It stimulates weight loss, improves insulin sensitivity, decreases inflammation, and improves muscle performance.

AMPK is also involved in several longevity pathways and promotes healthy aging. Check out how you can improve your AMPK activity.

AMPK Introduction

AMPK benefits F3.large (3)

AMPK  (5′ AMP-activated protein kinase) is an enzyme that plays a key role in energy balance. All creatures from yeast to humans have this enzyme (R).

AMPK can detect the level of energy (number of ATP molecules) in a cell and helps regulate responses when it gets too low or high.

AMPK is produced in a number of tissues, including the liver, brain, fat cells and muscle (R).

While much of AMPK activity is dependent on external factors such as diet and exercise we all have a genetic disposition inherited from our parents.

To learn more about how you can have your own genetic makeup analyzedfor AMPK related factors go to SelfDecode.

Hormones/Pathways that Activate AMPK (in liver, fat, and muscle)

Practically, AMPK can be activated by any modulator that causes AMP (depleted ATP) or calcium accumulation (R).


1) Adiponectin

Fat cells produce adiponectin (R), which serves as a starvation signal (R).

In fasting, adiponectin increases and stimulates AMPK, leading to induction of food intake and reduction of energy expenditure. After refeeding, a decrease in adiponectin level is accompanied by blunted AMPK activity (R).

2) Leptin

Leptin, the satiety and anti-obesity hormone secreted by fat cells in the presence of insulin, prevents overeating by inhibiting AMPK in the hypothalamus to suppress appetite (R) but activates AMPK in muscle (R).

3) Thyroid hormone T3

The thyroid hormone T3 increases cellular oxygen consumption and activates AMPK in the muscles (R).

4) Nitric Oxide

Nitric oxide activates AMPK (R,R).

5) ROS-producing agents

Any modulators capable of inducing intracellular reactive oxygen species(ROS) generation can activate AMPK. Such a modulator is cryptotanshinone from red sage (Salvia miltiorrhiza), which exerts antidiabetic and anticancer effects through ROS-dependent AMPK activation. DNA-damaging agents, such as cisplatin or metals, including arsenite, vanadate, and cobalt, also activate AMPK through ROS generation (R).

Drugs that Activate AMPK

1) Metformin

Metformin is a blood-sugar-lowering agent. It is widely used for the treatment of type 2 diabetes (R).

AMPK mediates many of the antidiabetic actions of metformin: stimulation of fat burning and glucose uptake, and decreased fat production and liver glucose production (R).

2) Aspirin

Salicylate is a direct activator of AMPK (R).

Aspirin reduces circulating free fatty acids and TG levels in obese patients with type-2 diabetes and increases fat breakdown during fasting in healthy humans, which can be explained by the direct effect of aspirin on AMPK activation (R).

3) Thiazolidinediones

Thiazolidinediones act primarily by activating PPARγ. However, they also exert their antidiabetic effect in part through AMPK activation (R).

Thiazolidinediones rapidly activate AMPK in a variety of tissues including muscle, liver, and fat tissue (R).

AMPK has been implicated in the TZDs induced body weight gain. TZDs are prescribed for blood sugar control, but induce body weight gain as a side effect. Pioglitazone treatment was reported to increase food intake and decrease energy expenditure by enhancing adiponectin and increasing the AMPK activity in the hypothalamus (R).

Hormones That Activate AMPK in the Hypothalamus

1) Ghrelin

Ghrelin is a hunger hormone produced in the stomach and released during fasting. Ghrelin is essential for survival during severe calorie restriction or fasting, when it maintains blood glucose levels (R).

Ghrelin activates AMPK in the hypothalamus and stimulates food intake (R), however, it inhibits AMPK in the fat tissue and liver (R).

2) Cannabinoids

Cannabinoids stimulate AMPK activity in the hypothalamus leading to increased appetite (R).  However, it decreases AMPK in fat cells and liver, similar to Ghrelin (R).

3) Cortisol

Cortisol stimulates AMPK activity in the hypothalamus (R)

Hormones That Inhibit AMPK in the Hypothalamus

Natural Substances that Inhibit AMPK in Hypothalamus

  • Lipoic acid (RR)…it increases AMPK in muscles, fat and liver cells (RR2R3)
  • Quercetin (R)…it increases AMPK in fat, liver, and muscle (RR2R3),
  • Nicotine (R) – Smokers around the world commonly report increased body weight after smoking cessation. Nicotine-induced weight loss is associated with inactivation of hypothalamic AMPK (R).
  • Ketones (R)


  • AMPK can be activated by LKB1, CaMKKβ or Tak1 (R).
  • AMPK inhibits the ‘master regulator’ of lipogenesis SREBPc (R).
  • AMPK may activate NRF2 (R).
  • AMPK acts as an upstream inhibitor of mTOR (R).
  • AMPK can directly activate FOXO family members (R).

AMPK activation results in the reduction of mTOR. But you can have scenarios where both AMPK is activated and mTOR is also activated because AMPK doesn’t inhibit it directly; it inhibits another protein that directly increases mTOR.  For example, Ghrelin, the hunger hormone, activates AMPK and mTOR in the hypothalamus (R).


Disclaimer and Caveats

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