5′ adenosine monophosphate-activated protein kinase (AMPK) is an enzyme that plays a key role in regulating cellular energy, activating glucose and fatty acid oxidation.
AMPK stands for AMP-protein activated protein kinase or adenosine monophosphate activated protein kinase. It is an enzyme found in all mammalian cells and phylogenetically senses conserved fuel. It is regulated by the ratio of AMP to ATP. When the ratio of AMP:ATP increases, it activates AMPK. Since it is activated by AMP, it’s considered as an energy sensor for the cell. When energy levels are depleted, it is activated and it regulates many processes in the cell, thus being known as the master regulator of energy metabolism. It restores the energy balance during metabolic hormesis at the cellular and physiological level.
WHAT ACTIVATES AMPK
There are several things that activate AMPK. A few of them include:
- LKB1 – stands for liver kinase B1
WHAT DOES AMPK DO?
In the cell, AMPK is a negative regulator of mTOR signaling. In other words, it phosphorylates or inactivates mTOR, which is an activator of protein synthesis. Click here for an overview of the longevity pathway, mTOR. AMPK will suppress protein synthesis. In addition, AMPK activates ULK1, which is an indispensable protein involved in macro-autophagy. By the activation of ULK1, autophagy is induced through AMPK signalling. Moreover, ATGL or adipose triglyceride lipase is activated through AMPK. ATGL is the first enzyme involved in the release of fatty acids from a triglyceride molecule, which leads to fatty acid catabolism. Also, AMPK inhibits ACC or acetyl-CoA carboxylase, which is a multifunctional enzyme that is indispensable for fatty acid synthesis. Essentially AMPK activates fatty acid catabolism and oxidation and suppresses fatty acid synthesis. Similar to fatty acid synthesis is HMG-CoA reductase, which is the rate-controlling enzyme involved in cholesterol synthesis. It’s part of the mevalonate pathway that produces cholesterol and other isoprenoids. By activating AMPK, HMG-CoA reductase is inhibited, thus inhibiting cholesterol synthesis.
AMPK AND GLUCOSE
AMPK activates glucose uptake through GLUT4 transporters through the process involving TBC1D1. This is another way that an insulin sensitive cell may be able to uptake glucose. Independent of insulin signalling, it can go through an AMPK dependent pathway and this is exactly what happens in exercise: exercise > activates AMPK > increases glucose via GLUT4 trans-localization > glycolysis. AMPK actually inhibits glycogen synthase, inhibiting glycogen synthesis. When the cells take in glucose through glucose uptake, it inhibits glycogen synthesis through AMPK.
AMPK signalling is leading to an uptake in utilization of nutrients. Essentially it’s utilizing the nutrients, but it’s utilizing them in catabolism, not in anabolism. AMPK is not utilizing nutrients for synthesis, but for making more ATP, which translates to more energy. AMPK signalling leads to an increase in catabolism and a decrease anabolism. Therefore, the main focus of AMPK is to upregulate pathways to decrease energy expenditure, while increasing energy production, so the AMP:ATP ratio can reverse to get more ATP and less AMP.
AMPK AND METFORMIN
Metformin acts by reducing the cellular energy stores of ATP, which causes an increase in activity of the AMPK. Activated AMPK stimulates glycogen storage in skeletal muscles, decreases hepatic glucose production, decreases blood glucose levels, increases tissue sensitivity to insulin. By being able to activate AMPK, one of the longevity pathways in the body, metformin is classified to be a longevity drug among leading anti-aging scientists. Although it is prescribed to diabetics, metformin has been shown to have anti-aging benefits such as anti-cancer properties, has neuroprotective properties, and reduces inflammation to name a dew. In addition, it is one of the safest drugs available and is very cost effective, costing a few cents per pill. In most countries around the world, it is available over the counter. Nir Barzilai is currently running a clinical trial to prove the efficacy of metformin on ameliorating age-associated pathologies and proving its safety on healthy humans.
AMPK signalling is leading to an uptake in utilization of nutrients. Essentially it’s utilizing the nutrients, but it’s utilizing them in catabolism, not in anabolism. AMPK is not utilizing nutrients for synthesis, but for making more ATP, which translates to more energy. AMPK signalling leads to an increase in catabolism and a decrease anabolism. Therefore, the main focus of AMPK is to upregulate pathways to decrease energy expenditure, while increasing energy production, so the AMP:ATP ratio can reverse to get more ATP and less AMP. To summarize AMPK’s roles, upon activation, it’ll:
- Increase glucose uptake and utilization
- Increase fatty acid oxidation through ATGL
- Increases autophagy through different mechanisms: ULK1, negative regulation of mTOR causes an increase in autophagy
- Decreases glycogen synthesis
- Inhibits fatty acid synthesis
- Inhibits protein synthesis
- Inhibits cholesterol synthesis
To activate AMPK, one can exercise or take metformin. Cautionary note, metformin is a prescription drug in a number of countries and does have side effects including GI upset. Until further data is concluded on the safety of metformin on healthy, young humans, one should practice caution on activating the AMPK signalling pathway. A sure safe way to do it is to get moving and exercise!