Category: signaling
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).