AMPK is an enzyme essential for maintaining energy balance. It consists of 3 proteins (called sub-units) that together create a functional enzyme. AMPK is expressed in various tissues, including the brain, liver, skeletal muscle, and fat cells. The net effects of AMPK activation include ketogenesis, stimulation of hepatic fatty acid oxidation, inhibition of cholesterol synthesis, triglyceride synthesis, and lipogenesis, and the stimulation of glucose uptake and skeletal muscle fatty acid oxidation.
AMPK is also an energy sensor. When activated in the proper tissues, it brings about a number of beneficial effects in the body. It improves insulin sensitivity, stimulates weight loss, enhances muscle performance, and reduces inflammation, among many other benefits. It also fosters healthy aging and is involved in multiple longevity pathways.
AMPK was initially discovered as an activity that was induced by AMP and that suppressed the preparations of 3-hydroxy-3-methylglutaryl-CoA reductase and acetyl-CoA carboxylase (ACC). AMPK induces a surge of events within the cells in the body, in response to the cell’s ever-changing energy charge. AMPK’s role in normalizing cellular energy charge makes it vital for maintaining homeostasis. Recent evidence shows that physiological stimuli can also regulate AMPK activity. This includes nutrients and hormones, and is independent of the cell’s energy charge.
- Structure of AMPK
- AMPK Signaling Pathway
- Benefits of AMPK Activation
- AMPK Side Effects
- How AMPK Affects Cancer and Neurodegenerative Diseases
- Natural Ways to Activate AMPK
- Drugs that Activate AMPK
- Hormones / Pathways that Activate AMPK (in the liver, fat, and muscle)
- Technical Information
Structure of AMPK
AMPK is a hetero-trimeric protein complex that is comprised of 3 sub-units: α, β, and γ. Each of these sub-units has a specific role in the activation and stability of AMPK.
If this section is a bit complex just skip down to benefits of ampk activation.
The γ sub-unit includes 4 distinct cystathionine beta synthase domains, which give AMPK the capability to sensitively detect changes in the AMP:ATP ratio. The 4 CBS domains create 2 sites where AMP can bind; these are commonly known as Bateman domains. When an AMP is bound to a Bateman domain, the binding affinity of the next AMP to the corresponding Bateman domain will increase.
AMPK sub-units are encoded in the following human genes:
γ – PRKAG1, PRKAG2, PRKAG3
β – PRKAB1, PRKAB2
α – PRKAA1, PRKAA2
Targets of AMPK
AMPK initiates signaling cascades that affect protein production, gene expression, and lipid and glucose metabolism. These effects are most beneficial for regulating metabolic processes in the liver, heart, skeletal muscle, pancreas, and adipose tissue.
In humans, the skeletal muscle’s uptake accounts for more than 70 percent of the removal of glucose from the serum. This is particularly important for the overall glucose homeostasis, bearing in mind that glucose uptake by adipocytes and cardiac muscle cannot be discounted from consideration. The glucose uptake increases drastically in response to exercise and stress, and is stimulated by the employment of glucose transporters (induced by insulin) to the plasma membrane (predominantly GLUT4).
The employment of glucose transporters (independent of insulin) also takes place in the skeletal muscle, this time, in response to muscle contraction (exercise). AMPK activation plays a crucial role in the employment of GLUT4 to the plasma membrane. AMPK does it by means of a mechanism different from that promoted by insulin, because together, the effects of AMPK and insulin are additive. Activating AMPK also leads to the enhanced expression of GLUT4 gene as it binds the transcription factor called MEF-2 (myocyte enhancer factor 2) to the stimulators in the GLUT4 gene.
Exercise and stress are strong inducers of AMPK activation in the skeletal muscle; regulators of its activation have also been identified. Metformin and the insulin-sensitizing drugs from the thiazolidinedione (TZD) family exert some of their effects by regulating AMPK activity. The activity of LKB1 (liver kinase B1) is crucial for regulating gluconeogenic flux and the resulting glucose homeostasis. In order for metformin to lower blood glucose levels, LKB1 must be activated in the liver. Additionally, several adipokines, which are hormones emitted by adipocytes, either inhibit or stimulate AMPK activation: adiponectin and leptin have been shown to induce AMPK activation, while resistin inhibits it.
Cardiac effects due to AMPK activation also include eNOS (endothelial nitric oxide synthase) phosphorylation in the cardiac endothelium. This increases activity and produces NO, and provides a relation between cardiac function and metabolic stresses. In platelets, the action of insulin results in increased eNOS activity caused by its AMPK-mediated phosphorylation. Production of NO in platelets causes a reduction in thrombin-induced aggregation, and thereby limits the pro-coagulant effects of the platelet activation. The way platelets respond to insulin function is a clear indication of why disrupting insulin action greatly contributes to the development of metabolic syndrome.
AMPK activation not only affects enzyme activity, it also influences the expression of many lipogenic and glycolytic enzymes in the adipose tissue and liver. These include the genes for ACC, fatty acid synthase, and liver isoform of L-PK or pyruvate kinase. AMPK activation results in reduced SREBP level. SREBP is a transcription factor largely involved in regulating the expression of a number of lipogenic enzymes. HNF4α, or hepatocyte nuclear factor, is another transcription factor decreased in response to the activation of AMPK. HNF4α is a member of the thyroid/steroid hormone super-family. It regulates the expression of numerous pancreatic and liver β-cell genes, including L-PK, GLUT2, and preproinsulin.
The target of TZD drugs is the PPARγ or peroxisome proliferator-activated receptor γ, which itself may likewise be a target for AMPK activity. AMPK inhibits the interaction of p300 with PPARy, retinoic acid receptor, thyroid hormone receptor, and retinoid X receptor, and phosphorylates p300 (which is a transcription co-activator). PPARy is largely expressed in the adipose tissue. Therefore, it was difficult at first to resolve how a drug that was performing only in adipose tissues could help improve insulin sensitivity of the other tissues. This was reconciled when TZDs were found to stimulate the release and expression of the adipocyte hormone called adiponectin.
Adiponectin induces fatty acid oxidation and glucose uptake in the skeletal muscle. It also induces fatty acid oxidation in the liver while inhibiting the expression of the gluconeogenic enzymes in that tissue. Such responses to adiponectin are put forth by activating AMPK.
AMPK targets another transcription factor called forkhead protein or FKHR, (now known as FoxO1). FoxO1 is implicated in activating glucose-6-phosphatase expression. Therefore, absence of FoxO1 activity due to AMPK activation will result in decreased hepatic production of glucose.
AMPK Signaling Pathway
AMPK acts as the “master regulator” of the cellular energy homeostasis. It is activated in response to the stimuli and stresses that use up the ATP supplies (e.g. low glucose, ischemia, hypoxia, heat shock). Activating AMPK positively regulates the signaling pathways (such as autophagy and fatty acid oxidation) that replenish the cellular ATP supplies.
On the other hand, AMPK negatively affects ATP-utilizing biosynthetic processes such as gluconeogenesis, protein and lipid synthesis. It accomplishes this by directly phosphorylating several enzymes that are directly involved in such processes, as well as by transcriptionally controlling metabolism through phosphorylation of transcription factors, co-repressors, and co-activators.
Due to its role as central regulator of glucose and lipid metabolism, AMPK can be a potential target for treating type-2 diabetes mellitus, cancer, and obesity, and for modulating aging by interacting with sirtuins and mTOR.
Benefits of AMPK Activation
1) Burns fat: AMPK blocks the production of cholesterol, triglycerides, and fatty acids, and instead promotes the burning of fat. For this reason, AMPK activation can be beneficial to people with weight and cardiovascular problems.
2) Improves metabolism: Hypothalamic AMPK senses the level of energy (in the form of Adenosine Triphosphate or ATP) being produced in the body. This results in increased energy expenditure, as well as in improved appetite when it takes place in the hypothalamus.
AMPK is activated when cellular energy drops. It targets an array of processes and brings about a coordinated reduction in energy usage and an increase in energy (ATP) production. In addition, it improves glucose uptake and production, and decreases heat production.
3) Produces and breaks down sugars: Glucose is the body’s primary source of fuel and is particularly vital for normal brain function. Hypoglycemia, a health condition in which the level of blood glucose drops below normal, poses a serious danger to brain function and stability, and consequently activates AMPK.
AMPK activation in the hypothalamus stimulates the production of glucose from the liver by inhibiting glycogen synthesis (glucose storage). It also promotes the breaking down of glucose for fuel (in the form of ATP) and the uptake of glucose into the muscles.
4) Inhibits protein production: In order to conserve energy, especially during the state of low energy, AMPK inhibits the production of protein, a process that generally requires high energy.
5) Acts as antioxidant: AMPK plays an essential role in boosting the body’s antioxidant defense in the event of oxidative stress. It stimulates the production of various antioxidant proteins, including superoxide dismutase, uncoupling protein 2, and NRF2.
6) Facilitates oxygen delivery: AMPK activation can protect against severe breathing instability during sleep or hypoxia (a state in which oxygen level is low). The absence of AMPK has been shown to trigger breathing impairment during hypoxia, according to an animal study conducted in mice.
7) Aids in weight loss: As mentioned, AMPK contributes to the body’s fat-burning ability, and therefore aids in weight loss. For weight loss, preferably, AMPK is activated in the liver, muscle, and fat, and inhibited in the hypothalamus. In this manner, energy and fat stores will burn and hunger will decrease simultaneously.
8) Provides similar benefits as exercise: You can obtain the benefits of physical exercise, partly, by activating AMPK. Sedentary mice who took an AMPK activator called AICAR for 4 weeks gained the same benefits as performing endurance training (in terms of actual treadmill endurance and muscle mitochondrial profiles).
9) Improves blood circulation: AMPK helps improve blood circulation through vasodilation or the widening of blood vessels). Further, it stimulates the release of nitric oxide in the blood vessels.
10) Helps with fertility: AMPK increases the production of sex hormones in both sexes. This helps with fertility in various animal species. On the other hand, loss of AMPK may lead to reduced fertility in either sex.
11) Promotes production of mitochondria: AMPK improves mitochondrial activity for both acute and long term. It also controls the turn-over and production of mitochondria. A study carried out in mice found that AMPK loss decreases mitochondrial activity and significantly reduces muscle performance.
12) Promotes autophagy (cellular renewal): Autophagy, a process that recycles cellular components, promotes cell and molecular sub-unit quality control. It degrades misfolded or damaged proteins and mitochondria. Autophagy also contributes to energy generation: it promotes the process of mitochondrial metabolism by providing sufficient fuel.
13) Fights aging and increases lifespan: As we age, AMPK activation progressively declines. This may be due to the age-related increase of inflammation in the body. On the other hand, AMPK activation has been shown to facilitate several longevity pathways to foster healthy aging. This is by means of enhancing autophagy and decreasing protein production.
14) Helps reduce inflammation: AMPK indirectly inhibits NFκB, a primary activator of chronic inflammation, and thereby decreases inflammation in the body. AMPK and inflammation, however, are like two opposing forces. AMPK can reduce inflammation but can also be reduced by inflammation.
15) Improves heart health: AMPK activation plays a crucial role in protecting against cardiovascular diseases. For one, it improves blood flow and reduces bad cholesterol and triglyceride levels.
16) Improves symptoms of diabetes: Activating AMPK enhances insulin sensitivity. Mice with AMPK deficiency showed dysfunctional glucose tolerance. Metformin, an AMPK activator, is the most commonly prescribed anti-diabetic medication for patients with type-2 diabetes.
17) Increases testosterone levels: AMPK may increase androgen/male hormones in human cells. On the contrary, Metformin (the same drug given to diabetic patients) is frequently prescribed to women with higher male hormones, a condition called PCOS.
AMPK Side Effects
AMPK activation may suppress PPAR gamma and PPAR alpha, two essential proteins with beneficial functions in the human body.
How AMPK Affects Cancer and Neurodegenerative Diseases
The effect of AMPK activation on cancer is rather complicated. On one hand, AMPK can protect against cell damage due to oxidative stress, which in turn protects against cancer and tumor initiation. On the other, AMPK promotes energy/glucose uptake by the cells, which can be used by a tumor once it has formed.
Considering the above, AMPK activation is deemed beneficial only for the prevention of cancer, and not for its treatment. Instead, AMPK inhibition may be helpful for treating established cancers as it can help inhibit the survival and adaptation of tumor stress.
When it comes to neurodegenerative diseases, AMPK has both contributing and protective properties. However, studies often have opposing conclusions as regard this enzyme and its actual role.
In mice infected with Alzheimer’s, AMPK activation by metformin resulted in increased levels of amyloid-beta protein (Aβ), and thereby contributed to the disease. However, the generation of Aβ was also shown to increase in AMPK-deficient mice. Further, AMPK activation by AICAR and resveratrol also reduced Aβ secretion.
Indeed, AMPK inactivation was associated with increased risk of Alzheimer’s disease in obese patients suffering from type-2 diabetes.
In mice infected with Huntington’s disease, the activation of AMPK promoted brain decay and neuronal loss. Then again, a different study showed that taking metformin dramatically prolonged the survival time of rodents with the same disease.
Natural Ways to Activate AMPK
If you have weight problems, you will want to activate AMPK in your liver, fat, and muscle cells and inhibit it in your hypothalamus. Here are some natural ways to do just that:
Exercise: When you exercise, you expend energy in the form of ATP. This results in lack of energy, which then stimulates AMPK. High-intensity workouts and exercises that involve muscle contraction can effectively activate AMPK. AMPK can also improve muscle performance.
Calorie restriction: Restricting calorie intake has been known to have several beneficial effects against cancer, aging, and diabetes. These effects are mostly facilitated by AMPK. Excess saturated fat and high levels of glucose and amino acids (particularly branched-chain amino acids) all inhibit AMPK.
Reduce inflammation: Pro-inflammatory cytokines inhibit AMPK while anti-inflammatory cytokines increase it. Decreased AMPK activity has been linked to increased inflammation in organ fat tissues and insulin resistance in severely obese individuals.
Exposure to cold: Cold exposure activates AMPK in the hypothalamus and induces food intake.
Natural Supplements That Activate AMPK
These natural supplements activate AMPK in the liver, fat tissue, and muscle. They bring about beneficial effects on metabolic syndrome and type-2 diabetes.
- Anthocyanins (a compound found in bilberries, blueberries, bark extract, and grape seed extract)
- Berberine (from Coptis chinensis, Berberis vulgaris, and Berberis asitata)
- compounds isolated from Solomon’s seal (Polygonatum odaratum)
- Curcumin (a compound found in turmeric )
- EGCG (from green tea)
- Genistein (found in soybeans and many other plants)
- Quercetin from numerous plants including grains, fruits, and vegetables (*Note: quercetin activates AMPK in liver, fat, and muscle, and inhibits it in the hypothalamus.)
- Resveratrol (from red grapes and knotweed)
- A-Lipoic Acid
- Apple Cider Vinegar / Pomegranate vinegar / Acetic acid
- Arctigenin from the seeds of burdock (Arctium lappa)
- Bitter Melon (Cucurbitane)
- Danshen / Salvia Miltiorrhiza / TanshioneIIA
- Extra-Virgin Olive Oil
- Fish Oil
- Ginseng/Ginsenoside RB1.
- Nicotine (in fat cells)
- Panduratin from Boesenbergia pandurate (Chinese ginger)
- Red yeast rice (ankaflavin and monascin)
- Vitamin E / gamma tocotrienols + Turkey tail / PSP
Drugs that Activate AMPK
Aspirin: Salicylate directly activates AMPK. Aspirin decreases TG levels and circulating fatty acids in obese, type-2 diabetic patients. It enhances fat-burning during the fasting state in healthy humans, which may be due to the direct impact of aspirin on the activation of AMPK.
Metformin: Metformin is a blood sugar-reducing agent. Many of its anti-diabetic functions are mediated by AMPK. These include stimulation of fat-burning and glucose uptake, and the reduction in liver glucose and fat production.
Thiazolidinediones: This drug acts largely by activating PPAR, but it also produces anti-diabetic effects partly by activating AMPK. It rapidly activates AMPK in various tissues including liver, fat tissues, and muscle. TZDs are commonly prescribed for controlling blood sugar, but cause weight gain as a side-effect.
Hormones / Pathways that Activate AMPK (in the liver, fat, and muscle)
Practically any modulator that causes calcium accumulation or AMP (depleted ATP) can activate AMPK.
Adiponectin: Adiponectin is produced by fat cells. It serves as a signal for starvation. During fasting, adiponectin stimulates and increases AMPK, resulting in induced food intake and reduced energy expenditure. Adiponectin level drops after refeeding; simultaneously, AMPK activity declines.
Leptin: Leptin is the anti-obesity and satiety hormone released by fat cells when insulin is present. It prevents overeating by preventing hypothalamic AMPK from suppressing appetite. It does, however, activate AMPK in the muscles.
Thyroid hormone T3: This hormone increases consumption of cellular oxygen and causes AMPK activation in the muscles.
ROS-producing agents: Modulators that induce the generation intracellular reactive oxygen species (ROS) can activate AMPK. Example of this is cryptotanshinone from Salvia Miltiorrhiza (red sage). It exerts anti-cancer and anti-diabetic effects by activating ROS-dependent AMPK. DNA-damaging agents, like cisplatin and metals (e.g. arsenite, cobalt, vanadate), also activate AMPK by generating ROS.
Hormones that Activate Hypothalamic AMPK
Cannabinoids: Found in the cannabis plant, cannabinoids promote AMPK activity which leads to increased appetite. However, these compounds tend to reduce AMPK in the liver and fat cells.
Ghrelin: This “hungry hormone” is produced in the stomach and discharged during fasting. It maintains normal blood glucose levels and is crucial for survival during fasting or strict calorie restriction. Ghrelin stimulates food consumption but inhibits AMPK in the liver and fat tissues, like cannabinoids.
Hormones that Inhibit Hypothalamic AMPK
Natural Substances that Inhibit Hypothalamic AMPK
Lipoic Acid: Inhibits AMPK in the hypothalamus but increases it in the liver, fat, and muscles.
Nicotine: Weight loss induced by nicotine is linked to the inactivation of AMPK in the hypothalamus.
Quercetin: Like lipoic acid, it increases AMPK in the liver, fat, and muscle, and inhibits it in the hypothalamus.
Ketones: Ketones are produced when the body enters the state of ketosis; that is, a state in which the body burns fat for fuel, instead of glucose.
AMPK acts as an up-stream inhibitor of mTOR
AMPK can be activated by Tak1, LKB1, or CaMKKβ
AMPK can directly activate the family members of FOXO
AMPK blocks the main regulator of SREBPc lipogenesis
AMPK may activate NRF2
AMPK activation often results in the decrease of mTOR. But there are some scenarios in which both AMPK and mTOR are activated. This is because AMPK does not inhibit mTOR directly; rather, it inhibits a protein that directly activates mTOR.