Metabolism, Nutrition, and Energy Balance

Detailed Notes

20.1 Metabolism: An Overview

Metabolism is the sum of all chemical reactions occurring in the body at any given moment. These reactions are organized into two broad, opposing categories:

• Catabolism (from Greek katabolē, "a throwing down"): The breakdown of complex organic molecules into simpler ones. Catabolic reactions are exergonic — they release energy, which is captured in the high-energy phosphate bonds of adenosine triphosphate (ATP) . Examples include glycolysis, the citric acid cycle, and beta-oxidation of fatty acids.
• Anabolism (from Greek anabolē, "a raising up"): The synthesis of complex molecules from simpler precursors. Anabolic reactions are endergonic — they consume energy (ATP). Examples include protein synthesis, glycogen synthesis (glycogenesis), and triglyceride synthesis (lipogenesis).

The ATP molecule serves as the universal energy currency of the cell. Its terminal high-energy phosphate bond (~7.3 kcal/mol under cellular conditions) is hydrolyzed by the enzyme ATPase to yield ADP + inorganic phosphate (Pi) + energy. This energy drives endergonic processes: active transport (e.g., the Na⁺/K⁺ pump), muscular contraction, and biosynthesis. Cells maintain a remarkably small ATP pool — the entire body contains only about 100 g of ATP at any moment, yet turns over roughly 40 kg/day through continuous synthesis and hydrolysis.

Oxidation-reduction (redox) reactions are central to energy metabolism. Oxidation is the loss of electrons (or hydrogen atoms); reduction is the gain of electrons. The coenzymes NAD⁺ (nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide) shuttle electrons between metabolic pathways. When reduced to NADH and FADH₂, they carry high-energy electrons to the electron transport chain, where oxidative phosphorylation generates the bulk of cellular ATP.

20.2 Carbohydrate Metabolism

Carbohydrates — primarily glucose — are the body's preferred fuel, particularly for the brain and red blood cells. Glucose catabolism proceeds through four sequential stages to extract the maximum possible energy.

Glucose Catabolism: The Complete Pathway

1. Glycolysis (cytoplasm): One molecule of glucose (6 carbons) is split into two molecules of pyruvate (3 carbons each). This anaerobic phase consumes 2 ATP but produces 4 ATP (net +2 ATP) by substrate-level phosphorylation and reduces 2 NAD⁺ → 2 NADH. Glycolysis does not require oxygen and can proceed under anaerobic conditions — in which case pyruvate is reduced to lactate (lactic acid) to regenerate NAD⁺, sustaining glycolysis.

1. Pyruvate Decarboxylation (mitochondrial matrix): In the presence of oxygen, each pyruvate enters the mitochondrion and is converted by the pyruvate dehydrogenase complex into acetyl coenzyme A (acetyl-CoA) . This irreversible step releases one CO₂ per pyruvate and reduces 1 NAD⁺ → 1 NADH.

1. The Citric Acid Cycle (TCA / Krebs cycle) (mitochondrial matrix): Each acetyl-CoA (2 carbons) combines with oxaloacetate (4 carbons) to form citrate (6 carbons). Through a cyclic series of reactions, two carbons are released as CO₂, and the cycle regenerates oxaloacetate. Per turn: 3 NADH, 1 FADH₂, and 1 GTP (equivalent to ATP) are produced.

1. Electron Transport Chain (ETC) and Oxidative Phosphorylation (inner mitochondrial membrane): NADH and FADH₂ donate electrons to a series of protein complexes (I–IV) embedded in the inner mitochondrial membrane. As electrons move down the chain, energy is used to pump protons (H⁺) from the matrix into the intermembrane space, generating a proton gradient. Protons flow back through ATP synthase (Complex V), driving the phosphorylation of ADP → ATP — a process called chemiosmosis. Oxygen serves as the final electron acceptor, forming water. Each NADH yields approximately 2.5 ATP; each FADH₂ yields approximately 1.5 ATP.

Total ATP yield per glucose molecule: Glycolysis (2 ATP + 2 NADH → ~5 ATP) + Pyruvate decarboxylation (2 NADH → ~5 ATP) + TCA (2 GTP + 6 NADH + 2 FADH₂ → ~18 ATP) = approximately 30–32 ATP. The range accounts for the variable cost of shuttling cytosolic NADH into the mitochondrion (malate-aspartate shuttle ~2.5 ATP/NADH; glycerol-3-phosphate shuttle ~1.5 ATP/NADH).

Glucose Anabolism and Storage

• Glycogenesis: When glucose is abundant (fed state), excess glucose is polymerized into glycogen — a branched polysaccharide stored primarily in the liver (which can release glucose into the blood) and skeletal muscle (which uses it locally). The process is driven by the hormone insulin and the enzyme glycogen synthase.
• Glycogenolysis: When blood glucose falls (fasted state), glycogen is cleaved back into glucose-1-phosphate (which is converted to glucose-6-phosphate and liberated as free glucose by the liver, which expresses glucose-6-phosphatase, or enters glycolysis in muscle). Stimulated by glucagon (liver) and epinephrine (muscle), mediated by the enzyme glycogen phosphorylase.
• Gluconeogenesis: Synthesis of new glucose from non-carbohydrate precursors — lactate, glycerol, and certain amino acids (glucogenic amino acids). Occurs mainly in the liver (and to a lesser extent the kidney cortex) during prolonged fasting or starvation, driven by glucagon and cortisol. Note: fatty acids cannot be converted to glucose in humans (no net synthesis of glucose from acetyl-CoA).

20.3 Lipid Metabolism

Lipids, predominantly stored as triglycerides (triacylglycerols) in adipose tissue, represent the body's largest energy reserve. Each gram of fat yields 9 kcal, more than double the yield of carbohydrate or protein.

Lipolysis and Fatty Acid Oxidation

• Lipolysis: In the fasted state, hormone-sensitive lipase (activated by glucagon, epinephrine, cortisol, and growth hormone) hydrolyzes stored triglycerides into glycerol and three free fatty acids (FFAs) . Glycerol enters the bloodstream and can serve as a gluconeogenic substrate in the liver. FFAs are transported in the blood bound to albumin.
• Beta-oxidation: FFAs enter cells and are activated to fatty acyl-CoA in the cytoplasm, then shuttled into the mitochondrial matrix via the carnitine shuttle (rate-limiting step: carnitine palmitoyltransferase I / CPT-I). Inside the mitochondrion, each cycle of beta-oxidation sequentially removes 2-carbon units as acetyl-CoA, also generating 1 NADH and 1 FADH₂ per cycle. The acetyl-CoA enters the TCA cycle, while NADH and FADH₂ feed the ETC. A single 16-carbon palmitate molecule yields approximately 106–129 ATP — far more than one glucose.

Ketogenesis

When carbohydrate availability is severely limited — as in prolonged fasting, starvation, or uncontrolled diabetes mellitus — the liver's TCA cycle becomes overwhelmed with acetyl-CoA (oxaloacetate is depleted because it is diverted to gluconeogenesis). Excess acetyl-CoA is shunted into ketogenesis, producing ketone bodies: acetoacetate, β-hydroxybutyrate, and acetone. Ketone bodies are released into the blood and can cross the blood-brain barrier, serving as an alternative fuel for the brain during prolonged fasting. However, excessive ketone production can overwhelm the body's buffering capacity, leading to metabolic acidosis (ketoacidosis) — a life-threatening complication of Type 1 diabetes mellitus.

Lipogenesis

In the well-fed state, excess carbohydrates and amino acids can be converted to fatty acids via lipogenesis in the liver. Acetyl-CoA, derived from glycolysis, is used to synthesize fatty acids, which are esterified with glycerol-3-phosphate to form triglycerides. These are packaged into very-low-density lipoproteins (VLDL) and exported to adipose tissue for storage.

20.4 Protein Metabolism

Unlike carbohydrates and lipids, proteins are not primarily stored as fuel. Body proteins — structural, enzymatic, transport — serve functional roles, and their catabolism for energy is a last resort.

• Transamination: The first step in amino acid catabolism. An amino group is transferred from an amino acid to α-ketoglutarate, forming glutamate and a corresponding α-keto acid. This reaction, catalyzed by aminotransferases (e.g., ALT — alanine aminotransferase; AST — aspartate aminotransferase), allows the carbon skeleton of amino acids to enter the TCA cycle at various points (glucogenic amino acids → pyruvate or TCA intermediates; ketogenic amino acids → acetyl-CoA or acetoacetyl-CoA).
• Deamination (Oxidative Deamination) : The removal of the amino group from glutamate by glutamate dehydrogenase in the liver, regenerating α-ketoglutarate and releasing free ammonia (NH₃). Ammonia is highly toxic, especially to the brain.
• The Urea Cycle (liver): Ammonia is detoxified by conversion to urea, a water-soluble, relatively non-toxic compound excreted by the kidneys. The urea cycle (ornithine cycle) occurs in hepatocytes and consumes 3 ATP per urea molecule formed. The overall reaction: 2 NH₃ + CO₂ → urea + H₂O.

Essential vs. Non-Essential Amino Acids

• Essential amino acids (9): Cannot be synthesized by the body and must be obtained from the diet. They include histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine.
• Non-essential amino acids (11): Can be synthesized by the body from metabolic intermediates.

A complete protein contains all essential amino acids in adequate proportions (animal proteins, soy, quinoa). An incomplete protein lacks one or more essential amino acids (most plant proteins).

20.5 Absorptive (Fed) State

The absorptive state lasts approximately 4 hours after a meal, during which ingested nutrients are absorbed from the GI tract and enter the bloodstream. The dominant hormone is insulin, secreted by the beta cells of the pancreatic islets in response to rising blood glucose and amino acid levels.

During the absorptive state:

• Glucose: Taken up by most cells (GLUT4 transporters are insulin-dependent in muscle and adipose tissue). In the liver and muscle, glucose is converted to glycogen (glycogenesis). Once glycogen stores are saturated, excess glucose enters lipogenesis and is stored as fat.
• Amino acids: Transported into cells for protein synthesis. Excess amino acids are deaminated in the liver — carbon skeletons enter lipogenesis or gluconeogenesis.
• Triglycerides: Dietary lipids are packaged into chylomicrons by intestinal epithelial cells, enter the lymphatic system, and are delivered to adipose tissue where lipoprotein lipase (activated by insulin) hydrolyzes them for uptake and re-esterification into stored triglycerides.

The net effect of the absorptive state is energy storage: glycogen in liver and muscle, triglycerides in adipose tissue, and protein in skeletal muscle.

20.6 Postabsorptive (Fasted) State

The postabsorptive state begins approximately 4 hours after the last meal, when nutrient absorption from the GI tract is complete. The dominant hormone transitions from insulin to glucagon, secreted by the alpha cells of the pancreatic islets. The sympathetic nervous system also contributes via epinephrine.

The primary goal is to maintain blood glucose within the normal range (~70–110 mg/dL) to sustain the brain, which relies heavily on glucose.

Key metabolic adjustments:

1. Glycogenolysis: Liver glycogen is rapidly broken down to release free glucose into the bloodstream. Hepatic glycogen stores (~100 g) are depleted within approximately 12–24 hours.
2. Gluconeogenesis: As glycogen wanes, the liver synthesizes glucose from lactate (Cori cycle), glycerol (from lipolysis), and glucogenic amino acids (from muscle proteolysis).
3. Lipolysis: Adipose tissue releases FFAs and glycerol. FFAs become the primary fuel for most tissues (skeletal muscle, cardiac muscle, liver), sparing glucose for the brain. The liver oxidizes FFAs to acetyl-CoA and produces ketone bodies.
4. Ketogenesis accelerates: After several days of fasting, ketone bodies can supply up to two-thirds of the brain's energy needs, reducing the demand for gluconeogenesis from amino acids and thus sparing muscle protein.
5. Proteolysis: Skeletal muscle protein is broken down to release amino acids for gluconeogenesis. This is minimized once ketone bodies adequately fuel the brain.

20.7 The Metabolic Role of the Liver

The liver is the body's central metabolic hub. Its hepatocytes carry out an extraordinary range of metabolic functions:

Table 20.1: Major Metabolic Functions of the Liver

20.8 Metabolic Rate

Basal Metabolic Rate (BMR)

The basal metabolic rate (BMR) is the energy expenditure of the body at complete physical and mental rest in a thermoneutral environment, approximately 12 hours after the last meal. It reflects the energy required to maintain basic physiological functions — cardiac contraction, respiration, maintenance of ion gradients, and cellular repair. BMR is measured in kilocalories per day (kcal/day) and accounts for approximately 60–70% of total daily energy expenditure in a sedentary adult.

Factors influencing BMR:

• Body surface area: BMR correlates more closely with surface area than with body mass — larger surface area means greater heat loss and therefore higher metabolic demand.
• Age: BMR declines with age; roughly 2% per decade after age 20, largely due to loss of lean body mass.
• Sex: Males typically have a higher BMR than females, primarily due to greater lean body mass (muscle is more metabolically active than adipose tissue).
• Thyroid hormones (T₃/T₄) : The single most important hormonal regulator of BMR. Thyroid hormones increase the expression of Na⁺/K⁺ ATPase and uncoupling proteins, raising metabolic rate. Hyperthyroidism elevates BMR; hypothyroidism depresses it.
• Sympathetic stimulation: Epinephrine and norepinephrine increase BMR through calorigenic effects.
• Body temperature: Fever increases BMR (~13% per 1°C rise in core temperature).
• Pregnancy and lactation: Increase BMR due to fetal metabolism and milk production.

Total Metabolic Rate (TMR)

Total metabolic rate (TMR) equals BMR plus:

1. Physical activity (most variable component; can add 15–100%+ above BMR depending on intensity and duration).
2. Thermic effect of food (TEF) : The energy expended to digest, absorb, and process nutrients — approximately 10% of ingested energy. Protein has the highest TEF (20–30% of its caloric value), followed by carbohydrate (5–10%), and fat (0–3%).

20.9 Nutrition

Macronutrients

Macronutrients are required in large quantities and supply energy.

Table 20.2: Macronutrient Energy Values and Functions

Essential fatty acids (linoleic acid — omega-6; alpha-linolenic acid — omega-3) cannot be synthesized by the body and must be obtained from the diet. They are precursors for eicosanoids and are critical for cell membrane integrity.

Micronutrients

Micronutrients are required in small quantities and do not provide energy directly but are essential cofactors for enzymatic reactions and physiological processes.

Vitamins:

• Fat-soluble vitamins (A, D, E, K) : Absorbed with dietary fat; can be stored in the body, so toxicity (hypervitaminosis) is possible with excess intake.
  • Vitamin A (retinol) : Vision (rhodopsin component), epithelial integrity, immune function. Deficiency → night blindness, xerophthalmia.
  • Vitamin D (cholecalciferol) : Calcium and phosphate homeostasis; synthesized in skin upon UV exposure. Deficiency → rickets (children), osteomalacia (adults).
  • Vitamin E (tocopherol) : Antioxidant; protects cell membranes from lipid peroxidation.
  • Vitamin K : Required for synthesis of clotting factors II, VII, IX, X (gamma-carboxylation). Deficiency → bleeding tendency.
• Water-soluble vitamins (B complex and C) : Not stored significantly; excess excreted in urine; regular intake required.
  • B complex (B₁ thiamine, B₂ riboflavin, B₃ niacin, B₅ pantothenic acid, B₆ pyridoxine, B₇ biotin, B₉ folate, B₁₂ cobalamin) : Act as coenzymes in energy metabolism, nucleotide synthesis, and red blood cell production. Folate deficiency → megaloblastic anemia, neural tube defects. B₁₂ deficiency → pernicious anemia, neurological damage.
  • Vitamin C (ascorbic acid) : Collagen synthesis (hydroxylation of proline and lysine), antioxidant, iron absorption enhancer. Deficiency → scurvy (impaired wound healing, bleeding gums, petechiae).

Minerals:

• Calcium (Ca²⁺) : Bone and teeth mineralization, muscle contraction, neurotransmitter release, blood clotting.
• Phosphorus (P) : Bone mineralization, ATP and nucleic acid structure, intracellular buffer.
• Magnesium (Mg²⁺) : Cofactor for ATP-dependent enzymes, neuromuscular function.
• Iron (Fe) : Component of hemoglobin and myoglobin (oxygen transport) and cytochromes (ETC). Deficiency → iron-deficiency anemia (microcytic, hypochromic).
• Iodine (I) : Component of thyroid hormones (T₃, T₄). Deficiency → goiter and hypothyroidism.
• Sodium (Na⁺) and Potassium (K⁺) : Membrane potential maintenance, fluid balance, nerve impulse conduction.

Dietary Guidelines

General recommendations include a balanced diet with approximately 45–65% of calories from carbohydrates, 20–35% from fats (with limited saturated and trans fats), and 10–35% from protein. Adequate fiber (25–30 g/day), water intake (approximately 2–3 L/day), and moderation of added sugars and sodium are emphasized. The Acceptable Macronutrient Distribution Range (AMDR) provides evidence-based ranges associated with reduced chronic disease risk.

20.10 Thermoregulation

The body maintains a relatively constant core body temperature of approximately 37°C (98.6°F) , despite wide variations in environmental temperature and metabolic heat production. This is a classic example of negative feedback homeostasis.

The Hypothalamic Thermostat

The preoptic area of the hypothalamus serves as the body's thermostat. It receives input from:

• Peripheral thermoreceptors in the skin (detect environmental temperature).
• Central thermoreceptors in the hypothalamus itself (detect blood temperature).

The hypothalamus integrates these signals and activates appropriate heat-promoting or heat-losing mechanisms to maintain the set point.

Heat Production (Thermogenesis)

When body temperature falls below the set point:

1. Thyroid hormone: Increases metabolic rate in most tissues, raising heat production (long-term adaptation).
2. Sympathetic stimulation: Epinephrine and norepinephrine increase metabolic rate (calorigenic effect).
3. Shivering thermogenesis: Involuntary, rapid skeletal muscle contractions that generate heat. The primary motor center for shivering (in the posterior hypothalamus) is normally inhibited by the preoptic area; it is disinhibited when core temperature drops.
4. Non-shivering thermogenesis: Especially important in infants, who possess brown adipose tissue (BAT) containing uncoupling protein 1 (UCP1 / thermogenin) that uncouples the ETC from ATP synthesis, dissipating the proton gradient as heat rather than ATP.

Heat Loss

When body temperature rises above the set point:

1. Radiation (~60% of heat loss at rest): Transfer of heat as infrared electromagnetic waves from the body to cooler surrounding objects.
2. Conduction: Direct transfer of heat to a cooler object in physical contact with the body (e.g., sitting on a cold bench).
3. Convection: Transfer of heat away from the body by the movement of air or water across the skin surface. Wind amplifies convective heat loss (wind chill).
4. Evaporation: When sweat evaporates from the skin surface, it removes approximately 0.58 kcal per gram. This is the only mechanism that can dissipate heat when environmental temperature exceeds body temperature. Insensible water loss from the skin and respiratory tract also contributes (~600 mL/day).

Behavioral responses — seeking shade, removing clothing, drinking cold fluids, turning on a fan — are consciously driven but integrally coordinated with the autonomic response.

Fever

Fever (pyrexia) is an elevation of the hypothalamic set point, most commonly triggered by pyrogens released during infection. Exogenous pyrogens (bacterial lipopolysaccharide / LPS) stimulate leukocytes to release endogenous pyrogens (IL-1, IL-6, TNF-α), which act on the hypothalamus to increase prostaglandin E₂ (PGE₂) production, resetting the thermostat upward. The body then activates heat-promoting mechanisms (shivering, vasoconstriction) to raise core temperature to the new set point, hence the "chills" experienced during the rising phase of fever. Antipyretics (aspirin, acetaminophen, ibuprofen) lower the set point by inhibiting cyclooxygenase (COX) and reducing PGE₂ synthesis.

20.11 Clinical Disorders of Metabolism and Nutrition

Obesity

Obesity is defined as excessive adipose tissue accumulation that poses a health risk, most commonly assessed by body mass index (BMI) = weight (kg) / height² (m²). A BMI ≥ 30 kg/m² is classified as obese. Obesity results from chronic positive energy balance (caloric intake > expenditure) and is a major risk factor for type 2 diabetes mellitus, cardiovascular disease, hypertension, obstructive sleep apnea, and certain cancers. Adipose tissue is not inert — visceral adipocytes secrete adipokines (leptin, adiponectin, resistin) and pro-inflammatory cytokines, contributing to a state of chronic low-grade inflammation that underlies the metabolic complications of obesity.

Diabetes Mellitus

Diabetes mellitus (DM) is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

Table 20.3: Comparison of Type 1 and Type 2 Diabetes Mellitus

Insulin resistance — the hallmark of Type 2 DM — is a state in which target tissues (muscle, liver, adipose) respond inadequately to normal circulating insulin levels. The pancreas compensates initially with hyperinsulinemia, but beta-cell exhaustion eventually ensues, leading to relative insulin deficiency and hyperglycemia.

Chronic hyperglycemia causes microvascular complications (retinopathy, nephropathy, neuropathy) via advanced glycation end products (AGEs) and activation of the polyol pathway, and macrovascular complications (accelerated atherosclerosis → myocardial infarction, stroke, peripheral vascular disease).

Metabolic Syndrome

Metabolic syndrome is a cluster of interrelated risk factors that dramatically increase the risk of cardiovascular disease and Type 2 DM. Diagnosis requires any three of the following five criteria:

1. Abdominal obesity: Waist circumference > 102 cm (men), > 88 cm (women).
2. Hypertriglyceridemia: ≥ 150 mg/dL or on drug treatment.
3. Low HDL cholesterol: < 40 mg/dL (men), < 50 mg/dL (women).
4. Hypertension: ≥ 130/85 mmHg or on antihypertensive treatment.
5. Fasting hyperglycemia: ≥ 100 mg/dL or on drug treatment.

The underlying pathophysiology involves insulin resistance and visceral adiposity driving dyslipidemia, hypertension, and a pro-inflammatory, pro-thrombotic state.

Protein-Energy Malnutrition

• Kwashiorkor: Results from adequate caloric intake but inadequate protein intake, leading to hypoalbuminemia, edema (due to decreased plasma oncotic pressure), fatty liver, skin lesions, and a characteristic distended abdomen. Despite wasting, subcutaneous fat may be preserved, creating a misleading appearance. Common in children weaned onto low-protein, high-carbohydrate diets.
• Marasmus: Results from chronic deficiency of both calories and protein, producing severe wasting of muscle and subcutaneous fat, growth retardation, and emaciation with no edema. The body has fully consumed its energy reserves.

Thyroid Disorders and Metabolism

• Hyperthyroidism (e.g., Graves disease): Excess T₃/T₄ → elevated BMR, weight loss despite increased appetite, heat intolerance, tachycardia, tremor. The body is in a hypermetabolic state.
• Hypothyroidism (e.g., Hashimoto thyroiditis): Deficient T₃/T₄ → depressed BMR, weight gain, cold intolerance, bradycardia, fatigue. Severe, prolonged hypothyroidism in adults produces myxedema.

Disorders of Thermoregulation

• Heat stroke: A life-threatening condition in which core body temperature exceeds 40°C (104°F) and the hypothalamic set point is intact but the body's heat-dissipating mechanisms are overwhelmed. Characterized by hot, dry skin (sweating ceases), confusion, and multiorgan failure. It is a medical emergency requiring rapid cooling.
• Hypothermia: Core body temperature falls below 35°C (95°F). As temperature drops, shivering ceases (at ~30–32°C), metabolism slows, and cardiac arrhythmias develop. Severe hypothermia (< 28°C) can produce a state resembling death, with profoundly slow heart rate and respiration, but resuscitation may still be possible — the guiding principle: "not dead until warm and dead."