AMPK is a well-understood energy sensor that is reliably activated by exercise, both directly in cells and through hormones. Fasting does this less than expected in muscle itself, and a ketogenic diet even lowers AMPK in skeletal muscle. The research is advanced but contains notable exceptions that add nuance to popular assumptions. For practical health purposes, regular physical exercise has the strongest support as an AMPK activator.
AMPK, short for adenosine monophosphate-activated protein kinase, is a protein found in virtually all cells that monitors their energy status. Whenever a cell runs low on energy, AMPK adjusts more than a hundred cellular processes: the handling of sugars, fats and proteins is recalibrated, and the clean-up process known as autophagy is set in motion. In this way, AMPK acts as a kind of emergency control centre that makes the cell more efficient the moment resources become scarce.
Exercise is the most well-established way to activate AMPK. During physical exertion, energy consumption rises rapidly, which places the cell in an immediate energy deficit and switches AMPK on. In addition, exercise triggers the release of hormones and signalling molecules, such as interleukin-6 and irisin, which activate AMPK in tissues beyond the muscle itself. Animal studies show that AMPK in the blood vessel wall is specifically switched on by exercise and may prevent vascular damage, but whether this translates directly to humans still requires further research.
Fasting has a more nuanced effect than is often assumed. Through hormones such as glucagon, adrenaline and ghrelin that are released during fasting, AMPK can be activated in multiple tissues. However, seven days of fasting in humans had no measurable effect on AMPK activity in skeletal muscle itself. This contradicts the widely heard claim that fasting strongly activates AMPK in muscles. Intermittent fasting did activate AMPK in the blood vessels of mice and thereby protected against vascular damage, but these are animal studies that still need to be translated to humans.
A ketogenic diet actually lowered AMPK levels in skeletal muscle, as shown by a twelve-week randomised study in healthy individuals. This puts nuance on the popular claim that 'keto is good for AMPK'. Where AMPK is concerned, keto therefore differs fundamentally from short-term fasting or from exercise.
The practical value of AMPK activation lies, among other things, in glucose regulation. AMPK causes glucose transporters to move to the surface of muscle cells, which improves the uptake of glucose from the blood. AMPK activation also suppresses glucose production by the liver, which is precisely the mechanism by which the diabetes drug metformin works. Exercise and short periods of fasting can influence this pathway in a comparable way, although the magnitude of the effect in humans is not always equally well documented.
Based on multiple human studies (including one randomised study with a ketogenic diet and one fasting study in muscle), supplemented by animal experiments in mice and review articles. The evidence is strong for the basic mechanism of AMPK, but moderate and sometimes surprisingly contradictory for specific interventions such as fasting in muscle or a ketogenic diet.