The AMPK pathway, fat burning, and more?

The AMPk pathway acts as an energy sensor that, when activated in certain tissues, increases fat burning.

The AMPk pathway also participates in several longevity pathways and may promote healthy aging. But, from the perspective of your goals, both at the muscular level and in terms of fat burning, there are some key considerations.

In addition to activating catabolic pathways that generate ATP, this pathway also deactivates almost all major anabolic pathways.

This “wheel” of targets shows the subprocesses through which this pathway induces or inhibits other processes.

AMPk was originally defined by its ability to phosphorylate and inactivate both acetyl-CoA carboxylase (ACC1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the key regulatory enzymes of fatty acid and sterol synthesis, respectively [139,140].

Fatty acid synthesis occurs through several processes, so when you are trying to lose weight by burning fat, you should understand them to some extent.

AMPk: The energy enzyme

The enzyme AMPk (5′-AMP-activated protein kinase) plays a key role in energy balance… all creatures, from yeast to humans, have this enzyme…

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

AMPk is produced in several tissues, including the liver, brain, fat cells, and muscles [1]. And although its activity depends on external factors such as diet and exercise, we all inherit it from our parents.

AMPk and the stimulation of metabolism

AMPk in the hypothalamus detects our level of energy production in the body (in the form of ATP), increases energy expenditure, and may also increase appetite (when activated in the hypothalamus).

When cellular energy is low, AMPk is activated and targets a variety of processes, whose net response is an increase in energy production and a coordinated decrease in energy use (ATP).

Hypothalamic AMPk increases appetite, increases glucose production and absorption, reduces heat production, and decreases energy production [2].

Although this pathway is likely involved in cellular control in most cells in the body, we focus on:

• The liver,
• Skeletal muscle and fat cells, and
• The brain (specifically the hypothalamus, which is the area primarily involved in appetite/hunger and body weight regulation)

To explain its action, we examine its role in the metabolism of carbohydrates, fats, and proteins in peripheral tissues and the regulation of body weight in the brain.

AMPk: carbohydrates and fats

With regard to carbohydrates, AMPk activation inhibits glycogen storage and increases glucose uptake, and for this reason appears to be heavily involved in improving insulin sensitivity.

So, what happens to fat metabolism?

• In the liver, its activation decreases fatty acid and cholesterol synthesis.
• In muscle cells, its activation increases fatty acid oxidation (in other words, more fat is burned).

It also appears that AMPk activation is one of the keys to how strength training causes adaptations such as increased mitochondrial protein synthesis [3].

In fat cells, this decreases both fatty acid synthesis and lipolysis (by inhibiting hormone-sensitive lipase).

AMPk: what about the muscles?

OK, so far so good, right? Except for the inhibition of lipolysis, it seems that AMPk activation is a great thing because it increases glucose uptake and fatty acid oxidation in skeletal muscle cells.

So, why not keep its levels elevated all the time?

• The first reason is that its activation suppresses protein synthesis by reducing the anabolic mTOR pathway, which is heavily involved in protein synthesis [4].
• The general picture is that it shuts down energy-costly processes (such as protein synthesis) and activates energy-producing processes (such as glucose and fat oxidation).

So, inhibition of skeletal muscle protein synthesis is the first response. For example, it can suppress PPAR alpha and PPAR gamma, two important proteins that regulate metabolism and gene expression.

• The second reason has to do with the effects of AMPk activation in the brain, where its activation has a negative effect: increasing appetite.
• Ghrelin, which tends to increase appetite and food intake, increases AMPk levels in the brain, while leptin, which tends to decrease appetite and food intake (more or less), decreases its levels.

Additionally, nutrient availability affects brain AMPk (probably through leptin and ghrelin). If you reduce appetite, you increase AMPk levels in muscle, which you can do with an appetite suppressant if you do not control it daily.

Multifunctions: mitochondria and more?

In addition to the processes related to fat loss through a well-studied mechanism, it also:

• It promotes cellular recycling by controlling the quality of molecular and cellular subunits, degrading damaged or misfolded proteins and even damaged mitochondria, thereby generating energy.
• It regulates the mitochondria and can improve their activity both in the short and long term, even renewing them.

In a way, reduced mitochondrial activity greatly reduces muscle performance [5].

• AMPk also acts as an antioxidant because it increases antioxidant defenses during oxidative stress. It does this by producing several antioxidant proteins, such as NRF2, superoxide dismutase, and uncoupling protein 2 (UCP2) [6].
• Surprisingly, it helps with oxygen delivery during sleep or at altitude, protecting against acute respiratory instability (such as hypoxia).
• It increases blood flow through vasodilation (widening of the blood vessels) by stimulating the release of nitric oxide in the blood vessels [7].
• AMPk activation improves insulin sensitivity, which is key both for definition and muscle gains. [6].

What happens with inflammation

In an interesting cycle, AMPk can reduce inflammation and be reduced by inflammation.

• When activated, it also exerts potent anti-inflammatory effects.
• It inhibits inflammation by acting indirectly on NFκB, a key activator of inflammation [6].

Although AMPk could have many beneficial effects on chronic inflammation, it is generally reduced in such states.

In this context, we suggest using omega-3s, which, in addition to activating AMPk/PGC-1alpha signaling, have notable anti-inflammatory power [8].

Links to longevity

Some researchers believe that the age-related increase in chronic inflammation levels is responsible for the suppression of AMPk activity over time.

However, its activation may support multiple longevity pathways and promote healthy aging, especially by reducing the production of certain proteins and improving autophagy (the renewal of cellular mitochondria).

The longevity pathways of AMPk:

• It activates the longevity proteins FOXO.
• It activates the master antioxidant regulator NRF2.
• It inhibits the “master regulator” of lipogenesis, SREBPc.
• It indirectly inhibits the mTOR pathway.

Research on longevity is a controversial field, and the enzyme's precise role is unknown; however, the mechanisms for activating several longevity-related elements are well established.

How to activate the AMPk pathway

There is no magic or secret formula; however, there are four or five factors that drive its activation for fat burning.

First of all, when you train at high intensity, ATP becomes ADP and then AMP, which activates AMPk. Activation stimulates GLUT-4 (a transporter complex), which induces greater glycolysis, and glycogen availability in this scenario is the factor that allows substrates such as fats to be used for energy.

• Exercise uses energy (in the form of ATP), and the resulting energy shortage stimulates AMPk through muscle contractions. The effects occur through increased insulin sensitivity.
• Caloric restriction activates AMPk through multiple mechanisms; one of them is the secretion of adiponectin by fat cells, which activates it in multiple tissues, including skeletal muscles.

When it is inhibited or suppressed, there are certain processes that produce the opposite effect.

• High glucose levels.
• high amino acid levels, especially branched-chain amino acids.
• Excess saturated fat and,
• Elevated insulin also inhibits AMPk.

In addition, at the hormonal level, anti-inflammatory cytokines activate AMPk, while pro-inflammatory cytokines suppress it.

Supplementation and AMPk

One indirect way that effectively helps burn fat is through this pathway and, to that end, in addition to reducing inflammation through omega-3s or using appetite suppressants, there are other natural supplements.

Plant-based quercetin, which is usually found in fruits, vegetables, and grains, activates or increases AMPk in fat cells, the liver, and muscles, but inhibits its hypothalamic counterpart [9], and the same occurs to some extent with many revitalizing supplements.

Several ginsenosides present in ginseng activate AMPK, resulting in increased glucose uptake, decreased triglyceride and cholesterol levels in the liver, and inhibition of fat and glucose production in the liver [10].

Acetyl-L-carnitine (ALC) inhibits insulin resistance through the AMPK pathway in skeletal muscle cells, resulting in improved performance and ultimately greater sensitivity to absorb key post-workout nutrients [11].

References

1. Cell Metabolism – 2005: AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism
2. Neural Plast. – 2016: Hypothalamic AMPK as a Regulator of Energy Homeostasis
3. Aschenback, WG et. al. 5′ Adenosine monophosphate-activated protein kinase, metabolism and exercise. Sports Med (2004) 91-103.
4. Bolster, DR. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapomyacin (mTOR) signaling. J Biol Chem (2002) 277: 23977-23980.
5. Cell Metab. – 2015: AMPK at the Nexus of Energetics and Aging
6. Exp Mol Med- 2016: Regulation and function of AMPK in physiology and diseases
7. Vascul Pharmacol – 2015: Vascular AMPK as an attractive target in the treatment of vascular complications of obesity
8. Mar Drugs – 2019: Omega-3 Fatty Acids-Enriched Fish Oil Activates AMPK/PGC-1alfa Signaling and Prevents Obesity-Related Skeletal Muscle Wasting
9. J Nutr Biochem – 2014: Quercetin inhibits AMPK/TXNIP activation and reduces inflammatory lesions to improve insulin signaling defect in the hypothalamus of high fructose-fed rats
10. Exp Mol Med – 2016: AMPK activators: mechanisms of action and physiological activities
11. Science Direct – 2009: Acetyl-L-carnitine inhibits TNF-α-induced insulin resistance via AMPK pathway in rat skeletal muscle cells