⚗️Biological Chemistry II Unit 8 – Metabolic Adaptation & Integration

Key Concepts

• Metabolism involves complex networks of biochemical reactions that enable organisms to maintain homeostasis and respond to changing environments
• Metabolic pathways are series of enzymatic reactions that transform substrates into products, often regulated by allosteric enzymes and hormones
• Catabolism breaks down complex molecules to release energy (ATP) while anabolism synthesizes complex molecules from simpler precursors, requiring energy input
• Metabolic integration coordinates the activities of different organs and tissues to maintain overall energy balance and homeostasis in the body
• Hormones (insulin, glucagon, cortisol) play crucial roles in regulating metabolic processes, such as glucose and lipid metabolism, in response to physiological conditions
• Metabolic adaptations enable organisms to adjust their metabolism in response to changes in diet, exercise, stress, and other physiological states
  • Fasting induces gluconeogenesis and ketogenesis to maintain blood glucose levels and provide alternative fuel sources for the brain and other tissues
  • Exercise enhances glucose uptake by muscles and stimulates mitochondrial biogenesis to improve oxidative capacity and endurance
• Metabolic disorders (diabetes, obesity) arise from dysregulation of metabolic pathways and can lead to serious health consequences, requiring therapeutic interventions and lifestyle modifications

Metabolic Pathways Overview

• Glycolysis is a central metabolic pathway that breaks down glucose into pyruvate, generating ATP and NADH in the cytosol
  • Key enzymes in glycolysis include hexokinase, phosphofructokinase (PFK), and pyruvate kinase, which are regulated by allosteric effectors and hormones
  • PFK is a key regulatory enzyme that catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1,6-bisphosphate, stimulated by AMP and inhibited by ATP and citrate
• Citric acid cycle (TCA cycle) is a series of reactions in the mitochondrial matrix that oxidizes acetyl-CoA derived from carbohydrates, fats, and proteins to generate NADH, FADH2, and ATP
  • Pyruvate dehydrogenase complex catalyzes the oxidative decarboxylation of pyruvate to form acetyl-CoA, linking glycolysis to the TCA cycle
  • Key enzymes in the TCA cycle include citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase, which are regulated by substrate availability and energy status
• Oxidative phosphorylation is the process by which electrons from NADH and FADH2 are transferred through the electron transport chain (ETC) to generate a proton gradient that drives ATP synthesis via ATP synthase
  • ETC consists of four protein complexes (I, II, III, IV) embedded in the inner mitochondrial membrane that transfer electrons from NADH and FADH2 to oxygen, the final electron acceptor
  • Chemiosmotic theory explains how the proton gradient generated by the ETC is coupled to ATP synthesis, with the proton motive force driving the rotation of ATP synthase
• Fatty acid oxidation (β-oxidation) is the process by which fatty acids are broken down in the mitochondria to generate acetyl-CoA, which can enter the TCA cycle for further oxidation
  • Carnitine palmitoyltransferase I (CPT-I) is a key regulatory enzyme that controls the entry of long-chain fatty acids into the mitochondria, inhibited by malonyl-CoA produced during fatty acid synthesis
• Amino acid metabolism involves the breakdown of amino acids to generate energy or the synthesis of new amino acids for protein production
  • Transamination reactions transfer the amino group from an amino acid to an α-ketoacid, forming a new amino acid and α-ketoacid
  • Glucogenic amino acids can be converted to glucose via gluconeogenesis, while ketogenic amino acids can be converted to ketone bodies or acetyl-CoA

Energy Production and Regulation

• ATP is the primary energy currency in biological systems, used to power various cellular processes such as biosynthesis, transport, and mechanical work
• ATP is produced through substrate-level phosphorylation (glycolysis, TCA cycle) and oxidative phosphorylation (ETC and ATP synthase)
  • Substrate-level phosphorylation directly transfers a phosphate group from a high-energy intermediate to ADP, forming ATP
  • Oxidative phosphorylation generates the majority of ATP in aerobic organisms, with each NADH yielding ~2.5 ATP and each FADH2 yielding ~1.5 ATP
• Energy charge, defined as $\frac{[ATP] + 0.5[ADP]}{[ATP] + [ADP] + [AMP]}$, is a key parameter that reflects the energy status of a cell and regulates metabolic pathways
  • High energy charge (>0.9) indicates sufficient ATP and inhibits catabolic pathways while stimulating anabolic pathways
  • Low energy charge (<0.7) indicates ATP depletion and stimulates catabolic pathways while inhibiting anabolic pathways
• AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis that is activated by increased AMP:ATP ratio, stimulating catabolic pathways and inhibiting anabolic pathways
  • AMPK phosphorylates key metabolic enzymes such as PFK, glycogen synthase, and acetyl-CoA carboxylase to regulate their activities
• Sirtuins are a family of NAD+-dependent deacetylases that link cellular energy status to the regulation of metabolism, stress resistance, and longevity
  • Sirtuins are activated by increased NAD+:NADH ratio, which occurs during calorie restriction, exercise, and fasting
  • SIRT1, the best-characterized sirtuin, deacetylates transcription factors (PGC-1α, FOXO) and enzymes (acetyl-CoA synthetase) to enhance mitochondrial biogenesis, fatty acid oxidation, and stress resistance

Hormonal Control of Metabolism

• Insulin is a peptide hormone secreted by pancreatic β-cells in response to elevated blood glucose levels, promoting glucose uptake and utilization by tissues
  • Insulin binds to its receptor on target cells, activating a signaling cascade that involves phosphorylation of insulin receptor substrate (IRS) proteins and activation of PI3K/Akt pathway
  • Insulin stimulates translocation of glucose transporter GLUT4 to the plasma membrane in muscle and adipose tissue, enhancing glucose uptake
  • Insulin promotes glycogen synthesis, lipogenesis, and protein synthesis while inhibiting gluconeogenesis, lipolysis, and protein breakdown
• Glucagon is a peptide hormone secreted by pancreatic α-cells in response to low blood glucose levels, promoting glucose production and release by the liver
  • Glucagon binds to its receptor on hepatocytes, activating adenylate cyclase and increasing cAMP levels, which activates protein kinase A (PKA)
  • PKA phosphorylates key enzymes in glycogen breakdown (glycogen phosphorylase), gluconeogenesis (phosphoenolpyruvate carboxykinase), and fatty acid oxidation (acetyl-CoA carboxylase) to increase their activities
• Cortisol is a steroid hormone secreted by the adrenal cortex in response to stress, with wide-ranging effects on metabolism, inflammation, and immune function
  • Cortisol binds to glucocorticoid receptors in the cytoplasm, which then translocate to the nucleus and regulate gene expression
  • Cortisol promotes gluconeogenesis, lipolysis, and protein catabolism to increase blood glucose levels and provide energy substrates during stress
  • Chronic elevation of cortisol (Cushing's syndrome) can lead to insulin resistance, obesity, and muscle wasting
• Thyroid hormones (T3 and T4) are produced by the thyroid gland and play crucial roles in regulating basal metabolic rate, growth, and development
  • Thyroid hormones bind to nuclear receptors and regulate gene expression of enzymes involved in glucose and lipid metabolism, mitochondrial function, and thermogenesis
  • Hyperthyroidism (excess thyroid hormones) increases basal metabolic rate, leading to weight loss, heat intolerance, and tachycardia, while hypothyroidism (deficiency of thyroid hormones) decreases basal metabolic rate, causing weight gain, cold intolerance, and bradycardia
• Adipokines are hormones secreted by adipose tissue that regulate energy balance, insulin sensitivity, and inflammation
  • Leptin is an adipokine that acts on the hypothalamus to suppress appetite and increase energy expenditure, with deficiency leading to severe obesity (ob/ob mice)
  • Adiponectin is an adipokine that enhances insulin sensitivity and has anti-inflammatory properties, with reduced levels associated with obesity and type 2 diabetes

Metabolic Integration Between Organs

• Liver plays a central role in metabolic integration, regulating glucose, lipid, and protein metabolism in response to hormonal and nutritional cues
  • During the fed state, liver takes up glucose and converts it to glycogen (glycogenesis) and fatty acids (de novo lipogenesis), which are stored or exported to other tissues
  • During fasting, liver breaks down glycogen (glycogenolysis) and synthesizes glucose from non-carbohydrate precursors (gluconeogenesis) to maintain blood glucose levels, while also producing ketone bodies from fatty acids for use by the brain and other tissues
• Skeletal muscle is a major site of glucose disposal and energy expenditure, accounting for ~80% of insulin-stimulated glucose uptake
  • During exercise, muscle contraction stimulates translocation of GLUT4 to the plasma membrane, enhancing glucose uptake independently of insulin
  • Exercise also activates AMPK, which promotes fatty acid oxidation and mitochondrial biogenesis to improve insulin sensitivity and metabolic flexibility
• Adipose tissue stores energy in the form of triglycerides and releases fatty acids and glycerol during fasting to provide fuel for other tissues
  • White adipose tissue (WAT) is the primary site of energy storage, with insulin promoting lipogenesis and inhibiting lipolysis, while glucagon and catecholamines stimulate lipolysis during fasting
  • Brown adipose tissue (BAT) is specialized for thermogenesis, expressing uncoupling protein 1 (UCP1) which dissipates the proton gradient in the ETC to generate heat instead of ATP
• Brain relies primarily on glucose for energy production, with tight regulation of blood glucose levels being critical for normal brain function
  • During prolonged fasting, brain can adapt to use ketone bodies produced by the liver as an alternative fuel source, sparing glucose for other tissues
  • Hypothalamus plays a key role in regulating energy balance and metabolism, integrating signals from hormones (insulin, leptin) and nutrients to control appetite and energy expenditure
• Gut-brain axis involves bidirectional communication between the gastrointestinal tract and the central nervous system, regulating food intake, digestion, and metabolism
  • Gut hormones such as ghrelin (hunger hormone) and peptide YY (satiety hormone) are released by enteroendocrine cells in response to food intake and signal to the hypothalamus to regulate appetite
  • Gut microbiota influences host metabolism by fermenting indigestible carbohydrates to produce short-chain fatty acids (acetate, propionate, butyrate), which serve as energy substrates and signaling molecules

Adaptations to Different Physiological States

• Fasting induces a coordinated metabolic response to conserve glucose and provide alternative fuel sources for the brain and other tissues
  • Decreased insulin and increased glucagon levels stimulate glycogenolysis and gluconeogenesis in the liver to maintain blood glucose levels
  • Lipolysis in adipose tissue releases fatty acids, which are oxidized by the liver to produce ketone bodies (β-hydroxybutyrate, acetoacetate) that can cross the blood-brain barrier and serve as an energy source for the brain
  • Protein catabolism in muscle provides amino acids for gluconeogenesis, with branched-chain amino acids (leucine, isoleucine, valine) being preferentially oxidized for energy
• Exercise elicits acute and chronic adaptations in skeletal muscle and other tissues to improve metabolic efficiency and performance
  • Acute effects of exercise include increased glucose uptake by muscle, enhanced fatty acid oxidation, and activation of AMPK and other signaling pathways that regulate metabolism
  • Chronic adaptations to endurance exercise (aerobic training) include increased mitochondrial biogenesis, capillary density, and oxidative enzyme activity in muscle, improving fatigue resistance and metabolic flexibility
  • Resistance exercise (strength training) stimulates muscle protein synthesis and hypertrophy, increasing muscle mass and strength
• Pregnancy induces metabolic adaptations to support fetal growth and development, with increased insulin resistance and nutrient partitioning towards the fetus
  • Early pregnancy is characterized by increased maternal fat accumulation and insulin sensitivity, providing energy reserves for later stages of pregnancy and lactation
  • Late pregnancy is associated with increased insulin resistance, lipolysis, and ketogenesis, ensuring adequate glucose and nutrient supply to the growing fetus
  • Gestational diabetes mellitus (GDM) occurs when maternal insulin resistance exceeds the capacity of pancreatic β-cells to compensate, leading to hyperglycemia and adverse pregnancy outcomes
• Aging is associated with progressive decline in metabolic function and increased risk of chronic diseases such as type 2 diabetes, cardiovascular disease, and sarcopenia
  • Mitochondrial dysfunction and increased oxidative stress contribute to age-related metabolic impairments and insulin resistance
  • Sarcopenia, the age-related loss of muscle mass and strength, is associated with reduced metabolic rate and increased risk of frailty and disability
  • Interventions such as calorie restriction, exercise, and pharmacological agents (metformin, rapamycin) have been shown to improve metabolic health and lifespan in animal models and humans

Clinical Relevance and Disorders

• Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both
  • Type 1 diabetes is caused by autoimmune destruction of pancreatic β-cells, leading to absolute insulin deficiency and requiring exogenous insulin therapy
  • Type 2 diabetes is characterized by insulin resistance and relative insulin deficiency, often associated with obesity and sedentary lifestyle, and managed with lifestyle modifications, oral medications (metformin, sulfonylureas), and injectable therapies (insulin, GLP-1 receptor agonists)
  • Complications of diabetes include microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (cardiovascular disease, stroke) disorders, resulting from chronic hyperglycemia and oxidative stress
• Obesity is a complex metabolic disorder characterized by excessive body fat accumulation, often defined by a body mass index (BMI) ≥30 kg/m²
  • Obesity is associated with insulin resistance, dyslipidemia, hypertension, and chronic low-grade inflammation, increasing the risk of type 2 diabetes, cardiovascular disease, and certain cancers
  • Management of obesity includes lifestyle modifications (diet, exercise), behavioral therapy, pharmacological agents (orlistat, liraglutide), and bariatric surgery for severe cases
• Metabolic syndrome is a cluster of metabolic abnormalities that increase the risk of cardiovascular disease and type 2 diabetes, including abdominal obesity, insulin resistance, hypertension, and dyslipidemia
  • Diagnostic criteria for metabolic syndrome vary, but commonly include waist circumference ≥102 cm in men or ≥88 cm in women, fasting glucose ≥100 mg/dL, blood pressure ≥130/85 mmHg, triglycerides ≥150 mg/dL, and HDL cholesterol <40 mg/dL in men or <50 mg/dL in women
  • Treatment of metabolic syndrome focuses on lifestyle modifications and management of individual components, such as weight loss, exercise, and pharmacological treatment of hypertension and dyslipidemia
• Inborn errors of metabolism are a group of rare genetic disorders caused by defects in enzymes or transporters involved in specific metabolic pathways, leading to accumulation of toxic intermediates or deficiency of essential products
  • Examples include phenylketonuria (PKU), caused by deficiency of phenylalanine