Metabolism

Metabolism is a coordinated, whole-body conversation between organs, conducted in the language of hormones. On the MCAT, understand why each tissue handles fuel the way it does, how hormones redirect fuel flow, and what happens when regulation breaks down. Treat the body as an integrated system, not a list of reactions.

Priority labels: Must know = cold; Know the logic = mechanism not names; Passage-level = recognize, don't memorize; Optional = skippable.

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Hormone Structure and Mechanism: The Foundation

How a hormone's structure dictates where and how fast it acts is one of the most commonly tested integrations on the MCAT.

Three Classes of Hormones

Must know

Lipophilic hormones cross the membrane and act slowly on gene expression via intracellular receptors; hydrophilic hormones can't cross, so they use surface receptors and act fast via second messengers.

• Peptide/protein hormones (chains of amino acids) are hydrophilic → bind cell-surface receptors, signal through second messengers. Metabolic examples: insulin, glucagon, growth hormone, leptin, ghrelin, and hypothalamic/pituitary releasing hormones.
• Steroid hormones (from cholesterol) are lipophilic → cross the membrane, bind intracellular (nuclear) receptors, act as transcription factors. Effects are slow (hours) but long-lasting. Examples: cortisol, aldosterone, estrogens, androgens, vitamin D.
• Amino acid–derived hormones vary by polarity: thyroid hormones ($\ce{T3}$, $\ce{T4}$, from tyrosine) are lipophilic and act on intracellular receptors; catecholamines (epinephrine, norepinephrine, from tyrosine) are hydrophilic and act on surface adrenergic GPCRs.

Memory rule: Lipophilic = intracellular receptor, slow, gene-level. Hydrophilic = surface receptor, fast, second messengers.

Second Messenger Pathways

Know the logic

Recognize these three, don't memorize every step:

• cAMP pathway (Gs/Gi GPCRs): hormone → G protein → adenylyl cyclase makes cAMP → PKA phosphorylates target enzymes. Glucagon and epinephrine raise cAMP (Gs).

$\ce{ATP ->[\text{adenylyl cyclase}] cAMP ->[\text{phosphodiesterase}] AMP}$

• IP3/DAG pathway (Gq GPCRs): phospholipase C cleaves $\ce{PIP2}$ → IP3 (releases $\ce{Ca^{2+}}$) + DAG (activates PKC). Passage-level
• Receptor tyrosine kinase (RTK): insulin is the key example. Insulin → receptor autophosphorylation → IRS-1 → PI3K/Akt → GLUT4 vesicle fusion, glycogen synthase activation, protein synthesis. Effects are both rapid (GLUT4) and sustained (gene expression).

Half-Life and Regulation

Know the logic

Peptide hormones are degraded in minutes (rapid, precise feedback). Steroid and thyroid hormones bind plasma carrier proteins and last hours to days — appropriate for slowly adjusting metabolic rate.

Quick check: A hormone, given IV, increases mRNA transcription of gluconeogenic enzymes within 4 hours. Peptide or steroid?

Answer: Steroid (or thyroid hormone). Peptide hormones act via second messengers in seconds to minutes; a 4-hour transcriptional time course fits a nuclear-receptor hormone.

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Tissue-Specific Metabolism

Each organ handles fuel in a characteristic way. Know these profiles cold for fed, fasted, and stress conditions.

Liver: The Metabolic Clearinghouse

Must know

The liver is the only tissue that runs all major fuel pathways. Its job is to buffer blood glucose and package and export fuel.

Fed state (high insulin): takes up glucose via GLUT2 (high $K_m$ — fills only when glucose is genuinely high), runs glycolysis, makes glycogen, converts excess acetyl-CoA to fatty acids packaged as VLDL for export.

Fasted state (high glucagon): glycogenolysis (exports glucose), gluconeogenesis (from lactate, glycerol, glucogenic amino acids), β-oxidation, and ketone body production (acetoacetate, β-hydroxybutyrate) for export to brain and muscle.

Key liver fact: The liver exports glucose. Muscle cannot, because muscle lacks glucose-6-phosphatase.

Skeletal Muscle: The High-Demand Consumer

Must know

Muscle is "selfish" — it keeps glucose and glycogen for itself.

• Fed/rest: takes up glucose via GLUT4 (insulin-dependent), makes glycogen. Cannot export glucose.
• Exercise/fasted: breaks down its own glycogen, but glucose-6-phosphate enters glycolysis directly (no glucose-6-phosphatase → no export). Relies on fatty acid oxidation in prolonged exercise; produces lactate anaerobically.

Cori cycle: muscle glucose → lactate → liver → gluconeogenesis → glucose back to muscle. Energetically costly for the liver but regenerates NAD⁺ for muscle.

Glucose–alanine cycle: muscle exports alanine (from pyruvate + glutamate) → liver converts back to pyruvate for gluconeogenesis, also delivering nitrogen for urea synthesis.

Brain: The Glucose Obligate (With an Exception)

Must know

Normally the brain uses glucose almost exclusively (~20% of resting energy) via GLUT1/GLUT3 (insulin-independent).

Prolonged fasting (>3–4 days): the brain shifts to ketone bodies (the majority of its fuel) to spare muscle protein — a high-yield adaptation. The brain never uses fatty acids directly (long-chain FAs don't cross the blood-brain barrier).

RBCs: lacking mitochondria, they rely 100% on anaerobic glycolysis, producing lactate the liver recycles.

Adipose Tissue: The Long-Term Fuel Depot

Must know

• Fed (high insulin): lipoprotein lipase (LPL) on capillaries cleaves triglycerides from chylomicrons/VLDL → fatty acids stored as triglycerides. Insulin promotes glucose uptake (GLUT4) and suppresses hormone-sensitive lipase (HSL).
• Fasted (glucagon/epinephrine): PKA activates HSL → triglycerides cleaved → free fatty acids (travel on albumin to muscle/liver) and glycerol (to liver for gluconeogenesis).

Quick check: A drug blocks PKA in adipocytes. During fasting, are plasma free fatty acids higher or lower than normal?

Answer: Lower. HSL is activated by PKA (downstream of glucagon/epinephrine → cAMP). Without PKA, HSL stays inactive, triglycerides aren't cleaved, and FFAs aren't released.

Heart

Must know

The heart is the most aerobic tissue, preferentially using fatty acids (it can also use glucose, lactate, ketones). It runs almost entirely on oxidative phosphorylation and stores little fuel — a pure consumer.

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Hormonal Regulation of Fuel Metabolism

Now the hormones that direct traffic. The insulin:glucagon ratio is the master switch between fed (storage) and fasting (mobilization) states.

Insulin: The Fed-State Master

Must know

Insulin is a peptide hormone from β-cells of the islets of Langerhans; the main stimulus is rising blood glucose (amino acids and gut incretins also stimulate it).

Know the logic

Secretion: glucose enters β-cells → ↑ATP/ADP → ATP-sensitive $\ce{K+}$ channels close → depolarization → voltage-gated $\ce{Ca^{2+}}$ entry → insulin exocytosis.

Anabolic effects (insulin = "store and build"):

Tissue	Insulin promotes	Insulin suppresses
Liver	Glycogenesis, lipogenesis, protein synthesis	Gluconeogenesis, glycogenolysis, ketogenesis
Muscle	Glucose uptake (GLUT4), glycogenesis, protein synthesis	Proteolysis
Adipose	Glucose uptake (GLUT4), lipogenesis, LPL	Lipolysis (HSL)

The insulin receptor is an RTK (autophosphorylation → IRS-1/PI3K/Akt).

Glucagon: The Fasted-State Counter-Hormone

Must know

Glucagon (from α-cells of the islets of Langerhans) responds to low blood glucose and acts mainly on the liver via a Gs-GPCR → ↑cAMP → ↑PKA.

Know the logic

PKA effects in liver: activates glycogen phosphorylase → glycogenolysis ↑; inactivates glycogen synthase → glycogenesis ↓; slows glycolysis; drives expression of gluconeogenic genes (PEPCK, glucose-6-phosphatase). (For the enzyme-level allosteric control of glycolysis/gluconeogenesis—PFK-1, F2,6-BP, reciprocal regulation—see the Principles of Metabolic Regulation guide.)

Glucagon does NOT cause muscle glycogenolysis — muscle lacks glucagon receptors (often tested).

Epinephrine: The Stress Hormone

Must know

Secreted by the adrenal medulla, epinephrine acts on α- and β-adrenergic GPCRs. It mimics glucagon on the liver but also acts on muscle:

• Muscle: β₂ → ↑cAMP → glycogenolysis → rapid ATP for fight-or-flight
• Adipose: β → ↑cAMP → HSL → lipolysis
• Suppresses insulin secretion (α₂ on β-cells)

Quick check (worked example): During intense exercise plasma glucose stays relatively stable despite massive muscle uptake. Give two mechanisms.

Answer:

1. Glucagon rises → hepatic glycogenolysis and gluconeogenesis output glucose.
2. Epinephrine stimulates hepatic glycogenolysis and adipose lipolysis (FFAs as alternative fuel, sparing glucose) and drives muscle glycogenolysis for local ATP, lowering muscle's draw on blood glucose.

Cortisol: The Permissive Glucocorticoid

Must know

Secreted by the adrenal cortex (HPA axis: CRH → ACTH → cortisol). Lipophilic → intracellular receptor → gene transcription.

Metabolic effects (catabolic, anti-insulin): ↑ hepatic gluconeogenesis; ↑ muscle proteolysis (amino acids for gluconeogenesis); permissive for adipose lipolysis. Chronic excess (Cushing's) → central fat redistribution and insulin resistance.

Thyroid Hormones (T3/T4)

Know the logic

Thyroid hormone sets the basal metabolic rate. $\ce{T4}$ is the prohormone, converted peripherally to active $\ce{T3}$. Net effect: ↑ mitochondrial/oxidative capacity, ↑ Na⁺/K⁺-ATPase activity (heat), ↑ β-adrenergic sensitivity → more fuel consumed at rest.

Passage-level

Hypothyroidism → low BMR, weight gain, cold intolerance, fatigue. Hyperthyroidism → high BMR, weight loss, heat intolerance, tachycardia.

Growth Hormone (GH)

Know the logic

From the anterior pituitary; counter-regulatory (anti-insulin): promotes lipolysis, stimulates IGF-1 (anabolic growth), raises blood glucose, and at chronic excess (acromegaly) causes insulin resistance.

Quick check: A patient with a GH-secreting adenoma has persistently high blood glucose. Why?

Answer: GH is counter-regulatory to insulin — it promotes lipolysis (FFAs compete with glucose uptake), reduces muscle glucose uptake, and raises hepatic glucose output. Chronic excess causes insulin resistance and elevated blood glucose, potentially secondary diabetes.

Integrated Fed/Fasted Hormone Summary

Must know

State	Dominant hormone	Liver activity	Adipose activity
Fed (0–4 h)	↑ Insulin	Glycogenesis, lipogenesis	Lipogenesis, LPL active
Post-absorptive (4–12 h)	↑ Glucagon	Glycogenolysis, early GNG	Lipolysis begins
Fasted (12–24 h)	↑ Glucagon, cortisol	Glycogenolysis, GNG, early ketogenesis	Active lipolysis
Prolonged fast (>24 h)	Glucagon, cortisol, GH	Ketogenesis major, GNG from AA	Maximal lipolysis
Stress/exercise	Epinephrine + glucagon	Glycogenolysis, GNG	Active lipolysis

(GNG = gluconeogenesis; AA = amino acids)

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Obesity and Regulation of Body Mass

Energy Balance

Must know

Body weight obeys energy in vs. energy out; chronic surplus is stored as adipose triglyceride. Obesity is screened by body mass index:

$\text{BMI} = \frac{\text{mass (kg)}}{\text{height (m)}^2}$

Normal 18.5–24.9; overweight 25–29.9; obese ≥ 30. BMI is a screening tool, not a direct measure of adiposity. Know the formula and interpretation, not the exact cutoffs.

Leptin and Ghrelin

Must know

Leptin is a peptide hormone from adipocytes, secreted in proportion to fat mass. It signals the hypothalamus that stores are adequate → suppresses appetite, increases energy expenditure.

• Leptin resistance (common in obesity): leptin is HIGH but the hypothalamus is insensitive → persistent hunger. Conceptually like insulin resistance in type 2 diabetes.

Ghrelin is a peptide hormone from the stomach, the main hunger (orexigenic) signal: it rises before meals and falls after eating.

Contrast: Leptin (fat) = "I'm full." Ghrelin (stomach) = "Feed me."

The Hypothalamic Set Point

Know the logic

The hypothalamus integrates leptin, ghrelin, insulin, and gut/neural signals to defend a body weight set point by balancing anorexigenic against orexigenic drive. Key takeaway: body weight is defended by powerful, hormonally driven biology — not just willpower.

Adiponectin

Passage-level

Adiponectin is an adipokine that improves insulin sensitivity. Unlike leptin, it is inversely proportional to fat mass — obese individuals have LOW adiponectin, contributing to insulin resistance.

Metabolic Syndrome and Insulin Resistance

Know the logic

Metabolic syndrome is a cluster tied to visceral obesity: abdominal obesity, high triglycerides, low HDL, hypertension, and elevated fasting glucose.

Excess visceral fat releases FFAs and inflammatory cytokines → impair insulin signaling → insulin resistance → β-cells compensate with more insulin → eventual β-cell exhaustion → type 2 diabetes.

Respiratory Quotient (RQ)

Know the logic

The respiratory quotient is $\ce{CO2}$ produced ÷ $\ce{O2}$ consumed, revealing which fuel is burning:

$\text{RQ} = \frac{\dot{V}\ce{CO2}}{\dot{V}\ce{O2}}$

Fuel	RQ
Carbohydrate	1.0
Protein	~0.8
Fat	~0.7
Mixed diet	~0.85

Fats are more reduced (more C–H bonds), so they need more $\ce{O2}$ per $\ce{CO2}$ → lower RQ. RQ > 1.0 indicates net lipogenesis.

Worked example: Glucose oxidation $\ce{C6H12O6 + 6O2 -> 6CO2 + 6H2O}$ gives $\text{RQ} = 6/6 = 1.0$. Palmitate $\ce{C16H32O2 + 23O2 -> 16CO2 + 16H2O}$ gives $\text{RQ} = 16/23 \approx 0.70$.

Quick check: A patient is on a prolonged fast. Is RQ closer to 1.0 or 0.7?

Answer: Closer to 0.7. Prolonged fasting shifts strongly to fat oxidation (FFAs and ketones), giving RQ near 0.7. (Early fasting, still burning some glycogen, sits between 0.7 and 1.0.)

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Common Confusions & Tricks

1. Glucagon acts on liver, NOT muscle. Muscle lacks glucagon receptors. Only epinephrine causes muscle glycogenolysis; glucagon's targets are liver and adipose.

2. Muscle glycogen cannot contribute to blood glucose. Muscle lacks glucose-6-phosphatase, so its glucose-6-phosphate goes straight into glycolysis. Only liver (and kidney) can release free glucose into blood.

3. Leptin is HIGH in obesity; ghrelin is typically lower. Obese individuals have high leptin (but are resistant) and often lower ghrelin, yet remain hungry due to leptin resistance.

4. Insulin vs. glucagon: both peptide hormones from the SAME organ. Islets of Langerhans contain β-cells (insulin) and α-cells (glucagon) — anatomically adjacent, hormonally antagonistic.

5. Cortisol is CATABOLIC (raises blood glucose). It breaks down muscle protein and fat to raise glucose. Mnemonic: Cortisol = "Costly."

6. T3 vs. T4 active form. $\ce{T4}$ (thyroxine) is the prohormone; $\ce{T3}$ is the active form (peripheral deiodinase conversion). Primary hypothyroidism: ↑TSH, ↓T4.

7. RQ trick: low RQ = burning fat; RQ = 1 = burning carbs; RQ > 1 = making fat. DKA (fasting, burning fat) → RQ ≈ 0.7; massive carb load → RQ > 1.

8. Ketone production is a liver function; ketone consumption is in muscle and brain. Hepatocytes lack the enzyme (SCOT) to use ketones — they make but cannot burn them.

9. GH and cortisol both cause "insulin resistance." Both counter-regulatory; acromegaly (excess GH) and Cushing's (excess cortisol) both present with elevated glucose and insulin resistance.

10. Adiponectin goes DOWN as fat mass goes UP. Unlike leptin, adiponectin is inversely correlated with adiposity. Low adiponectin → insulin resistance → metabolic syndrome.

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Key Equations

Equation	Variables and Use
$\text{BMI} = \dfrac{m \text{ (kg)}}{h^2 \text{ (m}^2\text{)}}$	Body mass index; screening for obesity (≥30 = obese).
$\text{RQ} = \dfrac{\dot{V}\ce{CO2}}{\dot{V}\ce{O2}}$	Respiratory quotient. ≈1.0 (carbs), 0.7 (fat), 0.8 (protein), >1 (net lipogenesis).
$\ce{C6H12O6 + 6O2 -> 6CO2 + 6H2O}$	Complete oxidation of glucose; RQ = 6/6 = 1.0.
$\ce{C16H32O2 + 23O2 -> 16CO2 + 16H2O}$	Complete oxidation of palmitate; RQ = 16/23 ≈ 0.70.
$\ce{ATP ->[\text{adenylyl cyclase}] cAMP ->[\text{phosphodiesterase}] AMP}$	cAMP second messenger cycle; activated by glucagon, epinephrine.
$\Delta E_{\text{stored}} = E_{\text{in}} - E_{\text{out}}$	Energy balance; positive → fat storage, negative → fat loss.