FA Regulation
Fatty acid synthesis and oxidation are tightly coordinated so the cell never wastes ATP by doing both at once. Insulin and glucagon are the main hormonal switches; malonyl-CoA is the key small-molecule regulator.
Insulin (Fed State)
- Dephosphorylates ACC → ACTIVE → malonyl-CoA levels rise → synthesis active, CPT-I blocked → no beta-oxidation.
- Dephosphorylates and INACTIVATES hormone-sensitive lipase → fat stays stored in adipose.
- Activates glucose uptake, glycolysis, and PDH → acetyl-CoA pool for fatty acid synthesis.
Net: storage mode. Carbs and fats stored; nothing mobilized.
Glucagon / Epinephrine (Fasted / Stressed)
- Phosphorylates ACC → INACTIVE → malonyl-CoA drops → CPT-I released → beta-oxidation activates.
- Phosphorylates and ACTIVATES hormone-sensitive lipase in adipose → fatty acids released into blood.
- Activates gluconeogenesis.
Net: mobilization mode. Fat released from stores; fatty acids burned by muscle and converted to ketone bodies by liver.
Malonyl-CoA: The Switchboard
Malonyl-CoA does two jobs simultaneously:
- It is the 2-carbon donor for fatty acid synthesis.
- It allosterically inhibits CPT-I, blocking beta-oxidation.
High insulin → high malonyl-CoA → synthesis runs, oxidation stops. Low insulin / high glucagon → low malonyl-CoA → synthesis halts, oxidation starts. One molecule, two opposite effects - textbook reciprocal regulation.
What is the effect of glucagon on fatty acid metabolism in adipose tissue?
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Glucagon activates PKA via cAMP, which phosphorylates and activates hormone-sensitive lipase. HSL hydrolyzes stored triglycerides, releasing free fatty acids and glycerol into the blood. Glycerol goes to the liver for gluconeogenesis; fatty acids travel bound to albumin to tissues (muscle, heart, liver) for beta-oxidation.
How does malonyl-CoA reciprocally regulate fatty acid synthesis and oxidation?
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Malonyl-CoA (the product of acetyl-CoA carboxylase) serves dual roles: it is the 2-carbon donor for fatty acid synthesis AND it inhibits carnitine palmitoyltransferase I (CPT-I), the rate-limiting step of beta-oxidation. High malonyl-CoA means synthesis on, oxidation off. Low malonyl-CoA means the reverse. A single molecule controls both directions at their respective first committed steps.
What does AMPK do when the cell is energy-starved, and why does this matter for fat burning?
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AMPK (AMP-activated protein kinase) senses rising AMP (low energy). It phosphorylates ACC, inactivating it and lowering malonyl-CoA. Reduced malonyl-CoA relieves CPT-I inhibition, so fatty acids are imported into mitochondria for beta-oxidation. This is how exercise activates fat burning. Metformin, a diabetes drug, is partly an AMPK activator.