AMPK – Metabolic Switch.

The machinery of the human body is vastly complicated.
However, there is one signal at the heart of it all, which controls how well that machinery works.
This is the enzyme, AMPK, which is found in the hypothalamus in the brain.

Hypothalamic AMPK has such omnipotence over the health of the body because it controls the rationing of energy throughout the body.

It responds to signals about the status of energy in the body, by receiving signals about energy storage (from the fat cells) and energy supply (the food which is consumed).
The hypothalamus uses this information about the energy supplies in the body to decided the quantity of energy which should be apportioned to different health systems. 
It also makes decisions about the distribution of energy throughout the body, prioritising certain health systems and depriving others.
These decisions about quantity and distribution of energy, throughout the body, determine how well individual health systems operate and the symptoms of disease which we experience.

When the signals received by the hypothalamus indicate energy abundance AMPK distributes energy generously throughout the body.
When a bodily system has plenty of energy available, it is able to work optimally and the manifestation of this is good health.

When the hypothalamic  receives signals that the energy status of the body is declining or deficient; the AMPK response is the restriction of energy rations to certain systems in the body.
The purpose of this is to ensure that the most basic functions of survival have enough energy.
More 'frivolous' functions, such as the reproductive system, may become deprived, whilst energy supplies are deemed to be low. 

The Mechanism

When the hypothalamus receives signals that energy stores are becoming depleted in the body; AMPK becomes activated in the hypothalamus.

AMPK activation in the hypothalamus causes AMPK to become inhibited in the rest of the body. R] R]

It is AMPK inhibition in the various health systems, throughout the rest of the body, which reduces the energy which is available for its utilisation and effective functioning.

AMPK Determines the Distribution, Number and Function of the Mitochondria

If you have been researching health for any length of time, you have no doubt heard about mitochondria.

Mitochondria are the energy-producing 'factories', where oxygen and food are burned to make energy.

AMPK activation determines the distribution, the number and the effectiveness of mitochondria , throughout the body.. R]

This is how AMPK controls the the sharing out of energy to the different bodily functions.
By controlling the number and effectiveness of energy- producing factories allotted to each health system; AMPK controls the amount of energy which is produced for each system to use.
Systems with more AMPK-induced mitochondria, will receive the most fuel (oxygen and food).
Systems which have less AMPK-induced mitochondria will receive more oxygen and food and be able to produce more energy for use. 
These systems, with more AMPK-induced mitochondria, will function more optimally, whilst systems with less mitochondria will receive less fuel, produce less energy for utilisation and function less effectively.

The manifestation of health systems operating with a low number of energy-producing mitochondria are the symptoms of metabolic syndrome and the endless number of  ‘associated’ health disorders.

Chronic Diseases of the 'West' are Symptoms of Environmentally-Induced Failure of AMPK 

The number of disorders which have been found to be associated with metabolic syndrome is huge and includes; autoimmune disorders, Alzheimer’s Disease, anxiety, irritable bowel syndrome, certain cancers, fatigue, allergies and many more.
They comprise all of  the diseases which are characteristic to the ‘Western’ civilisations and which are rare or absent in hunter-gatherer and other less westernized societies.

The number of disorders which have been found to be associated with metabolic syndrome is huge and includes; autoimmune disorders, Alzheimer’s Disease, anxiety, irritable bowel syndrome, certain cancers, fatigue, allergies and many more.
They comprise all of  the diseases which are characteristic to the ‘Western’ civilisations and which are rare or absent in hunter-gatherer and other less westernized societies.

The fact that these diseases are characteristic to the 'West', indicates that they all share an environmental root cause.
As I will discuss; all of these diseases are profoundly regulated by AMPK.
This indicates that the chronic diseases and disorders (including obesity) of the 'West' are symptoms of an environmentally-induced failure of the body's energy distribution system (the failure of AMPK).

Chronic Disease: The Hypothalamus is Inappropriately 'Stuck' in Emergency, Energy- Conservation Mode 

The energy conservation response to low fuel supply (food) and low energy stores (the loss of body fat), enacted by the hypothalamus, would once have been beneficial in helping our ancestors survive.
However, in the modern world, we are very rarely actually short of fuel supply (we eat in abundance) and very few of us are short of body fat stores.
In fact, by far the most common problem in the modern world is that we are eating too much and that we have an excess of fat stores on the body.
The majority of us have more than enough energy to go round.
So, why do so many of us suffer the symptoms of a hypothalamus which is clearly  operating on restricted rations of  energy?

Why are we perpetually, inappropriately hungry? (Increased appetite is another symptom of a hypothalamus in energy depletion mode).

Why is the energy supply (the food which we eat)  being stored on our body fat and around our internal organs, instead of being made available for use to optimise the healthy function of the body?
Why is the hypothalamus not getting the messages of energy sufficiency and translating that into generous energy distribution throughout the body?

The answer is that the hypothalamus has become ‘deaf’ to the signals of energy abundance.

Hypothalamic Failure: Insulin and Leptin Resistance

Two of the most important signals of energy status, which inform the hypothalamus about the amount of energy available in the body;   are the hormones: Leptin and insulin.
Leptin is released by fat cells, which are the body's fat storage facility. 
When the hypothalamus receives leptin signals, it knows that there are plenty of fat cells on the body and that there are plentiful energy stores. 
Insulin is released by the pancreas when we consume food and it tells the hypothalamus that energy has been consumed (that energy supply is plentiful).

This developing inability to ‘hear’ the signals of energy abundance in the body is called leptin and insulin ‘resistance’.
Leptin and insulin resistance play a vital role in the development of obesity and ‘Western’ disease

As I argue in this article; the initiating trigger which causes hypothalamic leptin and insulin resistance is the failure of certain intestinal signals.

GLP-1 and Intestinal Gluconeogenesis Maintain the Sensitivity of the Hypothalamus 

GLP-1 and Intestinal Gluconeogenesis have an inhibitory effect on AMPK in the hypothalamus, which increases leptin and insulin sensitivity. 
A study found that mice which were unable to undergo intestinal gluconeogenesis were 50% more leptin resistant. R]

GLP-1 activation was even found to restore leptin sensitivity  in obese mice fed a 'high fat' obesogenic diet. R]

Hypothalamic Endoplasmic Reticulum Stress and Ceramide Cause Hypothalamic Insulin and Leptin Resistance

When the intestinal signals, which should have a chronically inhibitory effect on the hypothalamus fail;  the hypothalamus becomes chronically activated and this causes insulin and leptin resistance. R]

Activation of AMPK leads to the induction of hypothalamic ceramide synthesis in the endoplasmic reticulum (ER)’. R]

Obese Zucker rats show increased hypothalamic ceramide levels and endoplasmic reticulum stress.
Other studies have also found that hypothalamic ceramide induced insulin resistance, glucose intolerance and decreased beta cell mass of the pancreas. R]

Studies have demonstrated that increasing hypothalamic ceramides induces hypothalamic lipotoxicity and ER stress.

When ER stress in the hypothalamus was prevented; ‘fat burning’ and glucose tolerance improved and weight gain was reversed.

ER stress increases leptin and insulin resistance and prevention of hypothalamic ER stress decreases leptin and insulin resistance. R]

Causes of Hypothalamic AMPK Activation: Failing GLP-1, insulin and leptin resistance

Reactive Oxygen Species Stimulate Ceramides and Cause Endoplasmic Reticulum Stress

Reactive Oxygen Species have been found to result in the formation of ceramides.R]

Antioxidant therapy reduces endoplasmic reticulum stress. R] 

When the cells were pre-treated with antioxidant N-acetylcysteine (NAC), apoptosis and ER-stress were attenuated significantly.' R]

Since we know that endoplasmic stress in the hypothalamus causes insulin and leptin resistance; this indicates a therapeutic role for antioxidants in the prevention and correction of hypothalamic leptin and insulin resistance.

Before I describe the most important physiological, diet and lifestyle factors which regulate hypothalamic AMPK, insulin and leptin resistance; I will outline some of the health parameters which are controlled by this omnipotent enzyme.

Health Systems which are Regulated by Hypothalamic AMPK.

 Diseases and weight gain caused by hypothalamic AMPK activation

 The Appetite and Excessive Food Cravings.

The most relevant  effect of hypothalamic AMPK (for those of us who are trying to lose weight), is the appetite response.
As part of its role as the manager of energy in the body; hypothalamic AMPK controls the appetite.
When food supply and storage is low, as indicated by insulin, leptin and ghrelin signals; hypothalamic AMPK activation increases the appetite to force us to go in search of food to replenish the energy reserves in the body.
The key hormones which control food intake, such as leptin, insulin and ghrelin exert their effects on food intake via modulation of hypothalamic AMPK.
Activation of hypothalamic AMPK increases appetite and inhibition of hypothalamic AMPK decreases appetite. R]

Browning of Fat Tissue to Increase Energy Expenditure

The job of regular white fat tissue is to store energy.
In contrast, brown fat is packed full of mitochondria, which means that brown fat burns fuel (food and stored fat) to liberate energy, as heat. 
This is called thermogenesis. 

AMPK activation increases the ‘browning’ of white fat tissue, transforming it into an energy liberating organ rather than energy STORAGE system.

Brown adipose tissue can be activated either by suppression of AMPK activity in the hypothalamus or by direct activation of AMPK in BAT. R]

AMPK Controls Blood Lipids, Fat ‘Burning’ and Lipid Synthesis

AMPK activation in the body reduces the synthesis of cholesterol, fatty acids, and triglycerides (via the reduction of the enzyme; SREBP)

Instead, AMPK activation in the body increases energy liberating pathways, including mitochondrial fatty acid oxidation (fat burning). R]

The result of both of these mechanisms is a reduction in the accumulation of triglycerides and cholesterol in the blood and liver R]

Note: AMPK activation also reduces cholesterol in the blood by contributing to increased bile synthesis (which extracts cholesterol from the blood for the formation of new bile salts).

The complicated mechanism involved is described in detail in this post.

Blood Pressure

Activation of AMPK in the arterial cell wall in vivo lowers blood pressure.

Hyperlipidemia has been found to inhibit AMPK and this is the mechanism behind  hyperlipidemia-induced high blood pressure.

Activating AMPK can reverse high blood pressure, even in the presence of higher lipids. R]

 Blood Sugar Regulation

There is more than one mechanism, by which AMPK affects glucoregulation. 

The first pathway is the induction of glucocorticoids by hypothalamic AMPK activation.

In this study fructose activated hypothalamic AMPK, which increased corticosterone levels.

By increasing glucocorticoid receptor binding to the liver gluconeogenesis (glucose producing) gene (PEPCK), AMPK activation in the hypothalamus increased liver gluconeogenesis (glucose production),  which raised blood sugar levels.

AMPK also affects blood sugar regulation via other pathways.

One of the pathways is  the effect of AMPK on ‘leaky gut’ and inflammation.

AMPK Inhibition Affects Glucoregulation by  Increasing Leaky Gut/Inflammation-Induced Lipolysis 

As described in more detail in THIS POST; leaky gut allows the escape of bacterial cell wall components in to the blood stream.

These bacterial toxins are called LPS and they are highly inflammatory when they escape the intestinal lumen.

Inflammation increases lipolysis of fat cells, which is the breakdown of fat cell triglycerides, and the release of free fatty acids in to the blood stream. 10] 11]

Lipolysis is highly implicated in the development of insulin resistance in the liver and failure of pancreatic function.  R] R]

Both of these pathways would result in failing control of liver gluconeogenesis (glucose production), i.e. raised blood glucose levels.

The symptom which is experienced before the experience of high blood glucose levels is usually hyperinsulinemia.

Insulin resistance and the corresponding hyperinsulinemia can be evident decades before pancreas cell failure and high blood sugar levels of type 2 diabetes. R]

This is because the pancreas attempts to control the high levels of glucose which are being produced by an insulin-resistant liver, by increasing insulin production. R]

This is the manifestation of hyperinsulinemia (high insulin levels) and it is a symptom which precedes high glucose levels, since at first the compensatory high insulin levels are able to control glucose levels, despite the developing insulin resistance in the liver.

However, if lipolysis is chronic; insulin resistance in the liver will increase and pancreatic function will decline even further until the pancreas is unable to continue to produce enough insulin to control the increased production of glucose by an insulin resistant liver.

Note: The hormone GLP-1 also plays a role in pancreatic function. This appears to work via hypothalamic AMPK effects, but also via direct beneficial effects in the pancreas.

AMPK controls ‘leaky gut’and is highly anti-inflammatory. R]

By preventing the escape of  inflammatory LPS into the blood stream, by enhancing the gut barrier and preventing ‘leaky gut’ and by potent, direct  anti-inflammatory effects; AMPK prevents lipolysis, which helps to prevent liver insulin resistance, pancreatic failure and overt hyperglycemia. 

AMPK activation also appears to exert direct anti-lipolytic effects. 

AMPK prevents the inflammation/lipolysis axis of pancreatic failure and liver insulin resistance,  by several mechanisms and thereby is the ultimate defender against high blood sugar and hyperinsulinemia. 

Furthermore, there is another mechanism by which AMPK controls the pathogenesis of liver insulin resistance.
AMPK activation also prevents the build-up of fat in the liver by suppressing lipogenesis genes whilst simultaneously activating fat ‘burning’ genes. R]

The prevention of fat accumulation in the liver; prevents one of the causes of liver insulin resistance. 

Non-Alcoholic Fatty Liver Disease

The same mechanism which contributes to insulin resistance development in the liver is at play in the development of non -alcoholic fatty liver disease.

The leaky gut/ inflammation/ lipolysis pathway leads to the accumulation of fat in the liver, via reverse transport of adipose (fat) tissue (released by lipolysis) in to the liver. R]

This process in the development of NAFLD is described in more detail in THIS POST.

The other AMPK failure -induced mechanism behind liver insulin resistance also plays an important role in the development of NAFLD.

This is the increase of lipogenesis and the decrease of fat oxidation due to AMPK inhibition in the body, which contributes to the accumulation of triglycerides in the liver. R]

All of the mechanisms by which AMPK activation prevents these pathways to prevent liver insulin resistance, also apply to the prevention of NAFLD.

And, as expected; AMPK activation has been found to reverse NAFLD. R] R] R]

Protection from Heart Disease

The activation of AMPK also performs a protective role in cardiovascular diseases (R).
In the heart, signalling by AMPK increases the energetic function of the heart cells as well as the heart muscle and maintains the optimal function of its electrical pace makers.

Mutations in AMPK can cause rare but serious heart rhythm faults.
In the blood vessel endothelium, AMPK activation also exerts anti-atherosclerotic effects via ‘improving nitric oxide bioavailability, attenuating reactive oxygen species (ROS) stress, increasing endogenous antioxidant gene expression and activating pro-angiogenic factors.’ R]

AMPK Inhibition in the Body is Responsible for 'Metabolic Syndrome'

It has been noted that all of the  health disorders, which have been outlined so far, are highly associated with each other.
They often appear as a cluster. 
If you have one of these symptoms, there is a great likelihood that you will also have one or more of the other symptoms.

These symptoms, which are highly associated with each other, and often appear in a cluster, have been called the 'metabolic syndrome'.

When AMPK is inhibited in the body via AMPK activation in the hypothalamus, the cluster of systems which have been called ‘metabolic syndrome’ manifest.

The ‘metabolic syndrome’ includes hyperinsulinemia, insulin resistance, belly fat gain, high cholesterol, high blood pressure, high triglycerides and high blood sugar, as described above.

These are the most well known symptoms of ‘metabolic syndrome’ and I argue that diet-induced ‘metabolic syndrome’ is primarily the result of AMPK inhibition in the body. REF

However, the symptoms of failing hypothalamic AMPK extend far beyond these well recognised symptoms.
These are symptoms which are ‘associated with metabolic syndrome’ and I will outline some of these here:

Health Disorders which are Also the Result of Failing Hypothalamic AMPK and are ‘Associated with Metabolic Syndrome’.

Certain Cancers 

Cancer growth and metastasis depends on the availability of energy. R] AMPK activation prompts cells to produce energy at the expense of growth and motility, opposing the actions of insulin and growth factors.
Increasing AMPK activity may thus prevent the proliferation and metastasis of tumour cells.
Activated AMPK also suppresses aromatase, which lowers oestrogen formation and prevents breast cancer growth. R] Recent work suggests that metformin, an AMPK activator, directly antagonizes cancer cell growth R] It was also found that ‘a combination of grape polyphenols (resveratrol, quercetin and catechin); reduces breast cancer growth and metastasis and activates AMPK, (an inhibitor of mTOR) in metastatic breast cancer cells.’

In vivo experiments, using mice with implanted tumors from metastatic breast cancer cells, demonstrated that administration of quercetin at 15mg/kg body weight resulted in a ~70% reduction in tumour growth. R]

By protecting against DNA damage by reactive oxygen species; AMPK activation should protect against the initiation of tumour development. R]

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

Researchers concluded that for the AMPK activator, metformin; the most important mechanism may involve the inhibition of mTOR signalling R]

Saturated fatty acids have also been found to inhibit AMPK in the body, which increased activation of mTOR signalling.
It is not clear what relevance dietary saturated fats have for this mechanism, since dietary saturated fats may also ACTIVATE AMPK in certain dietary contexts, such as low carb diets, due to improved bile signals.
Oleate (a type of fatty acid found in olive oil) was found to ‘reverse these effects through a metformin-like activation of AMPK.’ R]
This likely supports the observation that olive oil is‘safer’ oil, in the context of a high carbohydrate diet, at least.

Premature Skin Aging (Grey, Dry, Wrinkled Skin).

Matrix metalloproteinases (MMPs) are the enzymes which degrade collagen and other extracellular matrix (ECM) proteins that comprise the skin connective tissue and promote premature ageing of the skin.

AMPK is known to suppress this skin degrading enzyme, Matrix metalloproteinase. R]

Activation of MMP is critical to the ageing effects on the skin by UV– radiation R]
When human skin cells were exposed to hydrogen peroxide at low concentrations, the cells were prematurely aged.
When the cells were also cultured with resveratrol, an AMPK activator, the cells were completely prevented from the premature ageing effects. R]

When human subjects were treated with an algae extract, which was found to increase AMPK activation in the skin; the expression of collagen I and III in aged fibroblasts was up regulated by 63% and 240% relatively compared to untreated cells.
The algae extract increased oxidative stress resistance, increased hydration and significantly reduced the over expression of matrix metalloproteinase I and III, by 47 and 40% respectively.
After 2 months, the cream, applied by 5 women in the age of 55 – 67, increased their skin surface thickness by 30.5% compared to placebo. R]

This property of AMPK to prevent MMPs is what highlights AMPK activation as a target for the prevention of nasal polyps and pathological tissue remodelling in the eye... R] R]

Chronic Fatigue 

Researchers have recently discovered that there is ‘impaired activation of AMPK in cultured skeletal muscles from subjects with chronic fatigue- impaired stimulation of glucose uptake and diminished release of IL-6. R] This identifies AMPK activation in skeletal muscle as a potential target for therapeutic/corrective action.

Fibromyalgia

 Researchers have discovered that AMPK was not activated in fibroblasts from fibromyalgia (FM) patients and ‘was associated with decreased mitochondrial biogenesis, reduced oxygen consumption, decreased antioxidant enzymes expression levels and mitochondrial dysfunction.’
AMPK activation in fibromyalgia fibroblast was impaired in response to moderate oxidative stress.
Exercise normally (in a healthy person) activates muscular AMPK via the exercise-induced increase in muscular oxidative stress. 

AMPK activation by metformin (an AMPK activator) improved the response to moderate oxidative stress (exercise) and improved mitochondrial metabolism.
The researchers concluded that ‘AMPK plays an essential role in fibromyalgia pathophysiology’. R]

AMPK and Neurological and Neurodegenerative Disease

Similarly to AMPK in the hypothalamus of the brain, whereby inappropriate activation of AMPK causes excessive appetite, food cravings and system-wide health decline; excessive activation of AMPK in the rest of the brain is a pathological process , which is an initiating trigger for Alzheimer’s’ disease, Parkinson’s disease and other.

Similarly to hypothalamic AMPK; AMPK activation in the rest of the body causes AMPK inhibition in the brain.

This is why AMPK activators benefit the brain; by activating AMPK in the body; AMPK is therapeutically inhibited in the brain.

Alzheimer’s Disease

It has been demonstrated that AMPK activation in mouse primary neurons induced an increase of tau protein phosphorylation at multiple sites, whereas AMPK inhibition led to a rapid decrease of tau protein phosphorylation.

The researchers also found that brain AMPK deficiency reduced tau pathology in a mouse model of tau pathology.
They concluded that ‘ these results show that AMPK regulates tau phosphorylation in mouse primary neurons as well as in vivo, and thus suggest that AMPK could be a key player in the development of AD pathology.’ R]

Other studies have confirmed that AMPK plays a vital role in the Alzheimer’s disease pathology:

AMPK activation in the body (which inhibits AMPK in the hypothalamus); repairs mitochondrial functions; decreasing amyloid protein secretion and modulating tau phosphorylation and tau pathology in vivo R ] R] R]

Huntington’s Disease and Parkinson’s Disease

The same process of inappropriate AMPK activation in the brain appears to be the pathology behind Huntington’s and Parkinson’s disease.

This study elucidated the mechanism involved in Parkinson’s disease.

Researchers analysed the cells from patients suffering from Parkinson’s disease.
It was discovered that there was an overproduction of mitochondria in these cells.
Although this may be a beneficial thing in the rest of the body, an excess of mitochondria in the brain increases oxidative stress

Brain cells are extremely vulnerable to oxidative stress.

It is known that AMPK activation increases mitochondrial biogenesis, which is a good thing in the rest of the body, but not in the brain.

Metformin, by activating AMPK (in the intestine – see THIS POST), inhibits AMPK in the brain and this was found to ‘put a brake on the production of mitochondria and energy, thereby reducing oxidative stress.

AMPK activation (in the intestine) ‘improves energy metabolism and protein clearance in the brains of patients with vascular injury or neurodegenerative disease.’ R]

Anxiety and Depression and AMPK

Following brain damage, metformin improves anxiety-like behaviours and movement disability through AMPK-dependent regulation of autophagy. R]

Other studies have indicated that hypothalamic AMPK activation is the mechanism by which chronic corticosterone treatment causes depression-like behaviour in male mice. R]

Supporting the role of AMPK in depression; the AMPK activator metformin (which inhibits AMPK in the brain) has demonstrated antidepressant effects and enhancing effects on cognitive function. R]

Learning and Memory

Studies have demonstrated that plasticity in the brain is modulated by AMPK.

Since epilepsy is a condition of failing plasticity, AMPK modulation is indicated as a potential therapeutic target for the treatment of epilepsy. R]

A critical role for hypothalamic AMK in the regulation of learning and memory capacity is indicated by several studies.
It was demonstrated that ‘stimulation of the hypothalamus completely reverses learning and memory deficits caused by brain lesions in rats.’

The stimulation of the hypothalamus ‘activates several regions of the brain, especially the memory systems’.20]

Intestinal Inflammation.

AMPK activation exerts protective effects on intestinal epithelial function through multiple mechanisms by enhancing barrier function, suppressing inflammation and preventing colorectal cancer.’ R]

The fact that AMPK activation suppresses intestinal inflammation is likely a primary mechanism behind the observation that ‘metformin (an AMPK activator) attenuates irritable bowel disease severity and reduces inflammation’. R]

Since ‘low-grade intestinal inflammation plays a key role in the pathophysiology of irritable bowel syndrome (IBS)’ R], and we know that AMPK activation reduces intestinal inflammation; AMPK is highlighted as a target for the prevention and ‘cure’ of irritable bowel syndrome.

Auto-Immune Disease 

A study of the auto-immune inflammatory disease; multiple sclerosis found that AMPK controls the disease by ‘regulating the M1 phenotype-Th17 axis.’ R]

The AMPK activator, Metformin, has also been demonstrated to reduce the severity of rheumatoid arthritis.
The researchers concluded that ‘the results indicate that metformin (AMPK activation) had immunomodulatory actions influencing anti-inflammatory action on rheumatoid arthritis through the inhibition of Th17 cell differentiation and the up regulation of Treg cell differentiation along with the suppression of osteoclast differentiation.R]

Allergies

AMPK has also been found to inhibit mast cell activation, which ‘points to AMPK activators as therapeutic drugs for allergic diseases’ REF

AMPK Controls Innate Immunity and Anti-Viral Defence

The result of enhanced innate immune responses is the improved ‘containment’ and regulation of intestinal bacteria.
As described in detail in THIS POST; the regulation of intestinal bacteria is critical to the prevention and ‘cure ‘of all ‘Western’ disease and obesity.
R]

This AMPK-controlled health parameter plays a vital role in the exacerbation or prevention of AMPK signalling dysregulation.

The effect of AMPK activation to improve anti-viral defence would mean greater defence against viruses, such as the flu.
The AMPK activator, metformin has been demonstrated to ‘reduce mortality in patients with pneumonia and in mouse models of influenza.’ R]

Infertility and Polycystic Ovary Syndrome

AMPK activation has been found to ‘restore reproductive function in PCOS and blunt excessive gonadotropin releasing and luteinising hormone release.’ R]

Acne

AMPK activators have been found to prevent and reverse acne.
AMPK controls mTORC1.
mTOR activates SREBP, the master transcription factor of lipogenesis.
Increased SREBP activation leads to an increase in sebum production by the sebaceous follicles in the skin.
Over-activated mTORC1
also increases androgen hormone secretion, which directly activates mTORC1.
This would amplify mTORC1 driven increased sebum production.
AMPK activation even antagonises (prevents) the direct effects of leucine- mediated mTORC1 activation. R] By antagonising the effects of leucine and other factors, which directly increase mTOR and sebum production, as well as by directly reducing mTOR; AMPK activation reduces mTOR-driven production of sebum and thereby reduces acne.

Cavities

Activation of AMPK was demonstrated to ‘induce stem cell mobilization and ‘completely restore dentin’.
This led the authors to conclude that ‘stimulation of endogenous stem cells (by AMPK) may represent a novel approach to clinical tooth restoration. ‘
R]

Sleep Apnoea

When mice were exposed to low levels of oxygen; they were unable to produce the AMPK enzyme.
They displayed symptoms similar to sleep apnoea.
When researchers activated AMPK, it enabled the mice to breathe, even though the oxygen levels remained low. R]

Gout

Researchers have demonstrated that AMPK activation limits crystal inflammation in vitro and in vivo.
These findings prompted researchers to conclude that AMPK activation is ‘a promising target for gout treatment’ R]

Migraine 

The AMPK Activator, Metformin has ‘demonstrated positive results in animal models of migraine in the laboratory.’R]

Chronic Pain

AMPK has been highlighted as ‘an emerging target for novel pain therapies’.

AMPK regulates a variety of cellular processes which are thought to contribute to pathological pain, including protein translation, activity of other kinases, and mitochondrial metabolism, many of which are thought to contribute to pathological pain.

Preclinical studies show positive, and in some cases disease-modifying effects of either pharmacological activation or genetic regulation of AMPK in models of nerve injury, chemotherapy-induced peripheral neuropathy (CIPN), postsurgical pain, inflammatory pain, and diabetic neuropathy. R]

It is clear that the stakes are high and that optimising hypothalamic AMPK function has profound implications for our energy levels and physical, mental, emotional and cognitive health.

If we want to correct the whole array of chronic health failures which are the result of the ‘Western’ diet and lifestyle, it is clear that improvement of AMPK signalling is the target.

We need to find diet, lifestyle and supplementation strategies which increase AMPK inhibition in the hypothalamus, whilst activating AMPK throughout the body.

This would be the most targeted strategy for the correction and prevention of the array of chronic health disorders listed above, (which no doubt, does not come close to covering the entire spectrum of diseases which could be affected beneficially by targeting AMPK).

AMPK: Health and weight loss benefits and how to activate AMPK and inhibit AMPK in the hypothalamus

Before I list some of the best known and available strategies to correct faulty AMPK signalling; I will outline the physiological factors involved in AMPK regulation, as a deeper understanding of the mechanisms involved can guide strategy.

Physiological Factors Which Control AMPK Inhibition in the Hypothalamus (and AMPK Activation in the Body)

Physiological factors which control hypothalamic AMPK Activation ( and health and weight loss)

Leptin

Leptin is a hormone which is secreted by fat cells. It informs the hypothalamus about the status of energy stores, i.e. fat cells.
‘Leptin inhibits AMPK activity in the hypothalamus, and its inhibition is necessary for the anorexic effect of leptin.’ R]

Estradiol

Estradiol is a steroid and oestrogen sex hormone.

It has been found to inhibit hypothalamic AMPK.

The loss of this inhibitory effect on hypothalamic AMPK during the menopause, when oestrogen levels decline, is plausibly the mechanism behind accelerated aging and weight gain following menopause.

Insulin

Insulin is a hormone which is produced by the pancreas in response to food intake.

It inhibits AMPK activation in the hypothalamus to act as a potent anorexigenic hormone.
The reason that insulin inhibits AMPK (which reduces the appetite) is to prevent over-eating following food consumption.

Glucagon-Like Peptide-1 (GLP-1)

GLP-1R agonists influence body weight by regulating either food intake or energy expenditure by inhibiting hypothalamic AMPK. R]

Physical Exercise 

AMPK is stimulated in the body by contractile activity in the skeletal muscle.

Contractile activity in the skeletal muscles causes the release of the cytokine il-6, which has an inhibitory effect on AMPK in the hypothalamus.

Exercise was also found to increase hypothalamic leptin and insulin sensitivity in diabetic rats, which would have further benefits for hypothalamic AMPK inhibition.

Hypothalamic Glucose

High glucose levels are another signal of energy abundance, and accordingly; hypothalamic glucose inhibits AMPK. R]

Hypothalamic glucose starvation activated AMPK and increased leptin resistance, whereas glucose dose-dependently enhanced leptin signalling.

Pharmacological inhibition of AMPK restored leptin sensitivity.

This indicates that hypothalamic glucose starvation causes leptin resistance by increasing the activation of hypothalamic AMPK. R]

Factors Which Cause AMPK Activation in the Hypothalamus and Decrease Leptin/Insulin Sensitivity

Cannabinoids

Cannabinoids, in contrast to leptin, can stimulate AMPK activity in the hypothalamus leading to increased appetite.
Endocannabinoids have been shown to be essential for the orexigenic and anorectic effects of ghrelin and leptin, respectively. R]

Cannabinoids activate CB1, which induces endoplasmic reticulum stress, which induces ceramide synthesis, which induces hypothalamic insulin and leptin resistance. R] R]

Glucocorticoids

Therapeutic doses of glucocorticoids induce obesity by stimulating AMPK in the hypothalamus.
This can occur directly or via the induction of endocannabinoids. R]

Hypoglycaemia

Hypoglycaemia is a condition in which the blood glucose drops below normal levels.
This sends a signal to the hypothalamus to activate AMPK, which induces hunger.

Fructose

Both ip and direct administration of fructose in to the brain, stimulated hypothalamic AMPK activation. R]

Diet/Lifestyle Factors Which Improve Health and Obesity via Modulation of AMPK

Low Carbohydrate/ Low Fat (‘Healthy’ Carb) / Intermittent Fasting Diet Strategies

The key role of AMPK in preventing or initiating failing general health and obesity is supported by multiple studies; whereby hypothalamic AMPK inhibition is found to prevent high-fat-diet-induced obesity. R] R] Note: Most of the studies which have analysed the relationship between AMPK and diet-induced obesity are rodent studies, due to a dearth of such studies in humans.

Diet-induced obesity has been found, unsurprisingly, to alter AMPK in muscles and the hypothalamus in mice. R]

As argued/described in detail in this article; the well-known dietary strategies which have been reported to have beneficial effects on chronic diseases and obesity; exert these effects via the modulation of intestinal signals, which improve AMPK signalling throughout the brain and body.

As I elaborate, in that article;  the ‘high fat/high refined carb diet’ which induces health dysregulation and obesity, exerts its negative effects via detrimentally altering bile signalling, which in turn, negatively affects AMPK signals.

As further detailed in that article; the high-fat, high-sugar ‘Western’ diet increases the hydrophobicity of bile, which increases activation of the problematic bile receptor: FXR, at the same time as decreasing the activation of the metabolically beneficial bile receptor:TGR5.

Excessive FXR activation by hydrophobic bile leads to the activation of AMPK in the hypothalamus and the suppression of AMPK in the body, which leads to the whole array of health disorders and obesity associated with the ‘Western‘ diet.

Conversely, activation of TGR5 by more hydrophilic bile; improves the inhibition of hypothalamic AMPK, which increases AMPK activation throughout the body and improvement of health symptoms throughout the body, including obesity.

Dietary strategies which correct chronic health disorders and obesity do so, in large part, by reducing bile hydrophobicity, which decreases activation of the bile receptor:FXR, whilst enhancing activation of the beneficial bile receptor:TGR5.

Nicotine

It has been demonstrated that ‘nicotine-induced weight loss is associated with inactivation of hypothalamic AMPK’ which results in ‘decreased orexigenic signalling in the hypothalamus, increased energy expenditure as a result of increased locomotor activity and increased thermogenesis in brown adipose tissue (BAT)R]

Short Chain Fatty Acids 

Exposure to ethanol significantly impairs gut barrier function, which induced metabolic stress.
However, pre-treatment with the short chain fatty acids; butyrate, propionate, and acetate, ‘significantly alleviated the ethanol-induced barrier dysfunction and metabolic stress.
The promoting effects on barrier function were abolished by inhibiting AMPK.’
These observations indicate that SCFAs exhibit protective effects against ethanol-induced barrier disruption via AMPK activation.R]

Thyroid Hormones

Researchers have demonstrated that ‘either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic (AMPK), increases sympathetic nervous system (SNS) activity and up regulates thermogenic markers in brown adipose tissue (BAT). ‘
Inhibition of hypothalamic pathways prevents activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism.
Inhibition of thyroid hormone receptors in the hypothalamus reverses the weight loss associated with hyperthyroidism.

What this study shows is that thyroid hormone activates brown adipose tissue to increase energy expenditure and causes weight loss VIA inhibitory action in the hypothalamus. R]

The Sleep Hormone AMPK 

Emerging evidence indicates that AMPK may be the link between sleep and health.
It has been demonstrated that hypothalamic AMPK suppression is the mechanisms by which melatonin has a protective effect on the liver. R] R]

Natural Food Supplements which Inhibit AMPK in the Hypothalamus and Activate AMPK in the Body

Alpha Lipoic Acid

Alpha Lipoic Acid is a short chain fatty acid, which activates G- protein coupled receptors in the intestine.
This sends a signal to the brain, which suppresses AMPK in the hypothalamus, thereby triggering the whole cascade of energetic benefits for the body, concurrent with improved appetite regulation. R]

Some of the benefits of alpha lipoic acid, due to enhanced AMPK signalling, include; increased energy expenditure in brown adipose tissue (thermogenesis); a decrease in fatty acid synthesis which results in reduced hepatic and skeletal triglyceride accumulation; improved insulin sensitivity and reduced liver steatosis.’ R] R] R]

Oleanolic Acid and Oleuropein in Olive Leaf Extract

Oleanolic acid in olive leaf extract activates the bile receptor, TGR5, (which increases cAMP and intestinal gluconeogenesis to optimise hypothalamic AMPK signalling).

Consistent with these properties, oleanolic acid lowers blood glucose and insulin levels in mice fed with a high fat diet and it enhances glucose tolerance. R]

Other effects of oleanolic acid which have been demonstrated in studies which are consistent with AMPK activation are; protective autophagy (self-digestion of failing cell components) through the AMPK-mTOR pathway in bladder cancer cells

Oleanolic acid also demonstrates anti-tumour function by interfering in the metabolic pathway in prostate cancer cells. R]

How to activate AMPK for weight loss and health

Experience an AMPK Activator: Alpha Lipoic Acid 

If you would like to experience the endless health and beauty benefits of an AMPK activator (as described in this article); I offer the potent AMPK activator: alpha-lipoic acid,  in my meticulously selected supplement range.
When you purchase any of the supplements from my range; you automatically become eligible for free Diet Coach online diet/nutrition support.

I offer diet support in conjunction with my products as it is clear that health and body composition optimisation requires a two pronged approach: diet and supplementation.

I am a degree level Nutritionist, formally educated in Nutrition and Molecular and Cellular Biology .
My education is continuous as I intensively research, analyse and incorporate the very latest scientific findings in ‘root cause’ physiology.

The advanced understanding I have gained from 20 years of research has enabled the formulation of highly targeted diet and lifestyle strategies for the correction of failing health and obesity progression.

Once you have placed your order for a Diet Coach product; you will receive an email from me, to which you may reply with your confirmation, if you wish to join the free diet support plan.

  • 11 months ago
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