AMPK is a key regulator of metabolic rate and fat burning. The mainline thinking on AMPK often follows the puritanical view of classic obesity research: AMPK senses LOW cellular energy levels by monitoring the ratio of ATP to ADP and AMP.1
This suggests that the best way to stimulate AMPK is by reducing caloric intake. When you fast, after all, AMPK is activated. If you want to burn fat, eat less and AMPK will be stimulated.
The problem with this is that it fails to take into account the fact that starch eating cultures like the tsimane farmer-foragers – who subsist on low linoleic acid, high starch foods such as plantain and cassava – have large caloric consumption and very high metabolic rates.2 Clearly they didn’t get lean from lowering calories consumed. How does this work?
Quick review on ATP, ADP and AMP
AMP is adenosine mono-phosphate. ADP is adenosine di-phosphate and ATP is adenosine tri-phosphate. So to go from ADP to ADP to ATP you just add phosphate groups. Each phosphate bond is a high energy bond. So ATP has more stored energy than does ADP.
When glucose is converted to pyruvate in the cytosol (cell water), the first few steps actually use ATP as an energy source to break the glucose down into glyceraldehyde-3-phosphate (G3P). The second half of glycolysis – resulting in pyruvate which enters the mitochondria – produces more ATP than was used to make the G3P, so the net result of glycolysis is more ATP.
When your mitochondria burns pyruvate via the krebs cycle, much more ATP is produced. So after a starchy meal, glycolysis is proceeding all the way through the krebs cycle and ATP levels are maximal. AMPK is activated by LOW ATP levels, so of course high cellular energy (high ATP) means minimally activated AMPK. That’s the common thinking.
Peter Explains Cellular Satiety after a Hi-Carb meal
Peter at Hyperlipid recently wrote this amazing post explaining how a starchy meal can lead to hydrogen peroxide production via the activity of the glycerophosphate shuttle. At the time at which the hydrogen peroxide is produced, energy levels in the cell are maximal. Glucose is high, lactose is high, The NADH/NAD+ ratio is high. ATP levels are maximal. Some amount of lipogenesis (fat making) is undoubtedly happening due to the stimulation of lipogenic genes such as ACC, FAS and SCD1 from insulin signalling. All of these things are forms of cellular energy. Lactate, NADH, Glucose, ATP, fat from lipogenesis. Cellular energy is high.
As Peter explains, high cytosolic NADH levels mean that NADH will be passed into the mitochondria via the glycerophosphate shuttle. This acts as an FADH2 input to the mitochondrial electron transport chain and creates hydrogen peroxide for the same reasons that saturated fat does as I explain in The ROS Theory of Obesity.
Hydrogen peroxide is generated in response to high cellular energy after a starchy meal.
Hydrogen Peroxide Stimulates AMPK through indirect means
It has been known since 2001 that adding hydrogen peroxide to cell culture results in a rapid activation of AMPK.3 Recently it was shown that the activation of AMPK by hydrogen peroxide happens via an increase in the ADP/ATP ratio, NOT through direct activation.4 But how does that work in our cell after a starchy meal? We have seen that NADH, ATP, glucose and lactate levels are all high.
Glyceraldehyde-3-Phosphate Dehydrogenase is a redox sensitive enzyme
I’ve talked about redox sensitive enzymes in Hydrogen Peroxide Flips The Switch.
Remember how I said that the first part of glycolysis consumes ATP, converting it to ADP? It’s only the second half of glycolysis that creates ATP and provides pyruvate as a starting material for the TCA cycle, which produces even more ATP. The bridge between the ATP consuming part of glucose metabolism and the ATP producing parts is an enzyme called Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH). It is highly redox sensitive and it’s activity level goes to zero when hydrogen peroxide levels are elevated to normal post-prandial physiological levels.5
So when high cellular energy levels lead to ROS production, GAPDH activity stops, glucose is converted to Glyceraldehyde-3-Phosphate, which converts ATP to ADP and ATP production slows. This results in a rapid increase in the ADP to ATP ratio and AMPK is activated.
AMPK is activated due to HIGH cellular energy levels after a starchy meal.
NOTE: If you read Peter’s article, you’ll see that he talks about glycerol-3-phosphate dehydrogenase. This is DIFFERENT FROM Glyceraldehyde-3-Phosphate Dehydrogenase.
AMPK turns off glucose metabolism and turns on fat metabolism
AMPK activates a suite of metabolic changes that switch a cell over from using glucose in response to insulin, to using fat. It activates PPAR alpha (PPARa)6, which in turn turns on PDK4 and CPT17. PDK4 turns off pyruvate dehydrogenase, which is what converts pyruvate generated through glycolysis to acetyl-CoA, allowing it to enter the mitochondria. CPT1 is the rate limiting enzyme that controls how fast fat can enter the mitochondria. More PDK4 means less glucose oxidation and more CPT1 means more fat oxidation.
AMPK also phosphorylates ACC and turns it OFF.8 ACC converts Acetyl-CoA to malonyl-CoA – the rate limiting step of lipogenesis (fat making). AMPK also phosphorylates SREBP-1c and turns it OFF. SREBP-1c turns on the lipogenic (fat making) genes.
AMPK turns off glucose burning and lipogenesis, and turns on fat burning in response to the redox inactivation of GAPDH caused by high cellular energy levels after a starchy meal.
- 1.Lin S-C, Hardie DG. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metabolism. Published online February 2018:299-313. doi:10.1016/j.cmet.2017.10.009
- 2.Gurven MD, Trumble BC, Stieglitz J, et al. High resting metabolic rate among Amazonian forager-horticulturalists experiencing high pathogen burden. Am J Phys Anthropol. Published online July 4, 2016:414-425. doi:10.1002/ajpa.23040
- 3.Choi S-L, Kim S-J, Lee K-T, et al. The Regulation of AMP-Activated Protein Kinase by H2O2. Biochemical and Biophysical Research Communications. Published online September 2001:92-97. doi:10.1006/bbrc.2001.5544
- 4.Hinchy EC, Gruszczyk AV, Willows R, et al. Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly. Journal of Biological Chemistry. Published online November 2018:17208-17217. doi:10.1074/jbc.ra118.002579
- 5.V. Danshina, E. V. Schmalhausen, A. P. Mildly Oxidized Glyceraldehyde-3-Phosphate Dehydrogenase as a Possible Regulator of Glycolysis. IUBMB Life (International Union of Biochemistry and Molecular Biology: Life). Published online May 1, 2001:309-314. doi:10.1080/152165401317190824
- 6.Lee WJ, Kim M, Park H-S, et al. AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARα and PGC-1. Biochemical and Biophysical Research Communications. Published online February 2006:291-295. doi:10.1016/j.bbrc.2005.12.011
- 7.Pettersen IKN, Tusubira D, Ashrafi H, et al. Upregulated PDK4 expression is a sensitive marker of increased fatty acid oxidation. Mitochondrion. Published online November 2019:97-110. doi:10.1016/j.mito.2019.07.009
- 8.Park SH, Gammon SR, Knippers JD, Paulsen SR, Rubink DS, Winder WW. Phosphorylation-activity relationships of AMPK and acetyl-CoA carboxylase in muscle. Journal of Applied Physiology. Published online June 1, 2002:2475-2482. doi:10.1152/japplphysiol.00071.2002