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

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 !!!

Key Junctions between Pathways

Metabolic Profile of Organs

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

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)

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

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)

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

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

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

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!

Blood-Glucose

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

Insulin Secretion –Stimulated by Glucose Uptake

Postabsorptive State -> after a Meal

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

Early Fasting State -> During the Night

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

-> energy needed for a 24 h period -> 1600 kcal - 6000 kcal 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

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

Mobilization at Starvation Also at not treated diabetes

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

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

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

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

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

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

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)

Hormonal Regulation of Metabolism

Action of Different Hormones

Hormone signals and their target tissues

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

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