitive lipase
How are stored TAGs mobilized for energy use in adipose in response to Glucagon?
- Glucagon stimulates adenylyl cyclase to produce cAMP;
- Activated PKA phosphorylates hormone-sensistive lipase and perilipins on the lipid droplet;
- Adding PO4 allows perilipins to be acted on by the Lipase; - Lipase hydrolyzes TAGs to fatty acids;
- Fatty acids leave the adipocyte and bind albumin in the blood and released as needed;
- Will enter a myocyte (muscle cell) by a specific transporter; oxidized to CO2 and energy is saved in ATP, which can then fueld muscle contraction and other metabolism in the myocute
What are Perilipins?
A family of proteins that restrict access to lipid droplets, preventing untimely lipid mobilization.
How does Epinephrine be involved in low blood glucose?
Epinephrine would also be involved with low blood glucose and during stress situations. → Epinephrine induces the release of glycerol stores in the MUSCLE to provide quick energy in needed stressful situations
Why is Phosphorylation so important in FA mobilization per the Lipase?
-Phosphorylation of hormone sensitive lipase increases its activity 2-3 fold. → Adding PO4 to hormone sensitive lipase INCREAESES activity to metabolize the TAG stores;
Why is Phosphorylation so important in FA mobilization per the Perilipins?
- The BIGGEST effect for increased lipid mobilization occurs with the phosphorylation of the PERILIPINS = 50 fold increase in lipid mobilization;
- Cells with defective perilipin genes have almost no response to the hormonal stimuli because their hormone sensitive lipase does not associate with the lipid droplets.
What are the controls of adipose tissue lipolysis?
- Insulin is the main regulator!;
- Lipolytic stimulus is turned OFF by:
1. Removal of stimulating hormone;
2. Lipase phosphatase;
3. Inhibition of adenylyl cyclase by lots of FFA and adenosine;
4. Inhibition of cAMP by Phosphodiesterase
What results from increase LIPASE activity during Phase 2?
- INCREASED amounts of blood levels of GLYCEROL (a substrate for gluconeogenesis in the liver) and free fatty acids;
- Glycerol can be used to make GLUCOSE (from a non-carb source);
- Fatty acids – beta oxidation for energy production
How are the free fatty acids used for energy during Phase 2?
- FFA are used by skeletal muscle, liver and adipose as their preferred metabolic fuel, so glucose is spared → Beta oxidation;
- In MUSCLE (liver and adipose), the acetyl Co-A formed by beta oxidation INHIBITS pyruvate dehydrogenase to prevent absorptive phase levels of glucose being converted to acetyl-CoA. → Have plenty of acetyl-CoA so DON’T NEED MORE!!;
- Glucose is spared;
- Pyruvate from glucose can be converted to OAA to maintain the activity of the Kreb’s cycle to handle the acetyl-CoA from fatty acid oxidation.
How do Glycolysis and Gluconeogenesis compare?
- Opposing:
- Glycolysis = breakdown of glucose;
- Gluconeogenesis = make glucose from a non-CHO source;
- Three steps are catalyzed by different enzymes = Gluconeogenesis “bypass reactions”;
- Seven steps are catalyzed by the same enzymes
How is Beta-Oxidation in the liver different than muscle?
- The liver has a greater capacity for beta-oxidation than muscle;
- Produces KETONE bodies for use by skeletal muscle, heart muscle and eventually if food is not consumed, the brain
How does the plasma concentration of Glucose change with the phases?
- Fed = 5.5
- 40 hrs starvation (Int) = 3.6
- 7 days starvation = 3.5
How does the plasma concentration of FFAs change with the phases?
- Fed =0.3
- 40 hrs starvation (Int) = 1.15
- 1.19
- 7 days starvation = 1.39
How does the plasma concentration of Ketone bodies change with the phases?
- Fed = Negligible
- 40 hrs starvation (Int) = 2.9
- 7 days starvation = 4.5
What is Pyruvate Kinase?
- Pyruvate kinase catalyzes phosphoenolpyruvate (PEP) to pyruvate;
- Needed for gluconeogenesis to synthesize glucose when needed to raise blood levels → Glucose created from a NON-CHO source!!
What is AMP-activated protein kinase (AMPK)?
- Controls cellular ENERGY homeostasis;
- Found in the liver, brain, and skeletal muscles → NO UNNECESSARY synthesis;
- Net effect of AMPK activation is stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic beta-cells
What is the role of AMP-activated protein kinase (AMPK) in regulating ATP metabolism?
- ADP produced in SYNTHEIC reactions is converted to AMP by adenylate kinase;
- AMP activates AMPK, which regulates anabolic and catabolic pathways by PHOSPHORYLATION of key enzymes
What is Adiponectin?
Produced when fat stores SHRINK;
- Telling you that you need MORE fat;
- Stimulates AMPK
What is Leptin?
- Also stimulates AMP-activated protein kinase (AMPK) in liver and muscle;
- INHIBITS fatty acid synthesis and stimulates fatty acid oxidation. → Leptin tells the body to stop consuming fats;
- My guess is that this may be a long term effect of high leptin and not short term with meal. Insulin may be stronger signal for fatty acid synthesis in short term
- Only leptin and insulin are known to act as adiposity signals that signify the amount of body fat → Have leptin circulating in proportion with body fat
What are the possible metabolic pathways for Glucose-6-PO4?
- Glycolysis for glucose to convert to pyruvate and yield Acetyl-CoA;
- If not needed for glucose, stored as glycogen;
- Or can enter into pentose phosphate pathway generating NADPH . This pathway also produces D-ribose 5-phosphate, a precursor for nucleotide biosynthesis
What can happen to the Acetyl-CoA generated from G6P?
- Acetyl-CoA can be oxidized by citric acid cycle (with electron transfer and oxidative phosphorylation)
- Or Acetyl-CoA can serve as precursor of fatty acids, incorporated into TAGs and phospholipids, or converted into cholesterol
What is the NADPH used for when generated from G6P?
- REDUCING power for bio- synthesis of fatty acids and cholesterol;
- Also detoxification and elimination of many drugs and other xenobiotics metabolized by the liver
What metabolic routes can AMINO ACIDS that enter the hepatocytes after digestion or protein degradation?
- protein synthesis → Biosynthesis of most plasma proteins and liver constantly renewing its own proteins;
- pass into blood to other organs for protein synthesis
- precursors for bio-synthesis of nucleotides, hormones and other nitrogenous compounds in liver and other tissues;
if NOT NEEDED then,
4a. transaminated or deaminated to yield PYRUVATE and citric acid cycle intermediates;
4b. ammonia released is converted to urea; - pyruvate and citric acid cycle intermediates converted to GLUCOSE (gluconeogenesis) and glycogen;
- converted to acetyl-CoA
What can happen to the Acetyl-CoA created from amino acids in the liver?
- oxidized via citric acid cycle and electrons to ETC coupled to oxidative phosphorylation;
- converted to fatty acids or cholesterol for transport to other tissues via VLDL
What are the possible metabolic routes of FATTY ACIDS in the liver?
- Some converted to liver lipids;
- Under most circumstances (except absorptive phase), fatty acids are primary oxidative fuel in liver. → Fatty acids converted to acetyl-CoA and reducing compound, NADH; And Acetyl- CoA is further oxidized via citric acid cycle.
- Some converted to phospholipids and TAGs for VLDL;
- Some become bound to serum ALBUMIN to go to other tissues – heart, skeletal muscle
What happens to EXCESS Acetyl-CoA in the liver from Beta-Oxidation of FFAs?
-Excess acetyl-CoA from β-oxidation and not required by the liver is converted by the liver to KETONE bodies;
-These circulate in the blood to other tissues to be used as fuel for the TCA;
-Ketone bodies may be regarded as a transport form of acetyl groups. → They can supply a significant fraction of energy in some extrahepatic tissues:
•up to 1/3 in HEART and as much as 60 to 70% in BRAIN during prolonged fasting
How are Insulin and Leptin related?
- Insulin and leptin both INHIBIT food intake;
- Make sense because when insulin becomes elevated it means nutrients in blood;
- Something has to cause us to STOP eating – insulin and leptin;
- But insulin also promotes FAT STORAGE;
- Insulin sensitivity is the key!
What is the Lipostatic Theory?
- Leptin vs. adiponectin → Too much leptin for most overweight and obese;
- Homeostatic theory of hunger according to which the brain monitors the level in the blood of free fatty acids that result from the metabolism of fat. A low level indicates that fat has not recently been metabolized, and this leads to a lessening of hunger, whereas a high level indicates recent fat metabolism and increases hunger
How does a person gain weight?
- A person must be in POSITIVE energy balance to become overweight, obese or gain healthy weight → Consuming MORE than is BURNED;
- It is NOT positive energy balance if you normally consume 2000 kcal and expend 2000 kcal, then start consuming 2100 kcal and adapt and expend 2100 kcal
What work was done by Jules Hirsch?
- At Rockefeller University, 1995;
- Published a paper in which they UNDERFED people by 10% of the energy they needed to maintain their weight → they SLOWED their metabolism and maintained their weight;
- Also OVERFED people by 10% of the energy they needed to maintain their weight → they INCEAESED their metabolism and maintained their weight
- *Brought back the Set Point Hypothesis
What is the Set Point Hypothesis?
A deterministic theory that explains the interplay of appetite and other factors (fats and carbohydrates in weight control) → the brain is constantly adjusting the metabolic rate and manipulating behavior to maintain a target weight;
-Had fallen out of favor because scientists had fed people fairly large increases in energy and they gained weight; so it appears that the set point hypothesis has LIMITS → obesigenic environment
How does a “Western” high fat diet compare to the Mediterranean diet?
- Normally think of is a diet high in fat (usually high saturated), high sugar, high refined complex carb, high energy density;
- Mediterranean diets are high fat diets, but LOW in energy b/c they contain whole grains, fruits and vegetables; fiber and water dilute the energy density; and the fat is from PLANT sources → PUFA fats that are much healthier and beneficial than saturated animal fats!
What are the 3 energy brakes?
- Protein,
- Fiber,
- Water
- FIber and water DILUTE the energy density and may also promote satiety;
- PROTEIN is the most SATIATING of the three energy nutrients because there are NO STORES like with carbohydrate and fat
What did Walter Willet say about carbs and fat?
-Came to LSU in 2000;
-It is NOT the amount of CHO that is important, but the TYPE → he said the same for FAT;
Key for Willett was carbohydrates with low glycemic load and the key for fat was plant oils – high in unsaturated fatty acids
-(came to LSU after Bill Lands) stated that it didn’t matter as long as consumed unsaturated fatty acids (EB 2013 may have resolved)
What did Gary Taubes say about carbs and fat?
-“never met a carb he liked” (author of “what if it’s all a big fat lie”);
-He pointed out like Hirsch did in 1995 that:
oE retained = E intake - E expended
oE intake and E expended are NOT INDEPENDENT
*The behavior of eating less or expending more energy are not operating in a vacuum, but are LINKED → so if eat less, will expend less; and if expend more will eat more
What different groups did Taube present at Pennington?
- Presented people that:
1. Ate lower energy, but expended less;
2. People that expended a lot of energy at high energy-expending jobs, but were still obese because they ate a lot more energy
3. He presented people with lipodystrophy in upper body or lower body, but obese in the other half
What is Lipodystrophy?
-Medical condition characterized by abnormal or degenerative conditions of the body’s adipose tissue; loss of fat from one area → Characterized by a lack of circulating Leptin
