Fasting, the Ketogenic Diet and AMP-K: The New Kid on the Block

When I was growing up in the 80s, New Kids on the Block were a massive hit. Yet, I never understood why, nor was I interested in their music. With behemoths like Michael Jackson and Milli Vanilli, who had time for NKOTB? In fact, I even saw Milli Vanilli live in concert and it was definitely one of my fondest childhood memories.
Granted, they were lip-syncing everything, but when you are 10 years old and a concert starts out with Rob and Fab battling in a sword fight, it is hard to get more exciting than that...
With all the recent focus on carbohydrates in the diet and blood sugar, insulin, and the insulin receptor (the Fab Morvan, Rob Pilatus, and Michael Jackson of the metabolic world) the new kid on the block seems to be AMPK. AMPK, or AMP-activated protein kinase, is an enzyme extensively expressed in our skeletal muscle, liver, and brain. It serves as an energy regulator and this function is in response to several dietary and lifestyle habits.
Amping up AMPK
AMPK is basically an energy sensor that gets enhanced when our ATP is reduced (think of ATP as a transporter of energy) and AMP increases. ATP has three phosphates (the T is for tri) and when it loses one becomes ADP (the D is for di, or two) and when it loses two phosphates it becomes AMP (the M is mono for one). Without going too chemistry class on the reader, it can be simply viewed as:
ATP → ADP + P
ATP → AMP + 2P
AMPK works to bring that AMP back up to ATP. In other words, AMPK acts to increase our available energy molecules. AMPK achieves this through several mechanisms described in the pictorial below. The dark blue mechanisms involve breaking down glucose (sugar) to burn for energy. This can be done by pulling glucose out of our bloodstream and placing it into our cells to be consumed. The aqua circles represent the breaking down of cholesterol and fat to be used as an efficient source of energy. The purple includes building more mitochondria to use these fats and sugars to make more energy, and the light blue mechanisms turn off cell building and replication.
Basically, AMPK signals to our bodies and cells that it is not a time for building, but rather for breaking down and burning.


AMPK and Cancer:
AMPK is in essence the antithesis of cancer. While cancer cells are burning large amounts of glucose and nutrients, this is mostly to build up biomass — or, simply put, to keep growing and spreading. AMPK, on the other hand, shuts off this process, blocking cancer growth so we can feed our own cells.1,2 As you can see in the picture below, AMPK actually blocks mTOR, a pathway that leads to cancer survival and growth.3 This is the same pathway that is blocked with targeted cancer drugs. You will also notice in this picture that the pathways are all affected by intermittent fasting, labeled as “IF.” You may also notice that increased insulin sensitivity, which happens though exercise and a healthy diet, also appears to upregulate AMPK.


AMPK and Warburg
The Warburg hypothesis is something that comes up often around these parts. Very briefly put, Warburg showed that whether oxygen was present or not, cancer cells would rather use glucose for energy derivation. Even though when oxygen is present, cells can rely on mitochondria to make significantly more energy, cancer cells still seem to rely on the inefficient process of glycolysis (the breakdown of sugar).Well, while AMPK may stop cancer by blocking pathways like mTOR, newer data shows that it actually blocks the Warburg Effect by blocking the ability of cancer cells to use sugar for energy.4
Amping up AMPK
The great thing about AMPK, is the plethora of ways we seem to be able to manipulate it. AmpK seems to take away the helplessness of disease or “luck” of cancer and lets us know that we do have biologic pathways that can clearly be manipulated by our lifestyle to thwart off disease.
AMPK is upregulated via several mechanisms (in no apparent order):

1. Muscle contraction during exercise,5,6 with the more intense exercise resulting in increased expression of AMPK7
2. Carbohydrate restriction (with or without fasting and even in the face of an increase in calories)8
3. Intermittent fasting9

In a very nerdy, sciency kind of way, AMPK is one of the many reasons why the current and ancient lifestyle that relies on lower amounts of carbohydrates in the diet along with periodic lifting of heavy weights and intense exercise like sprinting puts so many people back in control of their health and in the driver's seat in the fight against cancer. Activation of AMPK, which we can directly affect through our actions, may be putting us in an enhanced metabolic state to fight disease.
Summing it up
With all the recent talk of fasting, a ketogenic diet, and even calorie restriction, insulin (the hormone raised after carbohydrates are consumed in the diet) and the insulin-like growth factor receptor (where insulin and IGF bind) have been getting most of the hype. While it is well-deserved, as they are heavily implicated in cancer diagnosis and progression, we seem to be forgetting about AMPK, the new kid on the block. If we can increase an enzyme that helps stop cancer by fasting, limited carbs, and lifting some weights, isn’t the effect of lifestyle on health common sense at this point?
And remember, even biochemically and metabolically, our lifestyles and actions translate to our health. While Milli Vanilli may not, AMPK helps prove this.
References:
1. Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9(8):563-575. doi:nrc2676 [pii] 10.1038/nrc2676.
2. Green AS, Chapuis N, Maciel TT, et al. The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation. Blood. 2010;116(20):4262-4273. doi:blood-2010-02-269837 [pii] 10.1182/blood-2010-02-269837.
3. Champ CE, Baserga R, Mishra M V, et al. Nutrient Restriction and Radiation Therapy for Cancer Treatment: When Less Is More. Oncologist. 2013;18(1):97-103. doi:10.1634/theoncologist.2012-0164.
4. Faubert B, Boily G, Izreig S, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013;17(1):113-124. doi:10.1016/j.cmet.2012.12.001.
5. Vavvas D, Apazidis A, Saha AK, et al. Contraction-induced changes in acetyl-CoA carboxylase and 5’-AMP-activated kinase in skeletal muscle. J Biol Chem. 1997;272(20):13255-13261. http://www.ncbi.nlm.nih.gov/pubmed/9148944. Accessed January 16, 2015.
6. Winder WW, Hardie DG. Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am J Physiol. 1996;270(2 Pt 1):E299-E304. http://www.ncbi.nlm.nih.gov/pubmed/8779952. Accessed January 16, 2015.
7. Rasmussen BB, Winder WW. Effect of exercise intensity on skeletal muscle malonyl-CoA and acetyl-CoA carboxylase. J Appl Physiol. 1997;83(4):1104-1109. http://www.ncbi.nlm.nih.gov/pubmed/9338417. Accessed January 16, 2015.
8. Draznin B, Wang C, Adochio R, Leitner JW, Cornier MA. Effect of Dietary Macronutrient Composition on AMPK and SIRT1 Expression and Activity in Human Skeletal Muscle. Horm Metab Res. 2012;44(09):650-655. doi:10.1055/s-0032-1312656.
9. Cantó C, Jiang LQ, Deshmukh AS, et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 2010;11(3):213-219. doi:10.1016/j.cmet.2010.02.006.
Source: http://www.myhealthwire.com/news/herbs-supplements/963