Evidence BasedThis post has 61 references 4.

4/5

AMPK: Metabolism & Insulin + Ways to Activate

Medically reviewed by Puya Yazdi, MD | Written by Biljana Novkovic, PhD | Last updated: December 13,
2019

//

CONTENTS

AMPK is an energy sensor that, when activated in certain tissues, has many
bene cial e ects on our bodies. It stimulates the metabolism, improves
insulin sensitivity, decreases in ammation, and improves muscle
performance. AMPK is also involved in several longevity pathways and may
promote healthy aging.

AMPK: The Energy Enzyme

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 [1].

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
[1].

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.

Health Effects of AMPK Activation

1) Increases Metabolism

AMPK in the hypothalamus senses our level of energy production in the body (in the
form of ATP). It increases energy expenditure and can also increase appetite (when it is
activated in the hypothalamus) [2].

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 [3].

Hypothalamic AMPK increases appetite, increases glucose production and uptake,

reduces heat production, and decreases energy output [2].

2) 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 [2].

Hypothalamic AMPK activation promotes glucose production from the liver [2] and
glucose uptake into the muscles [4].

AMPK inhibits glucose storage (glycogen synthesis), resulting in more glucose being
available for energy production [4].

In various cells, AMPK stimulates the breakdown of glucose for energy (in the form of
ATP) [4].

3) Burns Fat
AMPK inhibits the production of fatty acids, cholesterol, and triglycerides, and instead
stimulates the breakdown and burning of existing fat for energy [4].

4) 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
[4].

Inhibiting excessive protein production results in a much more energy-e cient and less
wasteful cell.

5) Promotes Cellular Recycling (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 [3].

Autophagy can contribute to energy generation by providing fuel for mitochondrial

metabolism, and AMPK promotes this process [4].

Advertisement

Coronavirus Causing Extra Stress? Get 36 Natural Remedies To

Reduce Anxiety

The Coronavirus pandemic is causing a lot of extra stress and anxiety, which can
actually weaken your immune system and put you more at risk. Download the Stress
Less guide to discover natural supplement and lifestyle recommendations designed to
help you beat stress and improve your mood.

Enter your email

REDUCE STRESS

Advertisement

Coronavirus Causing Extra Stress? Get 36 Natural Remedies To

Reduce Anxiety
The Coronavirus pandemic is causing a lot of extra stress and anxiety, which can
actually weaken your immune system and put you more at risk. Download the Stress
Less guide to discover natural supplement and lifestyle recommendations designed to
help you beat stress and improve your mood.

Enter your email

REDUCE STRESS

6) Regulates the Mitochondria

AMPK is capable of both acute and long-term improvement of mitochondrial activity [3].

AMPK also regulates the production and turnover of mitochondria. Loss of AMPK in
mice reduces mitochondrial activity and greatly diminishes muscle performance [3].

7) Acts as an Antioxidant

AMPK has a crucial role in increasing antioxidant defense during oxidative stress [4].

AMPK increases the production of several antioxidant proteins, such as NRF2,

superoxide dismutase and uncoupling protein 2 (UCP2) [4].

8) Helps With Oxygen Delivery

Upon hypoxia (low oxygen) at altitude or during sleep, activation of AMPK may protect
against acute breathing instability. Loss of AMPK was shown to cause breathing
dysfunction during hypoxia in mice [5].

Variations of gene components of AMPK has been found in high-altitude Andean

populations, presumably in order to improve survival in low oxygen conditions [5, 6].

9) Important for Fertility

In several animal species, AMPK increases the production of sex hormones [7].

The absence of AMPK leads to reduced fertility in both sexes [7].

10) Increases Blood Flow

AMPK plays a critical role in increasing blood ow through vasodilation (widening of the
blood vessels), by stimulating nitric oxide release in blood vessels [8].
11) May Promote Healthy Weight

AMPK outside of the brain increases fat burning, and this pathway can result in weight
loss [9].

By contrast, AMPK activation in the brain increases appetite. 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 [10].

Ghrelin, the hunger hormone, stimulates AMPK in the hypothalamus [11].

12) May Promote Longevity

AMPK activation gradually declines during aging. Some researchers believe that the
age-related increase in chronic in ammation levels is responsible for the suppression of
AMPK activity [4].

Activating AMPK may help multiple longevity pathways and promote healthy aging [3].

Many studies have shown that AMPK plays a crucial role in increasing longevity and
calorie restriction-induced lifespan extension in worms, fruit ies, and rodents [4].

In worms, AMPK activation can increase lifespan by as much as 15% [12].

AMPK increases longevity by reducing protein production [3] and enhancing autophagy
[3].

Longevity Pathways of AMPK

AMPK activates longevity FOXO proteins [3]

AMPK activates the master antioxidant regulator NRF2 [4]
AMPK inhibits the ‘master regulator’ of lipogenesis SREBPc [3]
AMPK inhibits mTOR indirectly [3]

Longevity research is a contentious and controversial eld, and the precise role of
AMPK in determining lifespan is unknown. Much more research is required to
determine this enzyme’s role in aging and longevity.

14) Helps Decrease Inflammation

AMPK can both decrease in ammation and be decreased by in ammation.

AMPK also exerts potent anti-in ammatory e ects. AMPK inhibits in ammation by
indirectly inhibiting NFκB, a key activator of in ammation [4].
While AMPK could have many bene cial e ects in chronic in ammation, it is typically
reduced in such states.

15) Improves Diabetes

AMPK activation improves insulin sensitivity [4].

AMPK de cient mice showed impaired glucose tolerance [13].

Metformin, an activator of AMPK, is the most frequently prescribed antidiabetic drug for
type-2 diabetic patients [4].

16) Benefits the Heart

The activation of AMPK also performs a protective role in cardiovascular diseases [14].

17) Increases Testosterone

AMPK can increase male hormones/androgens in human cells [15]. However, metformin
(AMPK activator) is commonly given to women with PCOS to a good e ect (PCOS is a
condition with higher male hormones); much more research is required to determine
AMPK’s role in testosterone production.

A Role in 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 [3].

However, Aβ generation was also shown to be increased in AMPK de cient mice [13].
Furthermore, AMPK activation by resveratrol and AICAR also decreased Aβ secretion
[3].

Indeed, the inactivation of AMPK was linked to increased Alzheimer’s risk in obese
patients with type 2 diabetes [3].

In mice with Huntington’s disease, AMPK activation promoted neuronal loss and brain
decay [3]. But then again, another study showed that treatment with metformin
signi cantly prolonged survival time in rodents with this disease [12].

Genetic activation of AMPK was also shown to protect against neuronal loss in
Parkinson’s disease models in ies [3].
 Overactivation or underactivation of AMPK may each contribute to
neurodegenerative disease, and the safest bet is to lead a healthy and balanced
life. More research is needed.

A Role in Cancer?

The role of AMPK in cancer is complicated and poorly understood [4].

AMPK activation can protect against DNA damage from oxidative stress. This would
protect against tumor initiation [4].

It’s also anti-cancer by inhibiting mTOR [4].

On the other hand, AMPK promotes glucose/energy uptake by cells, a process which
can be hijacked by tumors once they have formed [4].

Given the above, some researchers have suggested that AMPK activation is bene cial
for cancer prevention, but not necessarily for cancer treatment [4].

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 [16].

AMPK activation seems to be bene cial for cancer prevention, but not for cancer
treatment. More research is needed.

Potential Negatives of AMPK

AMPK can suppress PPAR alpha and PPAR gamma [17], two important proteins that
regulate metabolism and gene expression.

Activating AMPK (outside of the brain)

Healthy diet and exercise are the necessary rst steps to a healthy lifestyle, and they’re
also the most reliable bet for weight loss. Before adopting any other strategies, talk to
your doctor about the best ones for you.

Best AMPK Activators

1) Exercise
Exercise uses energy (in the form of ATP), and the resulting lack of energy stimulates
AMPK [2].

AMPK is stimulated by muscle contraction. High-intensity exercise signi cantly

increases the activity of AMPK in healthy humans [2].

Many bene cial e ects of exercise are carried out through AMPK, such as the insulin-
sensitizing e ect [4].

2) Calorie Restriction

Calorie restriction has been associated with many bene cial e ects on aging, diabetes,
and cancer. Some of these e ects are mediated by AMPK. It was shown that calorie
restriction activates AMPK through multiple mechanisms [4].

Overeating inhibits AMPK, and AMPK activity is decreased in obese individuals [4].

High glucose levels, high levels of amino acids, especially branched-chain amino acids,
and excess saturated fat inhibit AMPK. Elevated insulin also inhibits AMPK [4].

Calorie restriction stimulates adiponectin secretion from fat cells. Adiponectin activates
AMPK in multiple tissues, including skeletal muscles [4].

Adiponectin secretion is signi cantly reduced in obese individuals, which partially

explains reduced AMPK activity in these individuals [4].

3) Decrease Inflammation

AMPK can both decrease in ammation and be decreased by in ammation, so it’s

important to address any underlying in ammatory conditions.

Anti-in ammatory cytokines activate AMPK, while pro-in ammatory cytokines suppress
it [3].

AMPK suppression in chronic in ammation contributes to insulin resistance.

Reduced AMPK activity was associated with increased in ammation in the organ fat
tissue and insulin resistance in morbidly obese individuals [4].

4) Cold Exposure

In rats, exposure to cold increased AMPK activation in the hypothalamus and stimulates
food intake. This e ect has not been reproduced in humans [18].

5) Lipoic acid
α-Lipoic acid (ALA) may activate AMPK in muscles and other tissues, though its precise
mechanism and e ects have not been su ciently investigated. Some studies have
suggested that ALA may decrease hypothalamic AMPK, which could help reduce
appetite and food intake [19, 13].

Natural Supplements

These supplements have not been approved by the FDA for medical use and generally
lack solid clinical research. Regulations set manufacturing standards for them but don’t
guarantee that they’re safe or e ective. Speak with your doctor before supplementing.

That said, numerous polyphenols have been found to activate AMPK in cell and animal
studies. These include:

Resveratrol from red grapes [19, 13]

Quercetin from many plants including fruits, vegetables, and grains [19, 13]. Note
that quercetin increases AMPK in fat, liver, and muscle but inhibits hypothalamic
AMPK [20].
Genistein found in a number of plants such as soybeans [19].
EGCG from green tea [19, 13]
Berberine from Berberis vulgaris, Berberis asitata and Coptis chinensis [19, 13].
Curcumin from turmeric [19, 13]
compounds isolated from Solomon’s seal (Polygonatum odaratum) [13].
Anthocyanins found in blueberries, bilberries, grape seed extract and pine bark
extract [21].
Apigenin [22]
Zinc [23]
Nicotine (in fat cells) [24, 25] and mediates the anti-in ammatory e ect of nicotine
[26].
Palmitoylethanolamide (activates AMPK in fat tissue, but inhibits it in the
hypothalamus) [27]
Bitter Melon (Cucurbitane) [13]
Carnitine [28]
Glucosamine [29, 30]
Extra virgin olive Oil [31]
Fish Oil – EPA [32], DHA [33]
Cinnamon [34]
Astragalus [35, 36]
Reishi [37]
 Ginseng/Ginsenosides. A number of ginsenosides have been reported to activate
AMPK, resulting in an increased glucose uptake, decreased liver triglyceride and
cholesterol levels, and the inhibition of fat production and liver glucose production
[19].
Apple Cider Vinegar /Acetic acid [38], Pomegranate vinegar [39]
Rooibos [40]
Creatine [41]
CoQ10 [42]
Gynostemma [43]
Hydroxytyrosol [44]
Baicalin [45, 46]
Fucoidan [47]
Danshen/Salvia Miltiorrhiza/Tanshinone IIA [48]
Red yeast rice (monascin and anka avin) [49]
Arctigenin from the seeds of burdock (Arctium lappa) [13].
Panduratin from Chinese ginger (Boesenbergia pandurate) [13].

Hormone Pathways

These hormone pathways stimulate and regulate AMPK activation in everyday life.
Maintaining a healthy diet and exercising regularly is the best way to keep each of
these hormones in balance.

1) Adiponectin

Fat cells produce adiponectin [13], which serves as a starvation signal [2].

In fasting, adiponectin increases and stimulates AMPK, leading to the induction of food
intake and reduction of energy expenditure. After refeeding, a decrease in adiponectin
level is accompanied by blunted AMPK activity [2].

2) Leptin

Leptin, the satiety hormone secreted by fat cells in the presence of insulin, prevents
overeating by inhibiting AMPK in the hypothalamus to suppress appetite [4]. It also
activates AMPK in muscle [4].

3) Thyroid hormone T3

The thyroid hormone T3 increases cellular oxygen consumption and activates AMPK in
the muscles [50].
4) Nitric Oxide

Nitric oxide activates AMPK [51, 52].

Drugs

The drugs discussed here have not been approved for the purpose of activating AMPK.
Do not use medications without a prescription from your doctor.

1) Metformin

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

diabetes [13].

AMPK mediates many of the antidiabetic actions of metformin: stimulation of fat burning
and glucose uptake, and decreased fat production and liver glucose production [19].

2) Aspirin

Salicylate is a direct activator of AMPK [19].

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 e ect of aspirin on AMPK activation [4].

Hypothalamic AMPK

Activating AMPK in the brain (hypothalamus) has the opposite e ect as it does when
activating it in the liver, fat, and muscles. Activating AMPK in the brain increases
appetite and may increase weight gain. When it’s activated in non-brain tissue, it
promotes fat burning.

Inhibiting AMPK in the brain likewise reduces appetite and may cause weight loss.
However, no substance or strategy has su cient evidence to support claims of
activating or inhibiting hypothalamic AMPK. The best strategy for weight loss remains
diet and exercise.

Substances that Activate Hypothalamic AMPK

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 [4].
Ghrelin activates AMPK in the hypothalamus and stimulates food intake [4], however, it
inhibits AMPK in the fat tissue and liver [4].

2) Cannabinoids

Cannabinoids stimulate AMPK activity in the hypothalamus leading to increased

appetite [2]. However, it decreases AMPK in fat cells and liver, similar to Ghrelin [53].

3) Cortisol

Cortisol stimulates AMPK activity in the hypothalamus [2].

Substances that Inhibit Hypothalamic AMPK

Hormones

Leptin [4]
Insulin [2]
GLP-1 [2]
Estradiol [2]

Natural Substances

Lipoic acid [19, 13]… it increases AMPK in muscles, fat and liver cells [54, 55, 56]
Quercetin [20]… it increases AMPK in fat, liver, and muscle [57, 58, 59]
Nicotine [60] – Smokers around the world commonly report increased body
weight after smoking cessation. Nicotine-induced weight loss is associated with
the inactivation of hypothalamic AMPK [60].
Ketones [61]

Advertisement

Does Coronavirus have you stressed out?

Extra stress can weaken your immune system and it’s now more important than ever to
keep your immune system strong! Find out how to naturally improve your reduce stress
and anxiety with SelfDecode’s Mood DNA Wellness Report. It gives you personalized
genetic-based diet, lifestyle and supplement tips that can help improve your mood.

Improve My Mood
About the Author

Biljana Novkovic
PHD

Biljana received her PhD from Hokkaido University.

Before joining SelfHacked, she was a research scientist with extensive eld and laboratory
experience. She spent 4 years reviewing the scienti c literature on supplements, lab tests and
other areas of health sciences. She is passionate about releasing the most accurate science and
health information available on topics, and she's meticulous when writing and reviewing articles to
make sure the science is sound. She believes that SelfHacked has the best science that is also
layperson-friendly on the web.
 RATE THIS ARTICLE

FDA Compliance

The information on this website has not been evaluated by the Food & Drug Administration or any other medical
body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for
educational purposes only. You must consult your doctor before acting on any content on this website, especially
if you are pregnant, nursing, taking medication, or have a medical condition.

LOAD COMMENTS

Leave a Reply
Your email address will not be published. Required elds are marked *

Comment

Name *

Email *

Website

Save my name, email, and website in this browser for the next time I comment.

POST COMMENT

This site uses Akismet to reduce spam. Learn how your comment data is processed.
 JOE COHEN, CEO

About Joe

Joe Cohen won the genetic lottery of bad genes. As a kid, he su ered from in ammation, brain fog, fatigue,
digestive problems, anxiety, depression, and other issues that were poorly understood in both conventional
and alternative medicine.

Read More

Related Articles
VIEW ALL

Blood Tests 4.7 4

High & Low Basophil Count (Absolute) & Function

Pharmaceuticals 4.4 1

10 Indomethacin Uses, Side E ects & Dosage

 Hormones 4.5 29

9 Bene cial E ects of Oxytocin + 34 Ways to Increase it

SelfHacked Partner Solutions

What do your genes tell you about your health?

Align your health hacks with your genes for optimal health & cognitive function.

CHECK OUT SELFDECODE NOW

Our website services, content, and products are for informational purposes only. Sel acked LLC
does not provide medical advice, diagnosis, or treatment. See additional information.
SelfHacked © 2013 – 2020 All Rights Reserved

Navigation

Home

Posts

About

Genetics

Labs

VIP Login
Store

Careers

Contact us

Sitemap

Login

Our Policies

Advertising Policy

Genetics

Labs

Accessibility

Editorial Policy

Cookie Policy

Corrections Policy

Disclaimer

Terms and Conditions

Privacy Policy

Login

Contact Us
support@selfdecode.com