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Metabolic Effects of AMPK


AMP-activated protein Kinase (AMPK) is an important regulator of cellular metabolism. Once activated, AMPK switches the cell from ananabolic (energy-using) state to a catabolic (energy-producing) state by activating oxidative pathways that generate energy and inhibiting synthesis pathways. 

Both aging and excess nutrient intake contribute to a decline in AMPK activity. Studies of human subjects have revealed a correlation between low AMPK activity in adipose tissue and metabolic disorders associated with insulin resistance and obesity.

Evidence suggests that the strongest activator of AMPK is increasing cellular levels of AMP. 

Effects of AMPK Activation

AMPK for FAT LOSS


AMPK turns off processes involved in fat storage while activating processes involved in fat metabolism. AMPK activity is decreased in patients with obesity. 


AMPK & Fat Storage

“AMPK inhibits the ‘master regulator’ of lipogenesis, sterol regulatory element binding protein (SREBPc) via direct phosphorylation” (Burkewitz, Zhang, & Mair, 2014). 

Consumption of excess calories results in increased mTor activity.  This results in unwanted fat storage. 

mTOR has the opposite effects of AMPK. “Active AMPK stimulates autophagic breakdown of macromolecular complexes in the cell, thus producin genergy and nutrients. In contrast, active mTOR suppresses autophagy to promote cell growth and proliferation” (Brunton et al, 2013).

Nutrients (glucose and amino and fatty acids), insulin,growthfactors, hormones, and oxygen all activate mTOR.In turn, mTOR drives both growth and aging and regulates glucose and lipidmetabolism. Excess mTOR can cause insulin resistance and has been implicated in type 2 diabetes (Coughlan et al, 2013). 

High levels of mTOR causes excess calories to be stored as adipose tissue. Studies show that increasing AMPK activity turns down excess mTOR, encouraging cells to store less fat and instead burn it as energy. 

AMPK & Fat Utilization

In response to fasting and exercise, [muscle cells] switch from glucose to fat oxidation for energy, and AMPK isthe driving force for that switch” (Burkewitz, Zhang, &Mair, 2014). 

Fattyacid oxidation is the process by which the body converts fats intoenergy (ATP). AMPK’s ability to increase fatty acid oxidation has been attributed to two mechanisms. 

First, AMPK regulates ACCand malonyl-CoA, “alleviating the inhibition on carnitinepalmitoyl-transferase which catalyses the entry of fatty acids inmitochondria and constitutes the rate-limiting enzyme of fatty acidoxidation” (Daval, Foufelle, & Ferre, 2006). 

The second explanation is related to AMPK’s impact on mitochondrial biogenesis. Increasing numbers of mitochondria increases fat oxidation capacity which when combined with the above mechanism can turn ‘white adipocytes into fat-oxidizing machines’.

AMPK for Insulin Resistance


AMPK activation increases glucose uptake and lowers fasting plasma glucose levels in type 2 diabetics (Steneberg et al, 2018). Decreasing levels of AMPK have been linked to insulin resistance. 


AMPK increases glucose uptake in muscle cells:

AMPK increases glucose uptake in the muscle through regulation of glucose transporter 4(GLUT4).  When AMPK is activated, GLUT4 translocates to the cellular membrane, creating a doorway for glucose uptake, in muscle cells.

AMPK also inhibits the body’s own glucose production (gluconeogenesis).


AMPK increases glucose utilization

AMPK promotes glucose utilization by up-regulating glycolysis(glucose breakdown). “AMPK phosphorylates the 6-phosphofructo-2-kinase (PFK 2), a key enzyme of glucose depletion,to activate glycolysis” (Heidrich et al, 2010)

Increasing levels of AMP increases AMPK activation.


“AMP is a true physiological regulator of AMPK” (Gowans etal, 2013). AMPK is activated in response to changes in the AMP:ATP ratio, either by increasing AMP or decreasing ATP. 

Studies have found that oral AMP activates AMPK, resulting in improved hypertension,plasma triglycerides, HDL-cholesterol, and glucose  (Ardiansyah etal, 2011). Even a single oral administration of AMP was found to affect expression of b-oxidation, fatty acid synthesis, and AMPK.

Ardiansyah, Shirakawa, H., Koseki, T., Hiwatashi, K., Takahasi, S., Akiyama, Y., & Komai, M. (2011). Novel effect of adenosine 5'-monophosphate on ameliorating hypertension and the metabolism of lipids and glucose in stroke-prone spontaneously hypertensive rats. Journal of agricultural and food chemistry, 59(24), 13238–13245. https://doi.org/10.1021/jf203237c
Steneberg, P., Lindahl, E., Dahl, U., Lidh, E., Straseviciene, J., Backlund, F., Kjellkvist, E., Berggren, E., Lundberg, I., Bergqvist, I., Ericsson, M., Eriksson, B., Linde, K., Westman, J., Edlund, T., & Edlund, H. (2018). PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients. JCI insight, 3(12), e99114. https://doi.org/10.1172/jci.insight.99114
Brunton J, Steele S, Ziehr B, Moorman N, Kawula T (2013) Feeding Uninvited Guests: mTOR and AMPK Set the Table for Intracellular Pathogens. PLOS Pathogens 9(10): e1003552. https://doi.org/10.1371/journal.ppat.1003552
Coughlan, K. A., Valentine, R. J., Ruderman, N. B., & Saha, A. K. (2013). Nutrient Excess in AMPK Downregulation and Insulin Resistance. Journal of endocrinology, diabetes & obesity, 1(1), 1008.
Daval, M., Foufelle, F., & Ferré, P. (2006). Functions of AMP-activated protein kinase in adipose tissue. The Journal of physiology, 574(Pt 1), 55–62. https://doi.org/10.1113/jphysiol.2006.111484
Burkewitz, K., Zhang, Y., & Mair, W. B. (2014). AMPK at the nexus of energetics and aging. Cell metabolism, 20(1), 10–25. https://doi.org/10.1016/j.cmet.2014.03.002
Gowans, G. J., Hawley, S. A., Ross, F. A., & Hardie, D. G. (2013). AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell metabolism, 18(4), 556–566. https://doi.org/10.1016/j.cmet.2013.08.019
Heidrich, F., Schotola, H., Popov, A. F., Sohns, C., Schuenemann, J., Friedrich, M., Coskun, K. O., von Lewinski, D., Hinz, J., Bauer, M., Mokashi, S. A., Sossalla, S., & Schmitto, J. D. (2010). AMPK - Activated Protein Kinase and its Role in Energy Metabolism of the Heart. Current cardiology reviews, 6(4), 337–342. https://doi.org/10.2174/157340310793566073