Metabolic Integration PDF

High glucose → Insulin release...

High glucose → Insulin release **Post-Prandial State (Fed State)** Behavioral changes: Reduced activity, body Glucose uptake, glycogen synthesis, lipid temperature storage Structural adaptation: GI tract atrophy in Glycogen depletion prolonged fasting 8. Adaptation in Animals 1. Metabolic Specialization of Organs **Fasting State** Shift to gluconeogenesis and fat mobilization Fasting advantage: Conserving energy reserves during food scarcity Ketone bodies become primary fuel for the brain **Starvation State (Prolonged Fasting)** Conservation of muscle proteins Glycogenolysis (initial fasting), and then gluconeogenesis (extended) Primary fuel: The brain primarily uses glucose as its energy source in both the Fatty acid oxidation → ketone body production **Liver** fed and fasting states because fatty acids cannot cross the blood-brain barrier **Brain** Urea cycle adaptation (decreased in prolonged Starvation: During prolonged fasting (starvation), the liver synthesizes ketone fasting) bodies (e.g., β-hydroxybutyrate) from fatty acids. These ketone bodies cross the blood-brain barrier and serve as an alternative fuel source. Hormone-sensitive lipase activation → fatty acid release Muscle stores glycogen for local use, especially during intense exercise. **Adipose Tissue** Unlike liver glycogen, muscle glycogen is not available for blood glucose Glycerol released as a gluconeogenic substrate regulation because skeletal muscle lacks glucose-6-phosphatase. 7. Tissue-Specific Adaptations to Low insulin → reduced glucose uptake Fasting Heavy Physical Exercise (Anaerobic): Muscles use phosphocreatine (PCr) and ATP stores initially. Phosphocreatine donates a phosphate group to ADP to rapidly regenerate ATP. When these resources are During heavy exercise, muscle initially uses phosphocreatine for rapid ATP depleted, anaerobic glycolysis breaks down glycogen to lactate, providing ATP without needing oxygen. Switch to fatty acids, ketone bodies for fuel **Skeletal Muscle** production, then shifts to anaerobic glycolysis (converting glucose to **Skeletal Muscle** lactate). During prolonged exercise, aerobic metabolism predominates, utilizing fatty acids and, if necessary, ketone bodies Prolonged Exercise (Aerobic): For sustained activities, muscle cells rely on aerobic metabolism. Fatty acids are Protein degradation (amino acids for the primary fuel source, as they yield high amounts of ATP when oxidized in the mitochondria. Ketone bodies gluconeogenesis) also become viable fuel during extended fasting or depletion of glycogen stores. Initially dependent on glucose Muscle cells do not respond to glucagon but are highly responsive to **Brain** epinephrine, which promotes glycogen breakdown for quick energy Prolonged fasting: Gradual adaptation to ketone bodies, sparing glucose Energy Demand: The heart is almost exclusively reliant on aerobic metabolism, due to its high **Heart Muscle** and constant demand for ATP. It has an extensive mitochondrial network to sustain this Decrease in Glucose and Insulin, Increase in energy production. Glucagon: Low blood glucose and insulin levels trigger glucagon release, which initiates Adipose tissue stores triglycerides (TG) derived from dietary fats or glycogenolysis and gluconeogenesis in the liver 2. Organ-Specific Metabolism and synthesized from glucose via lipogenesis. Insulin promotes TG storage by to maintain blood glucose levels. Adaptations activating lipoprotein lipase Mobilization of Stored Fats: Adipose tissue releases fatty acids, which peripheral tissues like Glucagon ↑ → liver glycogenolysis, When energy demand increases, hormone-sensitive lipase is activated, **Gluconeogenic Phase (2-3 days)** **Adipose Tissue** breaking down TG into free fatty acids and glycerol. These fatty acids are muscle use for energy, sparing glucose for gluconeogenesis (lactate, alanine, glycerol) essential organs (brain, red blood cells). released into the bloodstream to supply energy for other tissues Gluconeogenesis Activation: The liver and kidney Adipose tissue activity is highly insulin-dependent use substrates like glycerol (from fat), alanine (from muscle), and lactate (from anaerobic metabolism) to produce glucose, ensuring that 6. Fasting Phases and Adaptations Metabolic Integration The liver controls blood glucose levels through glycogen storage and gluconeogenesis. In the fed state, insulin prompts glycogen synthesis. During fasting, vital organs continue receiving adequate energy. (As fasting continues, several metabolic changes occur:) and Fasting - Mind glucagon activates glycogenolysis and gluconeogenesis. **Muscle Protein Sparing:** Reduced reliance on muscle breakdown Map Enzyme: Glucose-6-phosphatase (releases glucose) **Liver** **Fatty Acid Oxidation**: Adipose tissue mobilizes stored fat, Starvation: Ketone body production and the liver oxidizes these fatty acids to produce energy (ketogenesis) Normal plasma ketone levels are around 0.2 mM, but during starvation, they can rise to 6-7 mM. **Prolonged Fasting / Starvation Adaptations** Degradation (porphyrins, nitrogen bases), iron **Ketogenesis**: Ketone bodies supply energy, Additional functions: This high level of ketones reduces the brain’s glucose requirement, sparing 70-80g of glucose storage, bile synthesis, detoxification especially to brain per day. The kidneys are essential for excreting metabolic waste and maintaining **Decreased Metabolic Rate**: The body reduces energy acid-base balance. They filter blood, removing nitrogenous wastes (such as expenditure by lowering thyroid hormone (T3) levels, urea) and other metabolic byproducts conserving both protein and fat reserves In the renal cortex (outer layer), aerobic metabolism dominates, while the **Kidney** renal medulla (inner layer) relies more on anaerobic metabolism. Insulin (secreted by the pancreas in response to During prolonged fasting, the kidney supports gluconeogenesis, high blood glucose) is anabolic: contributing to blood glucose regulation alongside the liver Promotes glucose uptake by tissues (especially muscle and adipose tissue). High blood glucose → promotes glucose Stimulates glycogen synthesis in the liver and uptake, glycogen & fat storage muscles. Fosters fatty acid synthesis in adipose tissue and **Absorptive/Postprandial state** (2-4 hours High insulin, anabolic processes, glucose storage the liver, storing excess energy as triglycerides. after meal) **Insulin** Encourages protein synthesis in muscle tissue. **Post-Absorptive** (4-12 hours post-meal) Glucose from glycogen, glucagon increases Anabolic: Glycogen, triglyceride, protein synthesis Initial (12-48 hours): Glycogen depletion, gluconeogenesis starts Glucagon (secreted when blood glucose levels 3. Metabolic States **Fasting** drop) is catabolic: Extended (2-10 days): Increased fat mobilization, Stimulates glycogen breakdown (glycogenolysis) muscle protein breakdown in the liver, releasing glucose into the blood. Low blood glucose → stimulates glycogen Promotes gluconeogenesis in the liver, helping breakdown, gluconeogenesis Energy from fatty acids, ketone bodies maintain blood glucose. **Starvation** (10+ days) Encourages lipolysis in adipose tissue, increasing **Glucagon** Muscle sparing adaptations (lower metabolic fatty acid availability for energy. rate) Catabolic: Breaks down glycogen, triglycerides Adrenaline (Epinephrine): Blood glucose and glycogen stores offer limited energy. Free glucose in blood and extracellular fluid (~12g) can only sustain the brain for a few hours. Hepatic glycogen Released in response to stress or low blood (~50-120g) provides glucose for roughly 24 hours under resting conditions. glucose, adrenaline acts as a rapid-response **Carbohydrates** hormone. ~24-hour fuel supply Increases blood glucose by stimulating Stress/low glucose → rapid mobilization of glycogenolysis in the liver and muscle. energy Promotes lipolysis in adipose tissue, making fatty 5. Hormonal Regulation Lipid stores in adipose tissue provide a more substantial and long- acids available for muscle fuel. lasting energy reserve, with the potential to sustain life for over 50 Enhances the body’s ability to respond to sudden days, depending on fat reserves and metabolic rate energy demands (fight-or-flight response). **Adrenaline** 4. Energy Storage and Utilization **Lipids** Primary fuel source in extended fasting Increases glycogenolysis (liver, muscle), lipolysis While proteins can provide energy, they are primarily structural and functional. In extreme (adipose) starvation, protein degradation impacts muscle function, which can lead to weakness, compromised immunity, and eventually death. Cortisol is a long-term stress hormone with **Proteins** several metabolic effects: Extreme starvation: Muscle breakdown → amino Inhibits peripheral glucose utilization, leaving acids for gluconeogenesis glucose available for the central nervous system (CNS), especially under prolonged fasting. In high concentrations, cortisol induces insulin resistance by reducing glucose uptake in muscles and adipose tissue. Long-term stress → shifts glucose to CNS, Stimulates gluconeogenesis in the liver and promotes gluconeogenesis promotes protein breakdown in muscle, increasing amino acid availability for glucose production. Cortisol also influences body composition, promoting fat accumulation around the abdomen, trunk, and face. **Cortisol** Inhibits glucose uptake (muscle, adipose), promotes protein breakdown Excess effects: Hyperglycemia, insulin resistance, fat redistribution, immunosuppression