Integration of Metabolism

1. Integration of Metabolism • Interconnection of pathways • Metabolic profile of organs • Food intake, starvation and obesity • Fuel choice during exercise • Ethanol alters energy metabolism • Hormonal regulation of metabolism

2. Connection of Pathways • ATP is the universal currency of energy • ATP is generated by oxidation of glucose, fatty acids, and amino acids ; common intermediate -> acetyl CoA ; electron carrier -> NADH and FADH2 • NADPH is major electron donor in reductive biosynthesis • Biomolecules are constructed from a small set of building blocks • Synthesis and degradation pathways almost always separated -> Compartmentation !!!

3. Key Junctions between Pathways

4. Metabolic Profile of Organs

5. 1. Metabolic Profile of Brain Glucose is fuel for human brain -> consumes 120g/day -> 60-70 % of utilization of glucose in starvation -> ketone bodies can replace glucose

6. 2. Metabolic Profile of Muscles Major fuels are glucose, fatty acids, and ketone bodies -> has a large storage of glycogen -> about ¾ of all glycogen stored in muscles -> glucose is preferred fuel for burst of activity -> production of lactate (anaerobe) -> fatty acid major fuel in resting muscles and in heart muscle (aerobe)

7. 3. Metabolic Profile of Adiposite tissue Triacylglycerols are stored in tissue -> enormous reservoir of metabolic fuel -> needs glucose to synthesis TAG; -> glucose level determines if fatty acids are released into blood

8. 4. Metabolic Profile of Kidney Production of urine -> secretion of waste products Blood plasma is filtered (60 X per day) -> water and glucose reabsorbed -> during starvation -> important site of gluconeogenesis (1/2 of blood glucose)

9. 5. Metabolic Profile of the Liver (Glucose) Essential for providing fuel to brain, muscle, other organs -> most compounds absorpt by diet -> pass through liver -> regulates metabolites in blood

10. Metabolic Activities of the Liver (Amino Acids) α-Ketoacids (derived from amino acid degradation) -> liver’s own fuel

11. Metabolic Activities of the Liver (Fatty Acids) cannot use acetoacetate as fuel -> almost no transferase to generate acetyl-CoA

12. Food Intake, Starvation, and Obesity • Normal Starved-Fed Cycle: • Postabsorptive state -> after a meal • Early fasting state -> during the night • Refed state -> after breakfast • -> Major goal is to maintain blood-glucose level!

13. Blood-Glucose

14. Postabsorptive state Glucose + Amino acids -> transport from intestine to blood Dietary lipids transported -> lymphatic system -> blood Glucose stimulates -> secretion of insulin Insulin: -> signals fed state -> stimulates storage of fuels and synthesis of proteins -> high level -> glucose enters muscle + adipose tissue (synthesis of TAG) -> stimulates glycogen synthesis in muscle + liver -> suppresses gluconeogenesis by the liver -> accelerates glycolysis in liver -> increases synthesis of fatty acids -> accelerates uptake of blood glucose into liver -> glucose 6-phosphate more rapidly formed than level of blood glucose rises -> built up of glycogen stores

15. Insulin Secretion –Stimulated by Glucose Uptake

16. Postabsorptive State -> after a Meal

17. 2. Early Fasting State Blood-glucose level drops after several hours after the meal -> decrease in insulin secretion -> rise in glucagon secretion Low blood-glucose level -> stimulates glucagon secretion of α-cells of the pancreas Glucagon: -> signals starved state -> mobilizes glycogen stores (break down) -> inhibits glycogen synthesis -> main target organ is liver -> inhibits fatty acid synthesis -> stimulates gluconeogenesis in liver -> large amount of glucose in liver released to blood stream -> maintain blood-glucose level Muscle + Liver use fatty acids as fuel when blood-glucose level drops

18. Early Fasting State -> During the Night

19. 3. Refed State Fat is processed in same way as normal fed state First -> Liver does not absorb glucose from blood (diet) Liver still synthesizes glucose to refill liver’s glycogen stores When liver has refilled glycogen stores + blood-glucose level still rises -> liver synthesizes fatty acids from excess glucose

20. Prolonged Starvation Well-fed 70 kg human ->fuel reserves about 161,000 kcal -> energy needed for a 24 h period -> 1600 kcal - 6000 kcal -> sufficient reserves for starvation up to 1 – 3 months -> however glucose reserves are exhausted in 1 day Even under starvation -> blood-glucose level must be above 40 mg/100 ml

21. Prolonged Starvation First priority -> provide sufficient glucose to brain and other tissues that are dependent on it Second priority -> preserve protein -> shift from utilization of glucose to utilization of fatty acids + ketone bodies -> mobilization of TAG in adipose tissues + gluconeogenesis by liver -> muscle shift from glucose to fatty acids as fuel After 3 days of starvation -> liver forms large amounts of ketone bodies (shortage of oxaloacetate) -> released into blood -> brain and heart start to use ketone bodies as fuel After several weeks of starvation -> ketone bodies major fuel of brain After depletion of TAG stores -> proteins degradation accelerates -> death due to loss of heart, liver, and kidney function

23. Mobilization at Starvation Also at not treated diabetes

24. Diabetes Mellitus – Insulin Insufficiency • Characterized by: -> high blood-glucose level • -> Glucose overproduced by liver • -> glucose underutilized by other organs • -> shift in fuel usage from carbohydrates to fats -> keton bodies (shortage of oxaloacetate) • -> high level of keton bodies -> kidney cannot balance pH any more -> lowered pH in blood and dehydration -> coma • Type I diabetes: insulin-dependent diabetes (requires insulin to live) • caused by autoimmune destruction of β-cells • begins before age 20 • -> insulin absent -> glycagon present • -> person in biochemical starvation mode + high blood-glucose level • -> entry of glucose into cells is blocked • -> glucose excreted into urine -> also water excreted -> feel hungry + thirsty • Type II diabetes: insulin-independent diabetes • have a normal-high level of insulin in blood -> unresponsive to hormone • develops in middle-aged, obese people

25. Obesity Mouse lacking leptin or Leptin receptor In the U. S. -> about 70% of adults are suffering from obesity (2009) Risk factor for: Diabetes + Cardiovascular diseases Cause of Obesity -> more food consumed than needed -> storage of energy as fat Two important signals for “caloric homeostasis” and “appetite” control -> insulin + leptin

27. The Role of Leptin and Insulin on Weight Control Leptin is a hormone that is produced in direct proportion to fat mass (adipocytes)

28. High Levels of Leptin and Insulin are a Signal for “caloric homeostasis”

29. Obese People Produce More Heat • Body can deal with excess calories: • Storage • Extra exercise • Production of heat

30. Fuel Choice During Exercise Fuels used are different in: -> sprinting -> anaerobic exercise -> lactate -> distance running -> aerobic exercise -> CO2 ATP directly powers myosin -> responsible for muscle contraction -> movement -> amount of ATP in muscle is small -> velocity depended on rate of ATP production -> creatine phosphate generates ATP under intense muscle contractions for 5-6 s Sprint: powered by ATP, creatine phosphate, and anaerobic glycolysis of glycogen -> lactate Medium length sprint: complete oxidation of muscle glycogen -> CO2 (production slower) -> velocity lower Marathon: complete oxidation of muscle and liver glycogen -> CO2 and complete oxidation of fatty acids from adipose tissues ->CO2 (ATP is generated even slower) Low blood-glucose level ->high glucagon/insulin ratio -> mobilization of fatty acids

33. Ethanol Alters Energy Metabolism in Liver • Consumption of EtOH in excess -> number of health problems • EtOH has to be metabolised: • EtOH + NAD+ -> Acetaldehyde + NADH (alcohol dehydrogenase, in cytoplasm) • Acetaldehyde + NAD+ -> Acetate + NADH (aldehyde dehydrogenase, in mitochondria) • -> EtOH consumption leads to accumulation of NADH • High level NADH causes: • -> inhibition of gluconeogenesis (prevent oxidation of lactate to pyruvate) -> lactate accumulates • -> inhibits fatty acid oxidation -> stimulates fatty acid synthesis in liver -> TAG accumulates -> fatty liver • -> inhibition of citric acid cycle • Ethanol inducible microsomal ethanol-oxidizing system (MEOS) -> P450 dependent pathway -> generates free oxygen radicals -> damages tissues • Acetate is converted into Acetyl CoA -> processing of Acetyl CoA by citric acid cycle is blocked by high amounts of NADH -> Ketone bodies are generated and released into the blood -> further drop of pH • Processing of acetate in liver inefficient -> high level of acetaldehyde in liver -> reacts with proteins -> become inactive -> damage liver -> cell death • Liver damage in 3 stages: Development of Fatty Liver -> alcoholic hepatitis (groups of cells die) -> cirrhosis (no convertion of Ammonium -> urea)

34. Hormonal Regulation of Metabolism

35. Action of Different Hormones

36. Hormone signals and their target tissues

37. Cascade of Hormone Release Following Central Nervous System Input to the Hypothalamus • Cortisol: • Signals stress !!! • signals low blood glucose -> counterbalances insulin

38. Epinephrine -> Signals Stress -> requires activity -> “Fighting or Fleeing”