Obesity has become a major global health problem, characterized by excessive fat accumulation and triggered by an energy intake larger than energy consumption. This condition leads to various complications, including cardiovascular diseases, type 2 diabetes, and obstructive pneumonia. As a result, there’s an escalating demand for effective therapeutics to reduce the burden of obesity and related diseases. The AMP-activated protein kinase (AMPK) has emerged as a key player in fat metabolism, particularly in regulating energy expenditure in adipose tissue. This article delves into the role of AMPK in fat metabolism, its potential benefits for weight loss, and strategies to activate it.
What is AMPK?
AMPK, or 5′ AMP-activated protein kinase, is an enzyme that plays a crucial role in energy balance within the body. It acts as an energy sensor, activated in certain tissues to produce beneficial effects, including stimulating metabolism, improving insulin sensitivity, decreasing inflammation, and enhancing muscle performance. AMPK is found inside every cell and serves as a master energy sensor. It helps determine your body’s balance between energy consumption and production. The body balances production of AMP by sensing its current AMP to adenosine triphosphate (ATP) ratio. Based on your current levels of AMP and ATP, energy production and usage can be altered.
Components and Activation of AMPK
AMPK is a highly conserved serine/threonine protein kinase composed of multiple heterotrimeric complexes. It consists of:
- An α catalytic subunit (isoforms α1 or α2)
- A regulatory β subunit (isoforms β1 or β2)
- A regulatory γ subunit (isoforms γ1, γ2, or γ3)
The α catalytic subunit contains a catalytic phosphorylation site, threonine-172 (Thr172), which is crucial for AMPK activation. This activation occurs when the Thr172 residue is phosphorylated by upstream kinases, such as calmodulin-dependent kinase kinases (CaMKKs), liver kinase B1 (LKB1), and transforming growth factor (TGF)-β-activated kinase-1 (TAK1).
The β regulatory subunit maintains the integrity of the AMPK heterotrimer and regulates the enzyme's reactivity to direct activators. The γ subunit contains four tandem cystathionine-beta-synthase (CBS) domains, forming the allosteric regulatory site for AMP/ATP binding.
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Compromised cellular energy status increases the AMP: ATP ratio, leading to AMP or ADP binding to the γ subunit. This binding causes a conformational change that activates AMPK via phosphorylation of the Thr172 site in the α subunit.
AMPK's Role in Fat Metabolism
AMPK plays a critical role in regulating adipose tissue metabolism. AMPK activation is associated with lipogenesis/adipogenesis, fatty acid (FA) oxidation, BAT thermogenesis, and browning of WAT.
Lipogenesis and Adipogenesis
Lipogenesis, particularly de novo synthesis (DNL), is a crucial pathway for converting excess carbohydrates into fatty acids, which are then esterified into stored triacylglycerol (TAG). AMPK inhibits fatty acid synthesis by phosphorylating acetyl-CoA carboxylase (ACC) at Ser79, reducing the conversion of acetyl-CoA to malonyl-CoA, a rate-limiting step in fatty acid synthesis.
AMPK also impacts adipogenesis by reducing the expression of C/EBPβ, which is essential for initiating the adipogenic transcriptional cascade. This leads to the subsequent inhibition of PPARγ, C/EBPα, and late adipogenic markers like FAS, aP2, and SREBP-1c. Furthermore, AMPK influences the WNT/β-catenin pathway, increasing β-catenin expression and nuclear accumulation, which reduces adipogenic gene expression.
Lipolysis
Lipolysis is the process in which TAG is hydrolyzed into glycerol and fatty acids in adipocytes. This process involves three stages, with key enzymes including adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and MAG lipase (MAGL).
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The role of AMPK in lipolysis is complex and somewhat controversial. Some studies suggest an anti-lipolytic effect of AMPK, while others indicate that AMPK stimulates lipolysis. These differences may stem from tissue-specific functions of AMPK under different conditions. AMPK can phosphorylate HSL, reducing its activity and inhibiting lipolysis in adipocytes. However, AMPK may also be indirectly activated by increased lipolysis due to the rise in the AMP/ATP ratio from fatty acid re-esterification.
Energy Expenditure and Browning of White Adipose Tissue
Obesity is characterized by an imbalance between energy intake and expenditure. Therapeutic strategies often focus on reducing energy intake and increasing energy output. Enhancing energy expenditure through the activation of brown and beige adipose tissue is an attractive approach.
White adipocytes store excess energy, while brown adipocytes are rich in mitochondria and express high levels of uncoupling protein 1 (UCP1), which dissipates energy as heat. Beige adipocytes, intermediate between brown and white adipocytes, appear in white adipose tissue under certain conditions like chronic cold stimulation or exercise. This process, known as 'browning,' increases energy expenditure.
AMPK activation is associated with increased energy expenditure in brown and beige adipose tissue, making it a promising target for obesity treatment.
The Role of AMPK in Appetite Regulation
AMPK in the hypothalamus senses our level of energy production in the body (in the form of ATP). Glucose is the main source of energy for the body and is particularly essential for normal brain activity.
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Hypothalamic AMPK and Food Intake
Activating AMPK in the brain (hypothalamus) has the opposite effect as it does when activating it in the liver, fat, and muscles. Activating AMPK in the brain increases appetite and may increase weight gain. Inhibiting AMPK in the brain likewise reduces appetite and may cause weight loss. However, no substance or strategy has sufficient evidence to support claims of activating or inhibiting hypothalamic AMPK.
Ghrelin is a hunger hormone produced in the stomach and released during fasting. Cannabinoids stimulate AMPK activity in the hypothalamus leading to increased appetite. Nicotine - Smokers around the world commonly report increased body weight after smoking cessation.
Strategies to Activate AMPK
Exercise
AMPK is stimulated by muscle contraction. Vigorous, high-intensity exercise has been shown to activate AMPK pathways. Exercise is perhaps the most sustainable and well-supported method, as long as it burns calories and creates a temporary energy deficit.
Calorie Restriction
Calorie restriction has been associated with many beneficial effects on aging, diabetes, and cancer. Some of these effects are mediated by AMPK. Caloric restriction supports AMPK activation, but make sure you are consuming enough protein, carbs and fats for your age, height, weight and gender to fuel your body with the energy it needs for your daily activities.
Diet
High glucose levels, high levels of amino acids, especially branched-chain amino acids, and excess saturated fat inhibit AMPK. Calorie restriction stimulates adiponectin secretion from fat cells. Adiponectin is secreted from fat cells to signal low energy status. On the other hand, overeating based on one’s energy requirements leads to inhibition of AMPK activity. Choose a diet rich in lean, healthy meats, healthy fats, and fresh fruits and vegetables.
Natural AMPK Activators
Numerous polyphenols have been found to activate AMPK in cell and animal studies. Polyphenols can lower lipids by activating AMPK, as displayed in human and animal research.
- Quercetin: Found in many plants, including fruits, vegetables, and grains.
- Ginseng/Ginsenosides.
- α-Lipoic acid (ALA): May activate AMPK in muscles and other tissues, though its precise mechanism and effects have not been sufficiently investigated.
- Gynostemma pentaphyllum: A plant extract that has shown promise in activating AMPK and reducing abdominal fat.
- Hesperidin: A citrus polyphenol that stimulates nitric oxide production, improves endothelial function, and reduces inflammatory markers.
Pharmaceutical AMPK Activators
- Metformin: A blood-sugar-lowering agent commonly used in type 2 diabetes treatment. Metformin’s best-studied mechanism of action is to promote the activation of a master metabolic regulator in cells, called AMPK.
- AICAR: Known as an “exercise pill,” that naturally activates AMPK.
Potential Benefits of AMPK Activation
Weight Loss
Activated AMPK triggers beneficial effects such as a reduction in fat deposition. Studies have suggested that adenosine 5′-monophosphate-activated protein kinase can help stimulate fat-burning and weight loss under certain conditions.
Metabolic Improvements
AMPK activation is linked with a host of metabolic improvements and appears to play a vital role in mediating the beneficial effects of various pharmaceuticals/nutraceuticals. Homeostasis controlled in part by AMPK activation can also lead to increased body temperature, reduced inflammation and improved hormone balance.
Anti-Inflammatory Effects
AMPK also exerts potent anti-inflammatory effects. This enzyme has anti-inflammatory potential.
Improved Glucose Uptake
In order to maintain homeostasis of blood sugar levels, AMPK activation promotes glucose uptake and utilization. Signaling pathways can increase glucose uptake within muscles so they continue to have a source of fuel. Hypothalamic AMPK is capable of increasing glucose production if it senses that cellular energy is low. Adenosine 5′-monophosphate-activated protein kinase can help prevent below-normal blood sugar levels, also called hypoglycemia.
Enhanced Cellular Renewal
Certain animal studies conducted on worms, fruit flies and rodents have found evidence that AMPK signaling can support cellular renewal and activate autophagy. Adenosine 5′-monophosphate-activated protein kinase seems to help regulate processes that turn over destroyed cell organelles, damaged mitochondria and other degraded material in order to form new cells.
Cancer Prevention
AMPK activation seems to be beneficial for cancer prevention, but not for cancer treatment.
Potential Side Effects and Considerations
Overall, studies have shown mixed results. It’s important to use caution if you choose to try any AMPK activator supplements, since the quality of supplements is not tightly regulated or controlled. More research is needed to show how different supplement combinations affect energy balance.
- AMPK can increase male hormones/androgens in human cells.
- Aβ generation was also shown to be increased in AMPK deficient mice.
- In mice with Huntington’s disease, AMPK activation promoted neuronal loss and brain decay.