Pathway

Energy sensing

AMP-activated protein kinase (AMPK)

The Fuel Gauge

32 blends on this site modulate it.

Also searched as AMP-activated protein kinase (AMPK).

You want this switch on: it is the longevity-adjacent state evoked by fasting, exertion and select botanicals.

In depth

The cell's master energy sensor — when fuel runs low it ignites fat-burning, glucose uptake and mitochondrial renewal while standing down growth.

What drives it

Fasting response increases it.

Cantó 2010, Cell Metab 11:213 — fasting raises the AMP:ATP ratio and activates AMPK (interdependently with SIRT1) to drive the metabolic adaptation to nutrient scarcity. Mechanism is a ratio, not a signal: during fasting the AMP:ATP ratio rises and AMPK is activated, triggering repair and inhibiting anabolic processes. AMPK is a fuel gauge reading a nucleotide ratio — nothing binds a receptor.

Training load increases it.

Energy-sensor review 2018 (PMID 31314464) — muscle contraction during exercise raises AMP:ATP and activates AMPK, the hub coordinating exercise metabolic adaptation. PMID 31314464. Loss-of-function: SIRT1-mediated adaptations to exercise and caloric restriction are blunted in AMPK-deficient skeletal muscle, and the same work used mice overexpressing a kinase-dead alpha-2 AMPK subunit to isolate the requirement. Human arm: skeletal-muscle biopsies from young men after 15 sessions of one-legged knee-extensor endurance training over three weeks — the untrained leg serves as a within-subject control, which is a stronger design than between-group comparison. PMID 31314464

Oxidative stress increases it.

AMPK/mROS study 2017 — mitochondrial reactive oxygen species are a physiological activator of AMPK, triggering a PGC-1α-dependent antioxidant response. PMID 28978464. Functionally confirmed: H2O2 and the glycolysis blocker 2-DG induced AMPK phosphorylation and autophagy in endothelial cells, and this was blocked by the antioxidants Tempol and N-acetylcysteine or by overexpressing superoxide dismutase 1 or catalase (PMC3046135). But the direct model failed its test: it was proposed that ROS act on redox-sensitive cysteines (Cys-299/Cys-304) on the AMPK alpha subunit. Murphy's group assessed whether physiological ROS directly alter AMPK activity and titled the result 'mitochondria-derived ROS activate AMPK indirectly' (J Biol Chem 2018, doi 10.1074/jbc.RA118.002579) — the effect runs through altered adenine-nucleotide ratios, not direct cysteine oxidation. And ROS here can be protective: conditional endothelial Nox2 overexpression raising EC-ROS 1.8-fold improved coronary vasodilation via a CaMKK-beta-AMPK-eNOS axis and induced autophagy that protected cells from oxidant death (PMC3765580) — the authors note recent antioxidant trials in cardiovascular disease failed, which challenges the blanket anti-ROS position. doi 10.1074/jbc.RA118.002579 · PMID 28978464 · PMC3046135

Sleep increases it.

Sleep loss affects key metabolic regulators, including AMPK signaling, and disrupts the secretion of metabolic hormones such as leptin and ghrelin. doi 10.1016/j.smrv.2011.05.001 · PMC3132857

Adaptive stress response increases it.

Energy stress activates AMPK, which is the metabolic arm of the hormetic response. Carried by the hormesis, inflammaging and thermogenesis reviews. doi 10.1002/med.21743

Acetaldehyde load reduces it.

Verbatim (PMID 31214376): 'ethanol reduces AMPK levels, which increases ACC1 activity, decreases PPARa levels, and increases mTORC1 activity. Increased mTORC1 further increases SREBP-1c activity and decreases autophagy.' this is the single switch that ties the alcoholic arm to the non-alcoholic one - AMPK down raises ACC1 and lowers PPARalpha in both diseases. The quote attributes it to ethanol; the acetaldehyde-specific step is stated separately in PMC7530314 and the edge carries the ethanol-level evidence. PMID 31214376 · PMC7530314

What it drives

It increases Fat cell clearance.

Activation of AMPK induced apoptotic cell death. doi 10.1016/j.bbrc.2005.11.159

It reduces Fat-burning brake.

Merrill 1997, Am J Physiol Endocrinol Metab 273:E1107 — AMPK activation phosphorylates and inhibits acetyl-CoA carboxylase, lowering malonyl-CoA and raising fatty-acid oxidation. Verified: AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC1 at Ser-659 and Ser-1157; ACC2 at Ser212), the rate-limiting enzyme producing malonyl-CoA from acetyl-CoA. Lower malonyl-CoA relieves its allosteric block on CPT1, permitting long-chain fatty acyl-CoA entry into mitochondria for beta-oxidation. the Ser1157 phosphosite work is yeast (Snf1, the AMPK homolog); mammalian ACC numbering differs. Mechanism at the residue: AMPK phosphorylates acetyl-CoA carboxylase at ACC1 Ser79 and ACC2 Ser212, which inhibits the enzyme that produces malonyl-CoA from acetyl-CoA. Genetic proof: alanine knock-in at those exact sites renders malonyl-CoA production insensitive to AMPK, which is how the causal direction was established rather than inferred. Sources: PMC3587157; PMID 26711141; PMC8535671. PMID 26711141 · PMC3587157

It increases Feeding drive.

Hypothalamic-AMPK/NPY study 2016, Autophagy — constitutively active AMPK in the medial hypothalamus increases orexigenic NPY/AgRP expression, driving food intake. doi 10.1080/15548627.2016.1215382

It increases Cellular fuel.

AMPK-SIRT1 review, Am J Physiol — AMPK activation raises cellular NAD+ and the NAD+/NADH ratio (via nampt in the salvage pathway) as a metabolic-stress response. PMC2853213. Mechanism and its brake are both named: AMPK upregulates NAD+ synthesis and sirtuin activity in a nampt-dependent manner, nampt being the rate-limiting enzyme of the salvage pathway that dominates NAD+ supply in most tissues. The AMPK activators metformin and aicar raise nampt by suppressing miR-146a — they phosphorylate ikk, which attenuates NF-kappa-B, which lowers miR-146a, which otherwise binds the Nampt 3'-utr and cuts nampt protein. AICAR produced an AMPK-driven rise in NAD+, higher sirtuin activity, greater oxidative mitochondrial activity and improved endurance. The brake strengthens with age: miR-146a rises in senescent cells, so the same AMPK signal buys less NAD+ in an old cell than a young one. PMC2853213

It increases Recycles mitochondria.

Egan 2011, Science — AMPK phosphorylates ULK1 (the Atg1 ortholog), connecting energy sensing to mitophagy; loss of AMPK/ULK1 causes defective mitophagy. doi:10.1126/science.1196371. Verified: AMPK directly phosphorylates mitochondrial fission factor (MFF) to drive DRP1-mediated fission -- fission being required for mitophagy -- and activates ULK1, the upstream kinase of autophagy and mitophagy. AMPK phosphorylation of ULK1 is required for targeting mitochondria to lysosomes in exercise-induced mitophagy. The prevailing view is under active challenge and the atlas should say so: a 2024 Molecular Cell paper titled 'opposing roles for AMPK in regulating distinct mitophagy pathways' states that the role of AMPK as a general ULK1 activator is not necessarily true — some AMPK sites on ULK1 are stimulatory, but the authors identified two that ARE not. AMPK phosphorylation at ULK1 Ser694 together with Ser556 is required for 14-3-3 binding, which sequesters ULK1 and prevents phagophore formation during mitophagy initiation. They propose ULK1 acts as a logic gate integrating AMPK and mTOR: under energy starvation AMPK inhibits ULK1 to prevent excess bulk autophagy, and that signal is overridden only when amino acids are absent. Their rationale: autophagy may itself be an energy-consuming pathway. The sign of this arrow is site-dependent and contested. doi 10.1126/science.1196371.

It reduces Stops fat storage.

Li 2011, Cell Metab 13:376 — AMPK phosphorylates ACC and SREBP-1c, suppressing hepatic de novo lipogenesis. Mouse + HepG2 in vitro. Asymmetric: a later paper reports AMPK re-activation suppresses hepatic steatosis but its downregulation does not promote fatty liver, and finds NO correlation between lipogenic gene expression and intracellular triglyceride (PMC5835560). Raising AMPK helps; lowering it does not cause the disease. Two separate mechanisms, acute and transcriptional. Acute: AMPK phosphorylates and inhibits ACC1, the rate-limiting enzyme of fatty-acid synthesis (Davies 1992; Munday 1988). Transcriptional: AMPK also down-regulates expression of lipogenic enzymes by phosphorylating and inhibiting SREBP-1c (Li 2011). It additionally inhibits HMG-CoA reductase, so the same switch restrains cholesterol synthesis. the SREBP-1c arm is stated with 'possibly' in the source — the acute ACC1 arm is the secure one. PMC5835560

It reduces Lowers liver sugar.

10.3389/fendo.2018.00802 — Foretz 2005, Diabetes 54:1331 — a constitutively active AMPKα2 in liver represses PEPCK and G6Pase, suppressing hepatic gluconeogenesis. Metformin is not an NAD+ booster. doi 10.3389/fendo.2018.00802

It increases Longevity gene.

Cantó 2009, Nature 458:1056 — AMPK raises cellular NAD+, activating SIRT1. PMID 19262508. Mouse skeletal muscle. The route is disputed: one group proposes NAMPT upregulation as the AMPK-SIRT1 linkage, while Canto found AMPK alters NAD+/NADH and activates SIRT1 apparently independently of NAMPT (PMC2853213). The link holds; the mechanism between them does not have one settled account. PMID 19262508 · PMC2853213

It increases Cellular cleanup.

Kim, Kundu, Viollet & Guan 2011, Nat Cell Biol 13:132 — AMPK directly phosphorylates ULK1 (Ser317/777), initiating autophagy. DOI 10.1038/ncb2152. Verified: AMPK promotes autophagy by phosphorylating ULK1 and by phosphorylating Raptor to relieve mTORC1's inhibitory Ser757 phosphorylation of ULK1, allowing Atg12-Atg5-Atg16L1 assembly, LC3 lipidation and autophagosome biogenesis. The prevailing view is under active challenge and the atlas should say so: a 2024 Molecular Cell paper titled 'opposing roles for AMPK in regulating distinct mitophagy pathways' states that the role of AMPK as a general ULK1 activator is not necessarily true — some AMPK sites on ULK1 are stimulatory, but the authors identified two that ARE not. AMPK phosphorylation at ULK1 Ser694 together with Ser556 is required for 14-3-3 binding, which sequesters ULK1 and prevents phagophore formation during mitophagy initiation. They propose ULK1 acts as a logic gate integrating AMPK and mTOR: under energy starvation AMPK inhibits ULK1 to prevent excess bulk autophagy, and that signal is overridden only when amino acids are absent. Their rationale: autophagy may itself be an energy-consuming pathway. The sign of this arrow is site-dependent and contested. doi 10.1038/ncb2152.

It increases Builds mitochondria.

Jäger 2007, PNAS 104:12017 — AMPK directly phosphorylates PGC-1α (Thr177/Ser538), driving mitochondrial biogenesis. PMID 17609368

It increases Lowers cholesterol.

AMPK is the switch between storing fat and burning it: activating AMPK enhances lipid oxidation and reduces incorporation of fatty acids into triacylglycerol, while inhibiting AMPK increases lipid accumulation (PMC5296945). The acute mechanism is phosphorylation of its target acetyl-CoA carboxylase, lowering malonyl-CoA (PMC2734509); the long-term arm is transcriptional — AMPK activation raises PPAR-alpha target genes and PGC-1, and silencing those prevents the increase in fatty-acid oxidation (PMID 16364253). Verbatim: “Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways”. doi 10.1073/pnas.0705070104 · PMID 16364253 · PMC5296945

It increases Fat burning.

AMPK phosphorylates and inactivates ACC2, which lowers malonyl-CoA and so relieves its inhibition of CPT1 — the rate-limiting gate for fatty acids entering the mitochondrion. Fatty acids can then cross as carnitine esters and be oxidized (PMC2734509, PMC4552526). This is why AMPK activation raises fat oxidation within minutes, before any change in gene expression. Mechanism: AMPK inhibits ACC2, lowering malonyl-CoA, which relieves malonyl-CoA's inhibition of CPT1 and lets fatty acids enter mitochondria to be burned. It is de-repression, not activation. And a knock-in disproves that this route is required. Mice carrying alanine knock-ins at both AMPK phosphosites — ACC1 Ser79 and ACC2 Ser212 (acc-dki) — make acc activity and malonyl-CoA insensitive to AMPK. Those mice had normal exercise capacity and normal whole-body fatty-acid oxidation during treadmill running despite elevated muscle ACC2 activity and elevated malonyl-CoA. The authors conclude ACC2-independent pathways are capable of regulating fatty-acid oxidation during muscle contraction (PMC4552526). The textbook chain is real biochemistry but is not the only route, and not the necessary one under exercise. PMC2734509

It increases Recovery.

Int J Mol Sci 2018;19(10):3125 (doi 10.3390/ijms19103125) -- review: AMPK-alpha1 stimulates anabolism and regulates satellite-cell dynamics during regeneration, while AMPK-alpha2 features in atrophy-associated degradation. Not yet read at source (ladder T3). doi 10.3390/ijms19103125

It reduces Growth restraint.

Gwinn 2008, Mol Cell 30:214 — AMPK phosphorylates Raptor (S722/S792), inhibiting mTORC1. PMID 18439900. Verified: AMPK inhibits mTORC1 by phosphorylating TSC2 and Raptor, alleviating mTORC1-mediated suppression of downstream anabolism. mTORC1 in turn drives translation via S6K1 and 4E-BP1, so AMPK inhibition of mTORC1 conserves ATP by reducing protein synthesis. AMPK inhibits mTORC1 by two routes: phosphorylating and activating TSC2 (which switches off Rheb), and directly inhibiting Raptor, mTORC1's binding partner. This is the energy-sensor-to-growth-switch link — no fuel, no anabolism. the same review marks several AMPK substrates as requiring independent validation; TSC2 and Raptor are not among the flagged ones. PMID 18439900