AMP-activated protein kinase (AMPK) is the cell-autonomous energy sensor — a heterotrimer (α catalytic + β regulatory + γ AMP-binding) activated by ↑AMP:ATP and ↑ADP:ATP ratios. Activation: γ-subunit AMP-binding → conformational change → allosteric activation + LKB1 (or CaMKKβ in T-cells / hypothalamus) phosphorylation of α-Thr172. Once active, AMPK switches cell from anabolic to catabolic: ↑fatty acid oxidation (ACC inhibition → ↓malonyl-CoA → CPT1 derepression), ↑glucose uptake (GLUT4 translocation in muscle), ↑mitochondrial biogenesis (PGC-1α phosphorylation), ↑autophagy (ULK1 activation + mTORC1 inhibition via TSC2/Raptor phosphorylation), ↓cholesterol/fatty acid synthesis (HMGCR, ACC1 inhibition), ↓protein synthesis (mTORC1 off). Therapeutic relevance: metformin (the largest-effect drug) activates AMPK indirectly via mitochondrial complex I inhibition → ↑ AMP/ATP — the action on hepatic gluconeogenesis is the diabetes mechanism. Berberine activates AMPK by similar mitochondrial mechanism. Exercise, fasting, ketogenic diet, and many polyphenols (resveratrol, EGCG, quercetin, curcumin) converge on AMPK. Cross-links: mtor signaling (counter-regulatory inhibition), autophagy lc3 axis (ULK1 activation), beta oxidation (ACC inhibition).
Organ Systems
nervous
cardiovascular
digestive
musculoskeletal
endocrine
Pathway Steps
↑AMP/ATP + ↑ADP/ATP ratios → AMPK-γ AMP binding — via energy stress (exercise, hypoxia, glucose deprivation, mitochondrial uncoupling). AMPK is the cell’s energy gauge: a rise in AMP/ATP (and ADP/ATP) — from exercise, hypoxia, glucose deprivation, or mitochondrial poisoning — signals low energy charge. AMP/ADP binding to the regulatory γ-subunit CBS domains is the trigger that allosterically activates the kinase and protects its activating phosphorylation from removal.
AMPK-γ AMP-bound → AMPK-α Thr172 phosphorylation — via LKB1 (constitutive) or CaMKKβ (Ca²⁺-dependent). AMP/ADP binding promotes phosphorylation of the catalytic α-subunit at Thr172. The constitutive upstream kinase LKB1 supplies this in most tissues (its loss causes Peutz-Jeghers syndrome), while CaMKKβ provides a Ca²⁺-dependent route. AMPK is also activated indirectly by metformin via mild complex-I inhibition.
AMPK active → ACC1 / ACC2 phosphorylation → inhibition — via ↓malonyl-CoA → CPT1 derepression → ↑fatty acid oxidation. Active AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC1/2), lowering malonyl-CoA. Less malonyl-CoA relieves inhibition of CPT1, so fatty acids enter mitochondria for β-oxidation — switching the cell from lipid synthesis to lipid burning, the core of AMPK’s catabolic-over-anabolic logic.
AMPK active → TSC2 + Raptor phosphorylation — via → mTORC1 inhibition → ↓protein synthesis + ↑autophagy. AMPK restrains growth by phosphorylating TSC2 (activating it) and Raptor — both inhibit mTORC1. The result is reduced protein/lipid synthesis and de-repressed autophagy, directly opposing the anabolic mTOR program when energy is scarce.
AMPK active → ULK1 phosphorylation — via → autophagy initiation; mTORC1 normally inhibits this. AMPK also activates autophagy directly by phosphorylating ULK1 at activating sites — a switch normally held off by mTORC1’s inhibitory phosphorylation of the same kinase. So AMPK promotes autophagy on two fronts: turning ULK1 on and turning its repressor mTORC1 off.
AMPK active → PGC-1α phosphorylation + SIRT1 NAD+ generation — via → mitochondrial biogenesis + oxidative gene programme. For the longer-term response, AMPK phosphorylates PGC-1α and raises NAD⁺ to activate SIRT1, driving mitochondrial biogenesis and an oxidative gene program — adapting capacity to chronic energy demand. This underlies much of the metabolic benefit of endurance exercise.
AMPK active (muscle) → TBC1D1 / TBC1D4 phosphorylation → GLUT4 translocation — via ↑insulin-independent glucose uptake. In muscle, AMPK phosphorylates the Rab-GAPs TBC1D1/TBC1D4 to trigger GLUT4 translocation, raising glucose uptake independently of insulin. This insulin-independent route is why exercise (and AMPK activation) improves glycemia even in insulin resistance.
Known Modulators
metformin (activator) — AMPK (indirect via complex I → ↑AMP). largest-effect AMPK activator clinically; hepatic gluconeogenesis suppression
berberine (activator) — AMPK (similar mitochondrial mechanism to metformin)