AMPK Activation


AMPK activators contribute to maintain naïve pluripotency in mouse embryonic stem cells

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Pluripotent stem cells retain the property to self-renew and differentiate into all cell types under defined conditions. Among mouse embryonic stem cells (ESCs), which are pluripotent but heterogenous in gene expression and morphology, an ESC population cultured in small molecule inhibitors of two kinases, MAPK/ERK kinase (Mek) and Glycogen synthase kinase 3 (Gsk3), and leukemia inhibitory factor (Lif) (2i/L) is considered to be naïve pluripotent with uniform pluripotent machinery operation. Though the gene regulatory mechanism for the naïve pluripotency has been investigated in recent years, it is still not fully elucidated. Here we show a novel signaling involved in the maintenance of naïve pluripotency. An AMP-activated protein kinase(AMPK) activator, AICAR (5-Aminoimidazole-4-carboxamied-1-β-riboside) blocked the differentiation of mouse naïve ESCs in the absence of 2i/L and maintained the naïve state. AICAR with Lif condition induced an almost comparable level of naïve pluripotent gene expression in mouse ESCs. Another AMPK activator, A769662, also showed similar effects. A p38 inhibitor, SB203580, blocked the AMPK activation-elicited naïve state maintenance. On the other hand, p38 activation partially mimicked the maintenance effects of AMPK activators, suggesting that p38 is one of the functional downstream molecules to conduct the AMPK effects. Thus, AMPK pathway should be involved in the molecular circuitry of naïve pluripotency in mouse ESCs. These findings would be a valuable clue to further elucidate the molecular machinery of naïve pluripotency.


AMPK is an energy sensor, that when activated in the right tissues has many beneficial effects on our bodies. 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.

What is AMPK?

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 analyzed for AMPK related factors go to SelfDecode.

AMPK Activation Benefits

1) AMPK Increases Metabolism

AMPK in the hypothalamus senses our level of energy production in the body (energy in the form of ATP). It increases energy expenditure and can also increase appetite (when increased in the hypothalamus) (R).

When cellular energy is low, AMPK is activated and targets a range of processes, the net response of which is an increase in energy production and a coordinated decrease in energy (ATP) usage (R).

Hypothalamic AMPK increases appetite, increases glucose production and uptake, reduces heat production, and decreases energy output (R).

2) AMPK Produces and Burns Sugars

Glucose is the main source of energy for the body and is particularly essential for normal brain activity. Hypoglycemia, a condition in which the blood glucose drops below normal levels, poses a great danger to the stability and functioning of the brain and therefore activates AMPK (R).

Hypothalamic AMPK activation promotes glucose production from the liver (R), and glucose uptake into the muscles (R).

AMPK inhibits glucose storage (glycogen synthesis), resulting in more glucose (R).

In various cells, AMPK stimulates the breakdown of glucose for energy (in the form of ATP) (R).

3) AMPK Burns Fat

AMPK inhibits the production of fatty acids, cholesterol, and triglycerides, and instead stimulates fat breakdown (R).

4) AMPK Inhibits Protein Production

Protein production is a high-energy process that is inhibited during low energy states to conserve energy. Therefore, it is not surprising that AMPK inhibits protein production (R).

Inhibiting excessive protein production results in a much more energy efficient and wasteful cell.

5) AMPK Promotes Cellular Renewal (Autophagy)

Autophagy is the process of recycling cellular components. This process promotes molecular and cell subunit quality control by degrading damaged or misfolded proteins and even damaged mitochondria (R).

Autophagy can contribute to energy generation by providing fuel for mitochondrial metabolism, and AMPK promotes this process (R).

6) AMPK Produces New Mitochondria

AMPK is capable of both acute and long-term improvement of mitochondrial activity (R).

AMPK also controls the production and turnover of mitochondria. Loss of AMPK in mice reduces mitochondrial activity and greatly diminishes muscle performance (R).

7) AMPK Acts as an Antioxidant

AMPK has a crucial role in increasing antioxidant defense during oxidative stress (R).

AMPK increases the production of several antioxidant proteins, such as NRF2superoxide dismutase and uncoupling protein 2 (UCP2) (RR).

8) AMPK Helps With Oxygen Delivery

Upon hypoxia (low oxygen) at altitude or during sleep, activation of AMPK can protect against acute breathing instability. Loss of AMPK was shown to cause breathing dysfunction during hypoxia in mice (R).

Variations of gene components of AMPK has been found in high-altitude Andean populations, presumably in order to help survival in low oxygen conditions (R, R).

9) AMPK is Important for Fertility

AMPK helps with fertility in both sexes in several animal species, by increasing the production of sex hormones (R).

The absence of AMPK leads to reduced fertility in both sexes (R).

10) AMPK Increases Blood Flow

AMPK plays a critical role in increasing blood flow through vasodilation (widening of the blood vessels), by stimulating nitric oxide release in blood vessels (R).

11) AMPK Provides the Benefits of Exercise

The benefits of exercise can be obtained, in part, by activating AMPK. Mice who took AICAR, an AMPK activator, for 4 weeks had the similar benefits as endurance training in “sedentary” mice (in terms of both muscle mitochondrial profiles and actual treadmill endurance) (R).

12) AMPK Increases Weightloss

AMPK increases ‘fat burning’ and this ‘pathway’ can result in weight loss (R).

For weight loss, ideally, we would want to activate AMPK in our liver, fat, and muscle and inhibit AMPK in the hypothalamus.  This way, we will burn fat and energy stores and decrease hunger at the same time.

In mice, when the activity of brain/hypothalamic AMPK was inhibited, the mice ate less and lost weight. When AMPK activity was raised the mice ate more and gained weight (R).

Ghrelin, the hunger hormone, stimulates AMPK in the hypothalamus (R).

While AMPK could have many beneficial effects on obesity, it is typically reduced in this disorder.

13) AMPK Increases Lifespan and is Antiaging

AMPK activation gradually declines during aging. It is possible that the age-related increase in chronic inflammation levels is responsible for the suppression in AMPK activity (R).

Activating AMPK may help multiple longevity pathways to promote healthy aging (R).

Many studies have shown that AMPK plays a crucial role in increasing longevity and calorie restriction-induced lifespan extension in worms, fruit flies, and rodents (R).

In worms, AMPK activation can increase lifespan by as much as 15% (R).

AMPK increases longevity by reducing protein production (R) and enhancing autophagy (R).

14) AMPK Helps Decrease Inflammation

AMPK can both decrease inflammation and be decreased by inflammation.

AMPK also exerts potent anti-inflammatory effects. AMPK inhibits inflammation by indirectly inhibiting NFκB, a key activator of inflammation (R).

While AMPK could have many beneficial effects in chronic inflammation, it is typically reduced in such states.

15) AMPK Improves Diabetes

AMPK activation improves insulin sensitivity (R).

AMPK deficient mice showed impaired glucose tolerance (R).

Metformin, an activator of AMPK, is the most frequently prescribed antidiabetic drug for type-2 diabetic patients (R).

16) AMPK Benefits the Heart

The activation of AMPK also performs a protective role in cardiovascular diseases (R).

17) AMPK Increases Testosterone

AMPK can increase male hormones/androgens in human cells (R). However, metformin (AMPK activator) is commonly given to women with PCOS to a good effect (PCOS is a condition with higher male hormones).

Negatives of AMPK

AMPK can suppress PPAR alpha and PPAR gamma (R), two important proteins that have beneficial functions in the body.

AMPK May Help or Hurt These Conditions

AMPK and Neurodegenerative Disease

AMPK has both protective and contributing properties when it comes to neurodegenerative diseases, and studies often come to opposing conclusions regarding this enzyme and its role.

In mice with Alzheimer’s, activation of AMPK by metformin was shown to increase amyloid-beta protein (Aβ) levels and therefore contribute to the disease (R).

However, Aβ generation was also shown to be increased in AMPK deficient mice (R). Furthermore, AMPK activation by resveratrol and AICAR also decreased Aβ secretion (R).

Indeed, the inactivation of AMPK was linked to increased Alzheimer’s risk in obese patients with type 2 diabetes (R).

In mice with Huntington’s disease, AMPK activation promoted neuronal loss and brain decay (R). But then again, another study showed that treatment with metformin significantly prolonged survival time in rodents with this disease (R).

Genetic activation of AMPK was also shown to protect against neuronal loss in Parkinson’s disease models in flies (R).

AMPK in Cancer

The role of AMPK in cancer is complicated (R).

AMPK activation can protect against DNA damage from oxidative stress.  This would protect against tumor initiation (R).

It’s also anti-cancer by inhibiting mTOR (R).

On the other hand, AMPK promotes glucose/energy uptake by cells, which can also be used by tumors once they have formed (R).

Given the above, it is suggested that AMPK activation is beneficial for cancer prevention but not for cancer treatment. Rather, AMPK inhibition could be useful for treating established cancers by inhibiting tumor stress adaptation and survival (R).

AMPK activation by its activators (AICAR and metformin) increased UVB-induced DNA repair in normal human skin cells. Topical treatment with AICAR and metformin not only delayed the onset of UVB-induced skin tumor formation but also reduced the number of tumors in mice (R).

Top 5 Ways to Increase AMPK Naturally

We want to increase AMPK in our muscle, fat, and liver cells and decrease it in our hypothalamus (if you have weight issues).

1) Exercise

Exercise uses energy (in the form of ATP), and the resulting lack of energy stimulates AMPK (R).

AMPK is stimulated by muscle contraction. High-intensity exercise significantly increases the activity of AMPK in healthy humans (R).

Many beneficial effects of exercise are carried out through AMPK, such as the insulin-sensitizing effect (R).

Through its effect on increasing the production of new mitochondria, AMPK can improve muscle performance.

The World Anti-Doping Agency (WADA) banned the AMPK activator AICAR because of its performance-enhancing effects (R).

2) Calorie Restriction

It is known that calorie restriction exerts many beneficial effects on aging, diabetes, and cancer. Some of these effects are mediated by AMPK. It was shown that calorie restriction activates AMPK through multiple mechanisms (R).

Overeating inhibits AMPK and AMPK activity is decreased in obese individuals (R).

High glucose levels, high levels of amino acids, especially branched-chain amino acids, and excess saturated fat inhibit AMPK. Elevated insulin also inhibits AMPK (R).

Calorie restriction stimulates adiponectin secretion from fat cells. Adiponectin activates AMPK in multiple tissues, including skeletal muscles (R).

Interestingly, adiponectin secretion is significantly reduced in obese individuals, which partially explains reduced AMPK activity in these individuals (R).

3) Decrease Inflammation

AMPK can both decrease inflammation and be decreased by inflammation.

Anti-inflammatory cytokines activate AMPK, while pro-inflammatory cytokines suppress it (R).

AMPK suppression in chronic inflammation contributes to insulin resistance. Reduced AMPK activity was associated with increased inflammation in the organ fat tissue and insulin resistance in morbidly obese individuals (R).

4) Cold Exposure

Exposure to cold increases AMPK activation in the hypothalamus and stimulates food intake (R).

5) Lipoic acid

α-Lipoic acid (ALA) can activate AMPK in muscles and other tissues. However, in the hypothalamus, ALA suppresses AMPK activity, leading to reduced food intake (R, R).

Natural Supplements to Activate AMPK (in liver, muscle or fat tissue)

Numerous polyphenols are capable of activating AMPK, and they exert beneficial effects on type 2 diabetes and metabolic syndrome. These include:

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

Practically, AMPK can be activated by any modulator that causes AMP (depleted ATP) or calciumaccumulation (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 (R, R2, R3)
  • Quercetin (R)…it increases AMPK in fat, liver, and muscle (RR2, R3),
  • 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








Hematol Oncol Stem Cell Ther.2018 Dec;11(4):189-194. doi: 10.1016/j.hemonc.2017.08.001. Epub 2017 Oct 19.

Aging and stem cell therapy: AMPK as an applicable pharmacological target for rejuvenation of aged stem cells and achieving higher efficacy in stem cell therapy.

Author information


In recent years, tissue regeneration has become a promising field for developing stem cell-based transplantation therapies for human patients. Adult stem cells are affected by the same aging mechanisms that involve somatic cells. One of the mechanisms involved in cellular aging is hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and disruption of 5′ adenosine monophosphate-activated protein kinase (AMPK). Aging of stem cells results in their impaired regenerative capacity and depletion of stem cell pools in adult tissue, which results in lower efficacy of stem cell therapy. By utilizing an effective therapeutic intervention for aged stem cells, stem cell therapy can become more promising for future application. mTORC1 inhibition is a practical approach to preserve the stem cell pool. In this article, we review the dynamic interaction between sirtuin (silent mating type information regulation 2 homolog) 1, AMPK, and mTORC1. We propose that using AMPK activators such as 5-aminoimidazole-4-carboxamide ribonucleotide, A769662, metformin, and oxidized nicotinamide adenine dinucleotide (NAD+) are practical ways to be employed for achieving better optimized results in stem cell-based transplantation therapies.



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