Premed · Premed · Anatomy Physiology 2

Lecture 16: Nutrition and Metabolism

Anatomy and Physiology II

Learning Objectives

By the end of this lecture, students will be able to:

1. Define metabolism, catabolism, and anabolism
2. Describe the major pathways of carbohydrate metabolism (glycolysis, Krebs cycle, oxidative phosphorylation)
3. Describe the major pathways of lipid and protein metabolism
4. Explain the absorptive and postabsorptive metabolic states
5. Describe the roles of insulin and glucagon in metabolic regulation
6. Identify the essential nutrients and their dietary importance

Lecture Content

I. Metabolism — Overview

Metabolism encompasses the sum of all chemical reactions in the body. These reactions fall into two broad categories. Catabolism is the breakdown of complex molecules into simpler ones, releasing energy (exergonic reactions). Anabolism is the synthesis of complex molecules from simpler ones, requiring energy input (endergonic reactions). The energy currency that links these processes is ATP (adenosine triphosphate). Energy is released when the terminal phosphate bond is hydrolyzed (ATP to ADP + Pi), and since cells store very little ATP, it must be continuously regenerated. ATP is generated by two main mechanisms: substrate-level phosphorylation, which directly transfers a phosphate group to ADP during glycolysis and the Krebs cycle, and oxidative phosphorylation, which uses ATP synthase powered by the electron transport chain in the mitochondria and produces the vast majority of cellular ATP.

II. Carbohydrate Metabolism

Cellular Respiration Overview

The complete oxidation of one molecule of glucose (C6H12O6 + 6O2 yields 6CO2 + 6H2O + approximately 30 to 32 ATP) proceeds through three main stages.

1. Glycolysis (Cytoplasm)

Glycolysis converts one molecule of glucose (6 carbons) into 2 molecules of pyruvate (3 carbons each) through a 10-step pathway that does not require oxygen (anaerobic). The net yield per glucose molecule is 2 ATP (via substrate-level phosphorylation) and 2 NADH. The key regulatory enzyme is phosphofructokinase (PFK), which is allosterically regulated by ATP, AMP, and citrate. The fate of pyruvate depends on oxygen availability. Under aerobic conditions, pyruvate enters the mitochondria and undergoes oxidative decarboxylation to form acetyl-CoA. Under anaerobic conditions, pyruvate is converted to lactate by lactate dehydrogenase, a reaction that regenerates NAD+ so glycolysis can continue.

2. Krebs Cycle (Citric Acid Cycle / TCA Cycle) — Mitochondrial Matrix

The transition reaction first converts pyruvate to acetyl-CoA, releasing CO2 and generating NADH (catalyzed by pyruvate dehydrogenase). Acetyl-CoA (2 carbons) then combines with oxaloacetate (4 carbons) to form citrate (6 carbons), which is progressively oxidized through a series of reactions that regenerate oxaloacetate. Per acetyl-CoA, the cycle produces 3 NADH, 1 FADH2, 1 GTP (equivalent to ATP), and 2 CO2. Per glucose (2 acetyl-CoA molecules), the totals are 6 NADH, 2 FADH2, 2 GTP, and 4 CO2. The key regulatory enzyme is isocitrate dehydrogenase, stimulated by ADP and inhibited by ATP.

3. Electron Transport Chain (ETC) and Oxidative Phosphorylation — Inner Mitochondrial Membrane

NADH and FADH2 donate their electrons to the electron transport chain (Complexes I through IV). As electrons pass through a series of carriers, the energy released is used to pump H+ from the mitochondrial matrix into the intermembrane space, creating an electrochemical (proton) gradient. Protons then flow back through ATP synthase (Complex V), driving ATP synthesis in a process called chemiosmosis. Oxygen serves as the final electron acceptor, combining with H+ to form water. Each NADH yields approximately 2.5 ATP, and each FADH2 yields approximately 1.5 ATP. The total ATP yield from one glucose molecule is approximately 30 to 32 ATP.

Other Carbohydrate Pathways

Glycogenesis converts glucose to glycogen for storage in the liver and skeletal muscle and is stimulated by insulin. Glycogenolysis breaks glycogen down to glucose and is stimulated by glucagon (in the liver) and epinephrine (in muscle). Gluconeogenesis synthesizes new glucose from non-carbohydrate sources (lactate, glycerol, and amino acids), occurs in the liver, and is stimulated by glucagon and cortisol. The pentose phosphate pathway produces NADPH for biosynthetic reactions and ribose-5-phosphate for nucleotide synthesis.

<image>A summary diagram of cellular respiration. Panel A: An overview showing glucose entering the cell, glycolysis in the cytoplasm producing pyruvate and 2 ATP + 2 NADH, pyruvate entering the mitochondrion, the transition reaction producing acetyl-CoA + CO2 + NADH, the Krebs cycle in the matrix producing NADH, FADH2, GTP, and CO2, and the electron transport chain on the inner membrane producing the majority of ATP via oxidative phosphorylation. Oxygen is shown as the final electron acceptor producing water. Panel B: A detailed view of the electron transport chain showing Complexes I through IV embedded in the inner mitochondrial membrane, electron flow along the chain, proton pumping from the matrix to the intermembrane space, the resulting proton gradient, and H+ flowing back through ATP synthase (Complex V) to generate ATP. The net ATP yield from one glucose molecule is summarized in a table: glycolysis (2 ATP, 2 NADH), transition (2 NADH), Krebs cycle (2 GTP, 6 NADH, 2 FADH2), ETC (~26 ATP from NADH/FADH2), total ~30–32 ATP.</image>

III. Lipid Metabolism

Beta-Oxidation (Fat Catabolism)

Triglycerides are first hydrolyzed by lipases into glycerol and three fatty acids. Glycerol is converted to glyceraldehyde-3-phosphate and enters the glycolytic pathway. Fatty acids undergo beta-oxidation in the mitochondrial matrix, a process in which the fatty acid chain is cleaved two carbons at a time to produce acetyl-CoA units, with each cleavage cycle also generating 1 NADH and 1 FADH2. The acetyl-CoA enters the Krebs cycle for further oxidation. Fat is an extremely dense energy source: a typical 16-carbon fatty acid (palmitate) yields approximately 106 ATP. Gram for gram, fat provides about 9 kcal, compared to approximately 4 kcal for carbohydrates or proteins.

Lipogenesis (Fat Synthesis)

When glucose or amino acids are consumed in excess, they can be converted to fatty acids and subsequently to triglycerides, a process that occurs mainly in the liver and adipose tissue and is stimulated by insulin.

Ketogenesis

When acetyl-CoA production outpaces the capacity of the Krebs cycle, as occurs during prolonged fasting or uncontrolled diabetes, the liver converts excess acetyl-CoA into ketone bodies (acetoacetate, beta-hydroxybutyrate, and acetone). Ketone bodies can serve as an alternative fuel for the brain, heart, and skeletal muscle. However, excessive accumulation leads to ketoacidosis, a dangerous form of metabolic acidosis, particularly in diabetic ketoacidosis (DKA).

IV. Protein Metabolism

Under normal conditions, proteins are used primarily for structural and functional purposes rather than energy. When they are used for energy or when amino acids are consumed in excess, the first step is deamination, removal of the amino group (NH2). The amino group is converted to ammonia (NH3) and then to urea in the liver via the urea cycle, with urea being excreted by the kidneys. The remaining carbon skeleton (keto acid) can be converted to pyruvate, acetyl-CoA, or Krebs cycle intermediates for ATP production, used for gluconeogenesis (glucogenic amino acids), or converted to fatty acids (ketogenic amino acids). Transamination is the transfer of an amino group from one amino acid to a keto acid to produce a new amino acid. This reaction is catalyzed by aminotransferases (AST and ALT), which are clinically important liver enzymes whose blood levels rise in liver damage.

V. Absorptive and Postabsorptive States

Absorptive State (Fed State)

During and shortly after eating (approximately 4 hours after a meal), nutrients are being absorbed from the GI tract and anabolic reactions predominate. Glucose is oxidized for energy or stored as glycogen (glycogenesis). Excess glucose is converted to fat (lipogenesis). Amino acids are used for protein synthesis or converted to fat. Dietary fats are stored in adipose tissue. Insulin, the dominant hormone of this state, is released from pancreatic beta cells in response to elevated blood glucose.

Postabsorptive State (Fasting State)

Between meals, when the GI tract is empty and energy must come from internal reserves, catabolic reactions predominate. Glycogenolysis in the liver releases glucose into the blood. Lipolysis breaks down triglycerides in adipose tissue, releasing fatty acids (used by most tissues) and glycerol (used for gluconeogenesis). Gluconeogenesis in the liver synthesizes new glucose from amino acids, lactate, and glycerol. As a last resort, protein catabolism breaks down skeletal muscle proteins for their amino acids. Glucagon, the dominant hormone of this state, is released from pancreatic alpha cells in response to low blood glucose.

Insulin vs. Glucagon

<image>A diagram comparing the absorptive and postabsorptive metabolic states. Panel A (Absorptive/Fed State — left side): A meal is shown being digested with glucose, amino acids, and fatty acids entering the bloodstream. Insulin (from pancreatic beta cells) is the dominant hormone. Arrows show: glucose entering liver (stored as glycogen and converted to fat), glucose entering muscle (stored as glycogen and used for ATP), glucose entering adipose tissue (stored as fat), amino acids entering various cells (protein synthesis), and dietary fats entering adipose tissue for storage. Panel B (Postabsorptive/Fasting State — right side): Glucagon (from pancreatic alpha cells) is the dominant hormone. Arrows show: liver glycogenolysis releasing glucose into the blood, adipose tissue lipolysis releasing fatty acids and glycerol, gluconeogenesis in the liver from amino acids, lactate, and glycerol, and muscle protein breakdown providing amino acids. The brain is shown always using glucose. A central blood glucose graph shows insulin maintaining the fed-state level and glucagon preventing it from dropping too low during fasting.</image>

VI. Nutrition — Essential Nutrients

Macronutrients

Carbohydrates should constitute 45 to 65% of caloric intake and serve as the primary energy source at 4 kcal/g. Complex carbohydrates (starches and fiber) are preferred over simple sugars. Dietary fiber, consisting of indigestible polysaccharides, promotes GI health. Lipids should provide 20 to 35% of calories at 9 kcal/g. The essential fatty acids, linoleic acid (omega-6) and alpha-linolenic acid (omega-3), must be obtained from the diet. Saturated fats and trans fats should be limited. Cholesterol is necessary for membrane structure and steroid hormone synthesis. Proteins should account for 10 to 35% of calories at 4 kcal/g and serve primarily structural and functional roles. Nine essential amino acids (histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine) cannot be synthesized and must come from the diet. Complete proteins from animal sources contain all essential amino acids, while most plant proteins are incomplete.

Micronutrients

Vitamins are organic molecules required in small amounts that serve as coenzymes or antioxidants. Fat-soluble vitamins (A, D, E, and K) can accumulate and carry a risk of toxicity. Water-soluble vitamins (the B vitamins and vitamin C) must be consumed regularly because excess is excreted. Minerals are inorganic elements divided into major minerals (calcium, phosphorus, potassium, sodium, chloride, magnesium, and sulfur) and trace minerals (iron, zinc, copper, manganese, iodine, selenium, chromium, molybdenum, and fluoride). Water is the most critical nutrient, with approximately 2.5 liters needed daily.

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