AMPK molecule
A paper recently appeared in the scientific literature demonstrating an enormous and previously unknown benefit of low-carbohydrate dieting. (1) I haven’t seen this study mentioned anywhere, so, important though it is, it seems to have flown under the radar of all the low-carb experts and the press.

The study is about how restricting carbohydrates – even in the face of overfeeding – drives profound signaling protein changes. This is an exciting study, but before we get to the specifics, I want to digress a bit.

First, a story about my own peripheral involvement in a similar study many years ago.

At a scientific meeting in the late 1980s I found myself in a hotel bar with a couple of young anti-aging researchers, who were affiliated with a major government nutritional research facility. The brunt of their research focused on the enzymatic changes in lab animals undergoing caloric restriction. In the course of their work, they found that calorically-restricted rodents exhibited the same changes as did primates and, they assumed, humans.

But they had no human data to confirm. They, along with everyone else in caloric-restriction research, knew that reducing the calories fed to rodents improved their health and extended their lives. And at that time, it was looking as if the primate research would show the same thing. (It ultimately did.) What these guys wondered about, though, were humans. Did humans undergoing caloric restriction display the same enzymatic changes?

No one knew because at that time there were no human caloric-restriction studies.

During the course of our conversation, I told these researchers about my practice and about the success I was having with patients on low-carb diets. I explained how my patients lost weight fairly easily and experienced significant and rapid changes in blood pressure, lipids, fasting insulin and blood sugar levels.

They became intrigued since these changes pretty much mirrored those seen over time in caloric-restriction studies on lab animals. It set them to wondering whether humans following low-carb diets would manifest the same enzymatic changes as calorically-restricted animals. They proposed an experiment.

Before we plunge ahead, though, let’s take a minute to review enzymes. Enzymes are such an integral part of everything that makes life possible that I often forget that they are not really common knowledge. This was brought home to me with great clarity when I was having a conversation a couple of weeks ago with someone who, though not a doctor or a scientists, has a pretty firm grasp of the overall workings of the metabolic system. I was rambling on about the phenomenal results of the study we’ll soon be delving into and mentioned enzymes. My friend fixed me with a quizzical look and asked, “What is an enzyme?” I figure if this guy didn’t know, there are many people out there in the same boat. If you know all about enzymes, feel free to skip on down to where I pick up on happy hour.

What are enzymes? Where do enzymes come from and what do they do?

Enzymes give us life. If it were not for enzymes catalyzing the unimaginable number of reactions required for us to live, we would all be giant lumps of fairly inert chemicals instead of the moving, breathing creatures we are. Every impulse we have, every beat of the heart and blink of the eye, every breath we take is the end result of a series of chemical reactions, none of which would take place without enzymes driving them. Every time you see a chemical reaction that takes place in the body, each step is catalyzed by a specific enzyme. Take a look at the partial pathway of glycolysis from Wikibooks. Each of the steps shown is catalyzed by a specific enzyme.
Below right is another well known biochemical pathway, the synthesis pathway for cholesterol. The most important enzyme in this pathway, hydroxyl-methylglutaryl coenzyme A reductase (HMG CoA reductase), is the rate-limiting enzyme in the cholesterol synthesis pathway. And it is the enzyme that statin drugs inhibit. Inhibiting HMG CoA reductase decreases the body’s production of cholesterol. Unfortunately, there are some downstream effects of this inhibition that the statin folks don’t like to talk about. The next molecule in the pathway, mevalonic acid, is catalyzed by yet another enzyme into farnesyl phosphate, which is the precursor to Coenzyme Q10, an important substance found throughout the body. So inhibiting HMG CoA reductase in an effort to reduce cholesterol often ends up also depleting the body of Coenzyme Q10. Graphic came  from this paper on statins and Coenzyme Q10.
Coenzyme Q10 pathway 2
Enzymes are large proteins coded for in the DNA and transcribed from an RNA template. Enzymes have varying degrees of activity, typically controlled by other enzymes upstream in the reaction cascade. The synthesis of new enzymes takes a while (which is why there is an adaption period when switching to low-carb dieting) but the activation of existing enzymes can take place almost instantly. Activation typically involves adding or removing a chemical group from one of the amino acid chains of the inactive enzyme.

Some enzymes catalyze only one reaction, while others catalyze many. A few are master regulator enzymes in that they catalyze many reactions and activate or deactivate multiple other enzymes and enzyme pathways. These enzymes, often called signaling proteins, drive and/or inhibit multiple systems. It is these enzymes that scientist measure the activity levels of to determine what effect various drug treatments or nutritional therapies bring about.

So, back to my happy hour conversation.

The two researchers proposed an experiment in which I saved a little blood from the regular labwork that I did on all my new patients. They wanted me to then send them a bit of blood from these same patients when they came in for their regular six-week blood tests. (I drew blood on all patients during their initial visit and again at six week intervals to monitor progress.) They sent me special collection vials and a coding system so that patients would remain anonymous. I asked the patients if they minded, and no one did, so the experiment started.

I dutifully collected the blood and sent if off. After enough patients had cycled through their first six weeks,

I got an enthusiastic call from the researchers. And enthusiastic is a mild word for their state of mind. They were practically gibbering with excitement, because they had found the same enzymatic changes in the blood from the patients who weren’t trying to restrict calories but were simply following a low-carb diet. They told me they were going to report their preliminary data to their boss to see if they could pursue funding to continue research with my patients.

When they called me back their enthusiasm was gone. In its place was an overwhelming glumness. They presented the data to their boss, who was the head of the research institute at which they worked, and the response was not what they expected. He told them that they had not followed academic protocol, they hadn’t gone through an institutional review board, and had no business doing an off the books experiment using the institute’s equipment.They got the lecture about how they put the institution at risk and how they could be fired if and on and on.

He told them to wash their hands of the whole thing. Which they did.

They didn’t share their data with me, so I never learned what changes had taken place. I did figure, however, that the changes must have been pretty good given the degree of excitement they generated. At that time, I was simply a clinician taking care of patients and hadn’t started my deep dive into the scientific literature, so I really had no idea what the enzymes they looked at were.

Which brings us 25 years later back to the paper just published online ahead of print in Hormone andMetabolic Research. This paper discusses the activity level of adenosine monophosphate-activated protein kinase (AMPK) as a function of carbohydrates in the diet. AMPK is an enzyme with all manner of downstream effects and can be considered as the Queen Mother of all enzymes, a powerful signaling protein that drives multiple metabolic pathways. You can see a photo of a 3D model of AMPK at the top right of this post from Wikipedia.

The ‘K’ in AMPK stands for kinase, which means that it adds a high-energy phosphate group to other downstream compounds. AMPK is itself activated by an upstream kinase called, appropriately enough, an AMP kinase kinase.

AMPK: what does it do?

AMPK basically monitors the energy levels inside the cells, and when it finds them low, it kicks off several chains of reactions directed toward energy repletion.(2)

As most of you know, ATP is the body’s energy currency. It is made from its precursors ADP and AMP. The food we eat ends up as high-energy electrons that drive the process designed to keep the cells filled with their high-octane energy molecules ATP. You can think of how a battery works. When it is charged, it is at the ready to discharge current to run an iPad, flashlight, cellular phone, whatever. After a time the battery needs recharging or it ceases to provide current. Human cells operate much the same way, but they have an advantage over an iPhone. Human cells have the ability to constantly recharge as their supplies of ATP are consumed. The ratio of the ATP precursors ADP and AMP to ATP signals whether the body should be in the energy discharging or energy storing state.

The signaling protein AMPK monitors this cellular ‘battery’ and sends the appropriate signals to ramp up the forces required to restore the ATP balance to the fully charged state.(3)

If we eat less or don’t eat, we discharge our cellular batteries, because we continue to use ATP but aren’t providing the energy via food to make more. If we exercise, we discharge our batteries, because we are consuming large amounts of ATP quickly, and unless we’re eating on the run – literally – we are not getting the food energy needed to replace our depleted ATP. So when we eat less and/or exercise, we put ourselves in a cellular battery discharge state.

Numerous studies have shown health and longevity benefits from eating less and exercising, though these prescriptions are tough to stick with for the long haul. If this is true, and I believe it is, then the body is better off health-wise to be in a battery-draining state more of the time than in a battery-charging state.

Just for clarity’s sake, a distinction should be made so that confusion doesn’t set in. By cellular battery, I’m referring to the ratio of ATP to ADP and AMP in the cells. I’m not talking about stored fat and sugar. In this model, stored fat and stored sugar would be considered the wall charger or power company where the power comes from to charge the batteries in our devices.

Whether the body is exercising or resting, eating or fasting, the cells need to have their ATP levels pretty much constant. But caloric restriction and/or exercise deplete ATP quickly, so this ATP needs to be restored just about as quickly as it is being depleted.(4) The new ATP needed to top off the tank comes from high energy electrons thrown off from burning fat and/or glucose. If there is no fat or glucose coming in via the mouth, it must come from stores socked away in the body. From glycogen (stored glucose) and body fat.(5)

When ATP levels fall as the batteries discharge, signals go out to the parts of the metabolic system that are responsible for harvesting the energy from stored sugar and fat to create the high energy electrons required to make more ATP.

AMPK is one of the primary signaling proteins that monitors the ATP levels in the cells and signals for more energy when levels drop. When AMPK is activated indicating our cellular energy tanks are depleted, all kinds of good things happen. Here is a short list of metabolic efforts all kicked into action by activated AMPK and why they’re important. (adapted from ref #6)

  • Increases glucose uptake: We want to get glucose out of the blood and into the cells to burn.
  • Increases glycolysis: We need to break down glycogen (stored sugar) to get the glucose to burn.
  • Increases fatty acid oxidation: An obvious one. We want to start burning fat to replenish the depleted energy stores.
  • Increases mitochondrial biogenesis: we want to make more mitochondria to burn fat and generate as much ATP as possible.
  • Inhibits gluconeogenesis: We don’t want to spend energy making more sugar – we want to burn it.
  • Inhibits glycogen synthesis: Same thing – we don’t want to store sugar, we want to burn it.
  • Inhibits fatty acid and cholesterol synthesis: We don’t want to spend energy making fat and cholesterol.
  • Inhibits insulin secretion: We want insulin to be low, so that we can move stored fat and sugar to where it needs to be burned.

When our ATP tanks are filled to the bursting, as when we eat and are stuffed with food (especially carbohydrates) and/or we don’t exercise, all the above pathways go in the opposite direction. If we chronically overeat the wrong foods, our metabolic systems end up sending all the above pathways in the opposite direction most of the time.

Viewed from this perspective, it’s pretty easy to see why AMPK activated by a calorically-restricted diet and/or exercise brings about many healthful changes. It also might make one wonder why drugs haven’t been developed to increase the activity of AMPK to provide these same benefits to people who suffer from obesity, high blood sugar, diabetes and all the other disorders caused by overnutrition. A drug designed to activate AMPK would be diet and exercise in a pill. Who wouldn’t want that?

Well, there are several such drugs. Most have probably heard of one of them: metformin (trade name Glucophage.) Metformin, derived from an ancient herbal remedy, is used by doctors to treat diabetes and insulin resistance and works by activating AMPK. In 2010, physicians wrote some 100 million prescriptions for metformin to treat type 2 diabetes.(5) Some use it to treat obesity, and many folks who can get access to it, take metformin in hopes of increasing longevity.

Drugs that increase the activity of AMPK, when used over time, along with all the effects mentioned above tend also to increase the number of mitochondria, which increases the capacity to burn fat and turn it into ATP. More mitochondria leads to improved endurance, and, consequently, many of these drugs have been placed on the banned list of the World Anti-Doping Agency, the regulating body that deals with drug abuse in sports.(7)

Up to this point in this post, your take away message should be that activated AMPK is a very good thing. If your AMPK is activated much of the time, it would indicate you are eating less, exercising more and making mitochondria. All to be desired. Plus, though it has no bearing on the study we’re about to discuss, it looks like AMPK activation modulates the immune response in a positive way (8) and may even prevent some kinds of cancer.(9) More good things.

At last, to the paper at hand.

Now that I’ve set the stage, lets get to the exciting study that kicked off this blog post.

The researchers knew that AMPK was activated with calorically-restricted diets. They wanted to test whether or not macronutrient composition had an effect on AMPK activity.

These folks from the medical school at the University of Colorado presented two different studies in this paper. I’m going to discuss them in reverse order.

Study #2

In the second study, eighteen obese subjects (8 men – 10 women; avg age 32.4 years and avg wt 227.3 lbs) went on a eucaloric (enough calories to match energy output) diet of 30% fat, 50% carbohydrate and 20% protein for five days to establish a baseline. After the five days, the subjects were randomized to receive either five days of a low-fat, high-carb diet (20% fat, 60% carb, 20% protein) or five days of a high-fat, low-carb diet (50% fat, 30% carb, 20% protein). Both of these diets were restricted to 30% of the calories in the baseline diet. On the night of the fifth day of the study, patients were hospitalized and after an overnight fast, the researchers performed insulin clamp studies and muscle biopsies.

What did study #2 show?

After five days on the calorically-restricted diet, obese subjects in both groups experienced modest weight loss. There were no significant changes in the subjects in either group in any parameters of insulin sensitivity. In both groups, as would be expected on a calorically-restricted diet, fasting insulin levels fell.
Since both diets were calorically restricted, it was expected that the activity levels of AMPK would be increased. And in the low-carb/high-fat diet, AMPK levels were significantly increased. The big surprise, however, was that the activation of AMPK in those subjects on the low-fat/high-carb diet was basically unchanged.

As the study authors put it, this change as a function of carb restriction

suggest[ed] that high carbohydrate intake prevents activation of AMPK… in skeletal muscle that otherwise would have been induced by caloric deprivation.

In other words, these subjects were rowing one way by reducing calories while rowing in the other direction by increasing carbs. Maybe this is the explanation of why it’s so difficult to lose weight and improve health parameters on a low-calorie, high-carbohydrate diet.

Study #1

In the first study – which I think is the much more interesting – the researchers recruited 21 lean (11 men, 10 women; avg age 27.8 yrs; avg wt 147.4 lbs), healthy, non-diabetic subjects, all of whom were started on the same five-day eucaloric baseline diet as the subjects in the other study (30% fat, 50% carb, 20% prot).

The subjects were then randomized into two different groups, both of which consumed 40% more calories as compared to baseline. These five-day overfeeding diets were either low-carb (50% fat, 30% carb, 20% prot) or low-fat (20% fat, 60% carb, 20% prot). As before, on the fifth day of the overfeeding study, subjects were hospitalized so that insulin clamp studies and muscle biopsies could be done the next morning. Then, unlike with the other study, this same group of subjects came back a month later and went through the process again except in a cross-over fashion so that each subject could act as his/her own control.

What did study #1 show?

Interestingly, despite the 40% caloric overfeeding, no significant changes in body weight occurred in either diet. And there were no changes in insulin sensitivity, glucose, lipids or other parameters measured. What was truly amazing, however, was what happened to AMPK activation. Low-fat/high-carb overfeeding did not produce any effect of AMPK activity as compared to baseline. But low-carb/high-fat overfeeding produced a significantly increased activation of AMPK.

In referring to these two studies, the researchers noted:

We observed that caloric restriction with [a low-fat/high-carb] diet did not alter the AMPK [activation], suggesting that increased dietary carbohydrate content even in the face of caloric restriction prevented activation of AMPK… in skeletal muscle of obese individuals. In contrast, overfeeding with [a low-carb/high-fat] diet increased the activity of this pathway [AMPK] indicating that low carbohydrate content may be sufficient for its activation.

And in summary, they commented:

Our data indicate that a relative deficiency in carbohydrate intake or, albeit less likely, a relative excess of fat intake even in the absence of caloric deprivation is sufficient to activate this network and increase fat oxidation.

These studies may provide an answer as to why most weight-loss studies comparing low-fat/high-carb diets to low-carb/high-fat diets almost always find the low-carb diet to bring about the greatest loss.

And this activation of AMPK even in the face of overfeeding may explain why it is difficult for most people to gain weight on a true low-carbohydrate diet. Even one with a large dollop of extra calories.

This paper is exciting because, at least in this case, researchers are looking at what macronutrient differences do to signaling proteins, even in the face of overfeeding. Up until now, most researchers have written if off to a caloric-restriction phenomenon. It’s nice to see that this group has tried to tease out what is really doing the heavy lifting in terms of AMPK activation. It appears to be the carb restriction.

If these findings hold up in other studies, then it would seem that, in a manner of speaking, you could have your cake and eat it, too. Wouldn’t it be nice to be able to go on a diet that truly allowed you to eat all you wanted and have that diet not only not put excess avoirdupois on you but even make your body think it had been exercising?

Before I get too carried away here, there are a few questions this study raises.

First, as anyone who looked at the different diets critically would notice, the low-carb arm of the diet wasn’t really all that low-carb. Reducing carbs to 30 percent of calories is a semi-sort-of low-carb diet. Most people following true low-carb diets get their carbs down to anywhere from 5-15% of total calories. If would be nice to know if these findings held with subjects following a really low-carb diet and not the minimal restriction studied. I would bet the findings would be even better. I base this on the enthusiasm of the researchers years ago who studied the blood of my own patients on very-low-carb diets. But that kind of data won’t feed the whippet, so we’ll have to wait until further studies are done with lower carb restriction to know for sure.

Second, these studies were of only five days duration. We don’t know if AMPK activity runs up and hits a max at five days only to begin to decline thereafter and end up lower on a low-carb diet after two weeks or a month or six months. We simply don’t know based on the data from this study.

Third, there weren’t a huge number of subjects in these studies, so, once again, though the data looks tantalizing, it might not hold if several hundred subjects were evaluated.

Given my bias, installed by several decades of using low-carb diets to treat all kinds of problems, I suspect the data will hold up and get even better with more carb restriction and longer study periods. But we’ll have to wait and see until we know for sure.

Such an exciting study as this one should drive a fair amount of research in this direction quickly. If you do a PubMed search for AMPK, you will find there is plenty of interest. I hope we don’t have to wait long. But until new research comes along definitively overriding this paper, I’m going to continue my own regimen of restricted carb dieting and recommend you to do the same.

1. Draznin B, et al. Effect of Dietary Macronutrient Composition on AMPK and SIRT1 Expression and Activity in Human Skeletal Muscle. Horm Metab Res. 2012 Aug;44(9):650-5.
2. Hardie DG, et al. Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett. 2003 Jul 3;546(1):113-20.
3. Kahn BB, et al. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005 Jan;1(1):15-25.
4. Hardie DG, et al. AMPK: a nutrient and energy sensor that maintains energy homeostasis.
Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251-62.
5. Hardie DG. Organismal carbohydrate and lipid homeostasis. Cold Spring Harb Perspect Biol.
2012 May 1;4(5).
6. Hasenour, C.M., et al. Emerging role of AMP-activated protein kinase in endocrine control of metabolism in the liver. Molecular and Cellular Endocrinology 2012, Epub ahead of print.
7. Hardie DG. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 2011 Sep 15;25(18):1895-908.
8. Lui TF, et al. Fueling the flame: bioenergy couples metabolism and inflammation. J Leukoc Biol. 2012 May 9. [Epub ahead of print]
9. Fogarty S & Hardie DG. Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer. Biochim Biophys Acta. 2010 Mar;1804(3):581-91.


Image at top: Race of Hero Spirits Pass.  Walter Crane.  1909


  1. Fantastic stuff, thanks for sharing this as it had fell under my radar also.
    Tim Noakes would probably be interested to see this as to my understanding he is doing work with athletes on low carb dieting and endurance performance. It would be interesting to see if this short term activation was sufficient to produce an improvement in acute performance measures, or, assuming the AMPK activation holds up over more chronic periods, whether this might be an important mechanism for how low carb diets appear to benefit athletes, particularly endurance athletes.
    Fasted training influences greater AMPK activation also and has shown greater adaptations in VO2max after a training intervention compared with a high carb pre-training intake, so it seems reasonable to speculate that low carb dieting and training might do the same.
    On another note, and as I know you are a fan of SlowBurn/HIT style training, you might be interested in a piece I published earlier this year in which I reviewed the mechanisms of AMPK activation in producing cardiovascular fitness improvement from high intensity resistance training.

    1. Thanks for the paper. I appreciate it. Why don’t you guys do a longer-term experiment on low-carb dieting and AMPK?

      1. Not a problem.
        Regarding a longer term study, I’m tied up in other areas at the moment as are the colleagues of mine who might be interested. It’s definitely something on the cards to look at in the future though.

  2. This is a nicely detailed write up about an exciting study. Thanks for taking the time, I love your writing style.
    In the section Study #1 you have:
    “These five-day overfeeding diets were either low-carb (60% fat, 30% carb, 20% prot)”
    Did you mean 50% fat?

    1. No, actually this was a special diet containing 110% of calories> 🙂
      Thanks for the heads up – I got it changed.

  3. There’s a typo in the composition in study #1 – the low carb adds up to 110%.
    Between the two studies, how did the result differ from undereating to overeating in the low carb group?
    Should also be noted that the amount of protein would also have decreased / increased in the studies as it was a percentage rather than a mass.

  4. Interesting study and post…but I wonder: did the levels of *protein* have an effect? What I mean is that although they were kept constant, would there have been a difference if, say, on the low carb diet, protein and fat were switched?

    1. I think the best results would be with the higher fat diet. Excess protein can be turned into carbohydrate, so would have the negative effects of a higher carb diet.

      1. Note one of the effects of activating AMPK:
        “Inhibits gluconeogenesis: We don’t want to spend energy making more sugar – we want to burn it.”
        In a low carb diet:
        1) Protein only become glucose if that glucose is needed
        2) Protein has other fates depending on needs and the energy balance.
        Protein needs to be at an optimal level to support lean body mass, not to mention hair, skin and nails.

  5. I am a competitive cyclist and made the switch to a low carb diet ( <50 grams a day ) 4 months ago and I've seen huge improvements in performance in terms of energy during races, longer rides and recovery. My carbs usually come in the form of sweet potato's ( a couple per week ) or veggies. Prior to going low carb I required energy bars or gels to finish a ride lasting longer than 90 minutes. Now I can ride much longer with no food and no drop in energy. My own experience says there is something to this! Of course my training mates think I'm crazy. And I'm not going to let them in on my secret! Thanks for posting this article.

  6. Wow a post! I have been coming here for eons awaiting the next one. I thought maybe you began eating a high carb diet and passed away 🙂 As usual though, one post a year from you is of higher value than a post a day from most people. Thanks!

    1. Thanks. No, I’m still on this side of the ground and still eschewing carbs. Just been very, very busy. I’m going to try to do better. Thanks for hanging in there over the long absence.

  7. Great to see you blogging again!
    There is a typo in the article when you talk about “study #1”:
    “These five-day overfeeding diets were either low-carb (60% fat, 30% carb, 20% prot)”
    It doesn’t add up to 100%.

    1. I knew this question was bound to come up. I should have put it in the post. Metformin comes from French lilac or goat’s rue (Galega officinalis).

      1. I think metformin is similar to the active compound in French lilac, which is too toxic for general use unless you have nothing else. So it doesn’t actually come from French lilac.
        You could discuss this fascinating tidbit at your appliance salesman conferences.

  8. Winner, winner, oyster dinner!
    Thanks Dr. Eades – this is great, and understandable, reading. It also appears, based on this paper and your comments, that my AMPK is on round the clock activation.
    To a long and HEALTHY life.

  9. Thanks for the article, very informative. However, you state that “low-carb (60% fat, 30% carb, 20% prot)”, those numbers add to 110%. Also, I would consider those ratios as low-prot, medium-carb, high-fat, but never low-carb. Is there a consensus about how much carb is low-carb?.

    1. Unfortunately, there is not a consensus as to what constitutes a low-carb diet. It would make things much easier if there were.

  10. Oh so interesting Dr Eades ! And so nice to see you have written a blog again after all this time ! You must be very busy with your sous vide 🙂

    1. Yes, I just thought I was busy when I had a busy medical practice. Never imagined the life of an appliance salesman could be so grueling. 🙂

  11. So great to have you back blogging, missed your postings! Very interesting topic. Just finished reading the chapter in “Primal Body, Primal Mind” talking about restricting calories and longevity, it was fascinating, but AMPK wasn’t mentioned, so this is new stuff. Can’t wait to hear more.

  12. Dr. Eades, I was thinking about you yesterday and how I needed my “fix” of your blog. It has been a long time since your last one. They always keep me motivated. I am down 30 lbs. this year and have 15 to go…Woohoo! Thanks for the blog!

  13. @James Steele: thanks for the link to that article. Very thorough and much needed reading (by me) on the subject of resistance exercise.
    @Mike (the competitive cyclist): Stephen Phinney wrote an article describing adaptation to carbohydrate reduction and physical activity ( The article describes how competitive cyclists on a very low-carb diet surpassed their performance prior to going on the diet. In summary, it took ~6 weeks for their bodies to fully adapt to the diet, which pretty much trumps the notion that optimal physical activity (or performance for that matter) is dependent on carbohydrate, and emphasizes the importance of adaptation when thinking about diet and physical performance.
    Under the light of AMPK activation, the fact that those cyclists improved upon their “pre-low-carb” performance makes a lot more sense now!

  14. Thank you for continuing your blogging.
    I remember reading articles about benefits of calories restriction and regretting that I wouldn’t be able to do it being hungry all the time. I have been LCarbing since November 2007, and hunger doesn’t exist for me any longer (sometimes I think that being never hungry is abnormal, but don’t want my old problem back).
    Doctor, what do you think about using LC diet for mild calories restriction? Too many people seems to boast on different blogs how they eat huge amounts of very fat food and still loosing weight, but is it not a good idea to use satisfying effect of LC food in order to eat less without being hungry?

    1. Typically, a low-carb diet causes people to spontaneously restrict calories. The nice thing about this paper was that the subjects in the overfeeding part of the study overate by 40%, which shows that – at least with 30% of cals as carbs – AMPK is activated despite overfeeding when carbs are even minimally restricted.

      1. Typically, a low-carb diet causes people to spontaneously restrict calories. The nice thing about this paper was that the subjects in the overfeeding part of the study overate by 40%, which shows that – at least with 30% of cals as carbs – AMPK is activated despite overfeeding when carbs are even minimally restricted.
        I’d love to see that longer term study on that.
        I have been in “induction” of Atkins (less 20g carbs / day) for about seven weeks and have lost 18 pounds (5’8″, 180 pounds.)
        And yes, I have spontaneously restricted calories.
        I use and probably have been averaging about 1100 – 1200 calories per day (I sit on my butt most days writing software) and apart from a few rough moments haven’t really been hungry hungry, though I have been aware I am dieting and if you offered me a nice hamburger would love to eat it. Haven’t gone to bed hungry either, but again, I miss that shot of whiskey once or twice a week.
        I look at this study with interest and would love to hear that I can increase my calories and still lose weight. Talk about a wonderful perpetual motion machine!
        Anyway, I’d love to see a like website set up for low carb diets — their stuff is good and can be adapted, but….

  15. I believe Bilberry also activates AMPK. Google for the recent study. I also know some non-diabetic bio hackers are using it in place of a Metformin Rx.

  16. This one was well worth the long, long wait. I signed up to follow your tweets, but got little from you and a lot of garbage.
    Fascinating study. Maybe it will lead others to do larger, more rigid and thorough studies. But this one provides much detail about why low-carb — even moderately low carb — diets work, and should silence some of your most rabid critics.
    And I’m still astounded that you bother to read these comments and respond. Few other bloggers of your eminence bother…

  17. Years ago, I found three separate studies (on lab animals, not humans) that all showed that the effects of calorie restriction were also produced by carb restriction alone. I put the links into a post into one or more of the Paleo Diet email lists.
    Like all things of major importance:
    – No one was interested
    – It was contrary to the ideas of some single-interest people (namely the calorie restriction fanboys)
    – Like everything in this general area, it threatens the livelihood of millions of average people and thousands of extremely wealthy people.

      1. I’m interested to see what Ken has. Some studies I’ve found that show a relationship of low carb to calorie restriction. I’m sure I’ve gotten some of them from your blog:
        Calorie restriction leads to fat burning. Methionine restriction, which also increases longevity leads to fat burning as well.
        These are what they all have in common:
        Inhibition of mTOR
        Lowering of serum IGF-1
        Increased mitochondrial uncoupling protein levels and activity.
        Increased mitochondrial glutathione
        Inhibition of ROS
        In this study, was designed to test C60. The rats fed olive oil + C60 lived the longest. The rats fed olive oil without C60 still lived longer though:
        I wonder what would have happened if it had been a full on ketogenic diet.

  18. Thank you for taking time to write such interesting, understandable and always very thorough blog posts. I’ve been following your blog for a couple of years and really enjoy your posts. I especially like reading the explanations from you and other very smart people so that I am more able to understand some of the research out there dealing with the low-carb lifestyle when I’m asked questions about why we eat this way.

  19. Just yesterday i was re-reading your previous blog, wondering when we would get to learn more about mitochondria rejuvenation. Thanks so much for wow-ing me with such exciting information! I would really like to see some of the follow-on studies being done with actually low carb diets (lasting more than 5 days). They definitely need you to help them design a study.

  20. Thanks for uncovering and interpreting this paper! Great stuff…
    I’d like to know if the type of carbs matters at all. Does the paper say what their diets consisted of?

    1. Here you go. Straight from the study.

      Food for all study diets was provided by the CTRC kitchen. Subjects selected food choices from the CTRC kitchen menu. The LF/HC diets were enriched in fruits and starches, and the HF/LC diets were enriched in dairy, nuts, and oils. Subjects presented to the CTRC every morning to pick up food and be weighed. Breakfast was consumed in the CTRC and other meals were packaged and taken with the subject. In both studies, subjects were instructed to maintain their usual level of activity throughout the study. Estimates of daily energy needs were made using several factors: 1) the Harris-Bene- dict equation, 2) baseline RMR plus an activity factor, and 3) lean body mass. Dietary lipid for all diets contained a 1:1:1 ratio of monounsaturated, polyunsaturated, and saturated fats.

  21. Dr. Eades,
    I was wondering your opinion of Dr. Ray Peat’s work, in that it seems to contradict the studies which show caloric restriction and carb restriction lead to increased longevity/heath? Do you see a problem with fruit sugars and milk comprising almost the entirety of a diet?

  22. Great post Dr. Mike. In the past two years I have been lecturing a lot more on AMPK pathways in my Biochemistry classes, just sort of figuring that they had to be important. Nice to feel my hunch was correct. This paper is one I’ll be having my biochemistry students read and analyze next week. Thanks so much for bringing it to our attention. (I may send the students to your blog too).
    Best wishes,

  23. Its not exactly pressing (medically speaking), but these studies need to be done on lean people as well, especially those who have always been so. Of course, it can’t be assumed that what is true for a sick body is the same for a non-sick one.
    In the meantime, the question of what-should-a-human-eat is actually most complicated for the slender individual — since it seems no one studies them!

    1. js290…unless you bought that study, you dont know the composition of the “high fat diet” that the researchers used. They are notoriously high carb/high fat. The fats always get blamed for the damage and the carbs skip away without a scratch. What about the type pf fats? Where they O6? O3? Sat? Mono? What were they ratios? If you have acess to this info, please post it. Till then, a summary of a paper is never proof or reliable.

      1. Once again, here is the nutritional info from the paper:

        Food for all study diets was provided by the CTRC kitchen. Subjects selected food choices from the CTRC kitchen menu. The LF/HC diets were enriched in fruits and starches, and the HF/LC diets were enriched in dairy, nuts, and oils. Subjects presented to the CTRC every morning to pick up food and be weighed. Breakfast was consumed in the CTRC and other meals were packaged and taken with the subject. In both studies, subjects were instructed to maintain their usual level of activity throughout the study. Estimates of daily energy needs were made using several factors: 1) the Harris-Bene- dict equation, 2) baseline RMR plus an activity factor, and 3) lean body mass. Dietary lipid for all diets contained a 1:1:1 ratio of monounsaturated, polyunsaturated, and saturated fats.

        1. Andre wasn’t referring to the study you commented on in your article, but to the study that js290 mentioned, which seems to contradict the one you commented on. 😉

    2. Yeah, mice…. Do you know what type of so called “high fat” diet these poor lab rodents are generally fed..? Well, most of the time, the diet is made of sugar and hydrogenated oils. Aaah, so eating lots of sugar and trans fats leads to health problems? You don’t say! :rolleyes:
      Most of these studies with so-called “high fat” diets are incompetently designed which leads to totally inept conclusions.
      As Andre put it, you can’t draw any conclusion from the study you mentioned, without knowing the actual composition of the so-called “high fat” diet they fed the mice. 😉

  24. I dropped biological sciences and organic chemistry when I was 14 in favour of the physical sciences so I really struggle with understanding some of this, but you do explain much more clearly than many other low-carb bloggers so thanks for that!
    What I find most difficult to understand, though, is why none of these experimenters ever seem to use a real low-carb diet in their work – they only ever slightly restrict carbs. Considering how all low-carb people (including me)constantly bang on about exactly how low carb a real ‘low-carb’ diet has to be, why don’t they get it?

  25. Nice post Mike. The study that probably most correlates laboratory changes from a diet with those seen in calorie restricted animals is from my very low carbohydrate, higher fat, and moderate but not high-protein diet.,%20JARCET-3.pdf
    The explanation for this can be found in multiple papers on my website and blog, especially “Insulin, Leptin, and the Control of Aging” that I presented at the ASBP conference that we both participated in;
    Thanks Mike

  26. @js290, I don’t have a subscription, so couldn’t read the article. But I wonder about the carb content of the “high-fat diet”. The implication in the fb summary was that the diet was not carb restricted, since it compared the high-fat diet to “consumption of a diet with excessive calories leading to obesity”.

  27. Taken together the results are very interesting, and generally confirm what most of us have probably suspected, without really knowing the mechanism. The results suggest that carb consumption at some level is harmful. People are designed to eat carbs, of course, but probably as a constituent of vegetable matter, not in some pure and refined acellular state.
    Your comments also suggest that something may go wrong after excessive carb consumption and lack of use of the pathways employed in fasting and exercise.
    As a lean person (and age 67 for another month…) I was amused by the over-feeding study. I eat all I want, but very few carbs. My friends are on statins and diabetes drugs. Not me. I tell them what i do and why and they eat ice cream and apple pie. And drink fruit juice. It’s frustrating sometimes.

  28. Interesting, all the more so if we consider the effects of hydrogen peroxide production by mitochondria in the presence of excess fuel and the subsequent effects. It would seem H2O2 sort of plays the opposite role of AMPK in terms of maintaining proper balance of ATP and ROS in the cells.
    I’m intrigued that AMPK drives mitochondrial biogenesis, and I wonder if H2O2 impairs it. One might naively think that a “smart” cellular adaption would be to increase the number of mitochondria in the presence of excess fuel, so avoid issues with the electron transport chain backing up and overproducing ROS. Instead the opposite occurs, and it appears the cell regulates fuel intake, e.g. H2O2 production may cause cellular insulin resistance. Further, it sounds like the interplay of these things (not surprisingly) follows from the evolutionary context of diet. In mice, a high-fat diet increases H2O2 production (and presumably suppresses AMPK), impairing mitochondrial biogenesis and leading to insulin resistance in the liver. For humans, it sounds as if excess carbohydrates do the same thing. Presumably in both organisms the cells are better adapted at shutting out the “preferred” fuel in times of excess, and mechanisms like appetite control this over longer time periods.

  29. Dr Mike– Thanks.
    As a long convinced low-carber, I have tried to deepen my understanding of diets for myself as well as my friends and fellows.
    I’m thinking that the key to the metabolic advantage is cycling time, though in much reading (Eades, Taubes et al) i’ve not seen it directly described as such.
    Please let me know how far out of whack is this explication:
    The low-carb diet emphasizes the primary importance of insulin response. A meal of 60% carbohydrates and 20% fat will promote far higher insulin response than a meal of 20% carbohydrates and 60% fat. [Note that the remaining 20% protein in both diets stimulates some insulin response, along with other hormones.] The more insulin, the more quickly the nutrients will be removed from the blood and packed away in the various cells. As the blood becomes (relatively) devoid of nutrients, the brain signals– “Feed me.” If there is food available, most humans will respond to this primal hunger by eating, rather than allowing the body to access stored nutrients– as it would if no food were available.
    By this view, the advantage of the low-carb diet is 1] less total insulin secreted, thus longer cycling of nutrients in the blood; 2] slower nutrient cycling in the bloodstream corresponds to a slower hunger response; and 3] a meal containing more fat and protein is digested and absorbed more slowly from the stomach into the bloodstream in the first place. This apparent curbing of the basis of hunger (ie brain responding to nutrient-depleted blood) must have an effect on our psycho/emotional sense of hunger and satiation.

  30. Thanks for the blog post…such great information! My 15 year old son watched you on the Fat Head documentary and has almost effortlessly dropped from 186.8 lbs (April 3rd) to 150.7 lbs (today – August 23). Thanks SO much. What a gift for him to be able to lose 36 pounds the first time he tried. He’s hooked on this new way to eat. He loves it. Thanks again!

    1. Tell your son congrats from me. I’m glad he’s learning early to eat the right way and what a powerful rejuvenative tool the low-carb diet is.

    2. Cynthia,
      Congrats to your son for his success. I have a 19 yo daughter who was LC until she started dating someone who isn’t. Now she is struggling with her lifestyle. Her biggest fear apparently, is that she is afraid everyone will think she’s weird if she doesn’t eat like the people she is hanging with especially the boyfriend’s parents. Do you or Dr. Eades or anybody else know what I can say to her to convince her that people will think she is still okay if she ditches the bun off her burger? Thanks.

      1. Just have her tell everyone she is gluten intolerant. That’s the in fave disease today, so everyone will understand. Of course, she’ll have to avoid all the other wheat products when her friends are around, too, but there is benefit in that.

      2. Cynthia,
        I never liked buns on burgers or hot dogs. As a kid, I found it awkward when people would look at me when I grabbed a fork and knife instead of a bun. Then my folks had a friend over for burgers one night. He didn’t like it either. I don’t know which one of us was more relieved not to get an odd look (my family was used to it… I was probably 14).
        I haven’t felt self-conscious since then. So, if the other suggestion doesn’t pan out, she could simply say, “Plenty of people prefer to skip the bun.” She’s welcome to use my name if anyone asks 🙂

      3. I’m sure it is challenging for your daughter, but I think Dr. Eades suggestion will be very effective…people do understand gluten intolerance. Another suggestion I have is that she sit down with her boyfriend and watch Fat Head. The beauty of Fat Head is the humor and entertainment value that accompanies the great information. Due to their age this might be the best way to bring her boyfriend along on the journey.
        Also, making some of the information in this article available to your daughter might help. To know that the benefits of low carb reach far beyond weight loss is a powerful incentive to commit to this new way of eating. We call ourselves a lower carb/ higher fat/ moderate protein family. We are a homeschool family and will actually be incorporating research such as this blog post into our science curriculum.

    1. Metformin comes from French lilac or goat’s rue (Galega officinalis). Others in the comments have pointed out other sources, so you might want to go back and skim.

      1. Hmmm, the website where I found goat’s rue supplements said it was for increasing breast size and milk production. I’d better have a look at those other sources… 😉

  31. Just a question. You wrote that increased activation of AMPK
    “Increases glucose uptake: We want to get glucose out of the blood and into the cells to burn.”
    Then you wrote a few lines later:
    “Inhibits insulin secretion: We want insulin to be low, so that we can move stored fat and sugar to where it needs to be burned.”
    I’m not exactly a biochemist (I’m a genetic epidemiologist and statistician by training), but I thought insulin was what moves glucose out of the blood and into cells. Is there another mechanism? Based on my current understanding, reduced insulin secretion would inhibit the movement of glucose into cells. Or perhaps it increases the activity of circulating insulin while inhibiting it’s production (which would lead to the question of the shelf-life of an insulin molecule).
    Very interesting. Thanks for sharing.

    1. AMPK stimulates glucose uptake in part by acting in a roundabout way (by phosphorylating the Rab-GAP protein, if you must know) that increases the fusion of GLUT4 with the cell membrane, all of which facilitates the uptake of glucose. Probably acts to make the insulin receptor more sensitive, too, but I’m not sure of that. In any case, when glucose comes across the cell membrane more easily, not as much insulin is needed.

      1. Thanks for explaining.
        I have to say, it’s been eons since I saw the word “phosphorylating” or any of its forms in writing. Rather refreshing. 🙂

  32. Thanks for wading through the science. I have assumed? heard? that the longevity benefit from underfeeding relied primarily on underfeeding carbohydrates (rational thought and clinical experience both confirming), so it’s nice to see some laboratory science weighing in on the discussion.
    Here’s hoping that a true low carb and greater duration study comes out of NUSI (Taubes & Attia) and that they study AMPK activity. (Hadn’t seen or tried to pronounce that word since medical school 30 years ago!)

    1. I don’t think so. I haven’t really taken the time to completely think it through, but at first blush, it would seem that creatine would increase the activity of AMPK given its effect on the ATP/AMP ratios. Anyone out there have any thoughts on this? If so, let’s hear them.

  33. It’s wonderful to have you back!
    1) What’s the latest on Protexid?
    2) Have you read John Burdett’s Bangkok series (first is Bangkok 8) with Detective Jitpleecheep? They’re fun.
    3) Although I think I know the answer to this, what’s your opinion of the “Safe”-Starch Movement within the Low carb/Paleo/Primal/Ketogenic world?

    1. 1) Protexid is in the works. It just takes a while. Hope to have it back in a month or so.
      2) No, I haven’t read them. Sounds interesting.
      3) I think what you think I would think of it. I’m not for it, at least not for most people. I’ve got a post in the works that sort of addresses that issue.

    2. Another way of stating the safe starch hypothesis that is a bit more appealing is the bad carb hypothesis. A number of writers have made strong cases against modern wheat and fructose as being toxic. Since these are among the most massively consumed carbs, their consumption and carb consumption might be hard to untangle. Any studies making claims about low and high carb should always state what carbs they are talking about.

  34. So, if I read this correctly, if some manager had not stepped in 20 years ago and stopped the research project, we may have had this knowledge in time to at least have a chance to prevent much of the current obesity epidemic. Is that correct?

  35. Such a refreshing read. Your viewpoints are indeed genius. The things you discussed here are helpful by the way that it can help one’s mindset on how food preferences affect one’s physique. Thank you and looking forward to more insights like this one.

    1. I don’t know that there are any long-term studies. The drug hasn’t been around that long. Many non-obese, type 2s have been able to talk their docs into Rxs without bad effects as far as I can tell. No reports that I’ve read in the literature about it, at any rate.

      1. Why would type 2s (non-obese) take drugs to lower blood glucose when you can just eat low carb? I was lucky when I was diagnosed that drugs weren’t ‘forced’ on me and I found Richard K. Bernstein’s diet to lose the excess weight and lower blood sugar to “non diabetic” levels. However, I continue to binge at times (possibly addictive genes?) but get back on the wagon and avoid drugs for diabetes,

        1. Have you tried eliminating wheat? I was low carb for years and could never beat the cravings until I completely eliminated even hidden sources of wheat. Now the cravings are gone. Worth a try, just don’t give up too soon. I started feeling better 3-4 weeks in.

  36. I think it will be a red herring that AMPK activation alone is all you need to prove low carb diets are the optimal diet.
    Even if you were to maintain weight overeating — I bet your cholesterol would be sky high (in comparison to a lower fat diet) and even if you body was performing well at the cellular level — you might still die of heart disease.
    Secondly how do we know that activating AMPK doesn’t make the mitochondria through out more junk from free radicals that might decrease longevity.

    1. You are obviously not a regular reader of this blog or you would know the answers to most of those questions.
      If you maintain wt – even while overeating on a low-carb diet – there is no reason your cholesterol should go up. And no evidence that you would be more likely to die from heart disease.

  37. Thanks for the information. Some 4 years ago my doctor prescribed Metformin to assist me in dealing with insulin resistance. He stated quite clearly that I did not have diabetes type 2 but I was heading that way. I had tried for a couple of years through diet an exercise to lose weight but with no success. My doctor also asvised me to go on a low GI/low refined car diet. This was for two reasons. Firstly because that would also support metabolic change andc weight loss. And second because eating high GI/high refined carb foods whilst taking Metformin promoted unpleasant side effects (gas, cramps, and diarrhea. Well, it worked a treat. Teh weight fell off and my aerobic capacity improved as well. Apparently the Metformin made it easier for my body to access and utilise energy stores. Nowdays I am off he Metformin and whenever I start to see my weight climbing I simply reduce my carbs (expecially the refined kind) and the weight drops off. I think I have a lot to thank my doctor for!

  38. Great post Dr. Eades! I like the way you can explain the science in a simple manner – I think that can only be done when you truly understand the material.
    On an only-slightly related note, I wonder if there is any way to further speed up the low carb adaption process (perhaps manipulating the synthesis of new enzymes quicker somehow?? I googled lipase protein activator and stuff, but I’m really shooting in the dark). My job is in a warehouse, and every time I try to go low carb I can’t pull it off fast enough, my quota plummets, and I get in trouble. After reading the art of low carb performance by Phinney and Volek I really think any athlete can be in ketosis. I’ve already read your low carb adaptation posts (many many times – thanks for that).
    I’m not sure if you’re aware of this, but (I even bought a ketone meter to confirm) ketones get to an acceptable level fairly quickly, in just a few days. However, your body isn’t used to using them.
    Which leads to this study abstract that I can’t figure out. Is walking good or bad for ketone adaptation?
    Wow, sorry for the novel. Don’t sweat the questions if you’re too busy, the bottom line is its great to have you back!

    1. I’m not sure this study would apply to your situation because these subjects were fasted from 3-5 days, not following a low-carb diet.
      It’s been my experience with a lot of patients over a lot of years that getting into ketosis quickly and getting adapted quickly is the best way to go for most people. But in your case, if you generate ketones quickly and have a fall off in performance as a consequence, it might be better to go at it a little more slowly. Cut the carbs, but not to the bone. And carry some little glucose tabs (for diabetics – you can get them at any drug store), so that if you start feeling less than optimal while at work, you can let one dissolve. It will slow down the ketosis a bit but won’t give you enough carb to really slow down your dietary progress. As you adapt over time, you should ultimately be able to do fine on a low-carb diet without it affecting your work.

      1. hi Doc,
        Great article.
        Not wanting to change the subject , but as we are talking about insulin which affects Cholesterol…..
        Would taking Stanols by way of a yogurt type drink daily to lower cholesterol successfully have any side effects in the body later?
        As the stanols prevent cholesterol from recording in the small intestine ….the reported reason why one would see a lower reading on Cholesterol using these product/drink,….so what happens as a result biologically/chemically in the body?
        thanks very much!

        1. Stanols prevent the reabsorption of cholesterol via the bile and may prevent a little uptake in the small intestine. But who cares? The majority of the cholesterol in the human body is made in the human body. If you consume more, you make less. If you reabsorb less, you make more. Why not simply eat foods that control insulin levels and reduce the production of cholesterol. Better yet, why worry about it at all since there have never been studies showing that reducing cholesterol accomplishes anything in terms of a reduction in all-cause mortality? Which is why it is called the lipid hypothesis and not the lipid fact.

  39. Interesting post, as always. However, I can’t help but think about peoples such as the Kitavans who eat a high carb diet. They exhibit excellent health, including leanness and decent musculature. Of course, the main source of carbs in their diet is yams, while the main source of fat in their diet appears to be coconut. So, their fat intake is largely saturated. Maybe, then, it is not necessarily carb quantity, but quality and perhaps more importantly, the quantity and kind of fat consumed. This might help explain the researchers’ summary: “Our data indicate that a relative deficiency in carbohydrate intake or, albeit less likely, a relative excess of fat intake even in the absence of caloric deprivation is sufficient to activate this network and increase fat oxidation”.
    Maybe I am way off the mark. However, as of late, I have been tinkering with a Kitavan-type diet and feel great. My main source of fat is definitely coconut, followed by that found in egg yolks. Some days i consume very high carb in the form of yams and some fruit, other days my fat intake exceeds carb intake.

    1. I can’t help but think of the Japanese, who have the highest rates of smoking of any industrialized society in the world and also have the greatest longevity. I guess this proves that cigarettes are healthful and promote longevity.
      I have a post coming up about this very thing soon. Keep watching.

      1. While cigarettes are not a macro-nutrient or food, it is a good point nonetheless. And, one which I remember you making at the beginning of your Ancestral Health presentation in 2011, a presentation which I might add was excellent.
        I am very much looking forward to that upcoming post.
        One of the main reasons I used the Kitavans as an example is because a lot of paleo people tout coconut as an excellent food (which i understand to be true), and sweet potatoes/yams as a “safe” or healthy carb choice.

        1. Thanks for the kudos on the presentation. The post will be that part of the presentation so that I can refer back to it when people talk about how this group or that group do well on particular diets.

      2. I quit smoking in 1984, age 40 and have been *sick* every since. Apparently low dopamine? It was suggested recently that I try nicotine gum to see if my health improves. Hypoglycemia, candida, horrible digestion, diabetes, severe chills, low thyroid, suicidal depression, etcccc. Googling quitting smoking=getting sick gets many responses — is this common? I seem to be “resistant” to the effects of all bioidentical hormones.

        1. Omg, get your thyroid treated pronto! Most of the things you mention could be due to low thyroid. Also, don’t be satisfied with a doc that only tests TSH, which is as useless as cholesterol testing. You need free t4, free t3, reverse t3, and antibodies at the least. If your antibodies show autoimmune, make sure you eliminate gluten since that tends to stir up the AI thyroid reaction. Good luck!

      3. The Japanese also load up on carbs. Could it be the fish and soy that give them an edge when it comes to health? They eat white rice, noodles, loads of vegetables and fruit, including potatoes.

        1. And they smoke heavily. In fact, the Japanese smoke more than any other industrialized people. Does that mean smoking is good for them?

  40. Smarties are cheaper, 5 is abt 2 grams, one roll is abt 6.5 grams. 2 grams seems to cure false lows for me. to see what they look like, I can usually find a bag of them for $1
    Also eat more protein, it seems to help some people feel stronger, or at least they feel weaker when they aren’t getting enough.

  41. A recent study showed that CoQ10 induced weight loss through the AMPK pathway, concluding
    “Collectively, these results demonstrate that CoQ10 induces PPARα expression via the calcium-mediated AMPK signal pathway and suppresses differentiation-induced adipogenesis.”
    It occurs to me that a low carbohydrate diet results in reduced triglyceride levels which is indicative of reduced inflammation. Reduced inflammation results in reduced utilization of CoQ10 and therefore higher serum CoQ10 which could contribute to suppressed “differentiation-induced adipogenisis”.
    Statins significantly reduce serum CoQ10 levels which it seems to me would result in loss of antioxident capacity which would tend to increase inflammation. By blocking the mevalonate pathway, statins also inhibit synthesis of geranylgeranyl pyrophosphate (GGPP)which is the source of inflammatory rho, thereby reducing inflammation. A Harvard study (PMID 19754385) attempts to portray the blockade of the mevalonate pathway as a good thing because is blocks rho synthesis. Unfortunately GGPP deficiency also causes contractile dysfunction of skeletal muscles, inhibits cell cycle progression and DNA synthesis and causes neuron cell death.

  42. I hope the scientific mainstream will abandon the anti-fat dogma based on this kind of research. I really do.
    But this type of article makes me worry it’s too late …
    I’m boggled over and over again by people who lament malnutrition in the developing world (people subsisting on starch staples and lacking fat and protein) with one side of their mouth and then trumpet so-called healthy living (people subsisting on starch staples and lacking fat and protein) with the other…

  43. “The most important enzyme in this pathway, hydroxyl-methylglutaryl coenzyme A reductase (HMG CoA reductase), is the rate-limiting enzyme in the cholesterol synthesis pathway. And it is the enzyme that statin drugs inhibit. Inhibiting HMG CoA reductase decreases the body’s production of cholesterol”.
    It is my understanding that statin drugs disable existing reductase thereby blocking the mevalonate pathway and thereby blocking cholesterol synthesis, but that the blockade of the mevalonate pathway triggers the production of more reductase and simultaneously triggers the production of more LDL receptors in order to provide cells vital isoprenoids necessary for cell survival. The studies to Akira Endo, Michael Brown and Joseph Geldstein, who all received a Nobel prize for their work on statin drugs, all indicate that it is the increased LDL receptors that cause the statin induced reduction in serum cholesterol, not the “inhibition of endogenous cholesterol synthesis.”
    When statin drugs were used on patients with 100% defective LDL receptors, serum LDL increased by 50% because the defective LDL receptors could not remove LDL from the blood. (Mabuchi, 1981) In patients with 50% LDL receptors, statin drugs reduced serum LDL. These studies indicate the importance of increased LDL receptors in statin induced lowering of cholesterol.
    The term “HMG Coa reductase inhibitors” as a term for statin drugs generates 25,000 hits on Pubmed. I am puzzled that the role of LDL receptors in statin induced cholesterol lowering seems to be totally unknown.

  44. Thank you Mike, very informative, and it is great to be able to see how this piece of the puzzle fits with the rest.
    It is always gratifying when the science reinforces what the practitioners see. Paul

  45. Dr. Mike, I just read this all for the second time and I think it clicked. With metabolic syndrome and menopause my weight loss has stopped about 60 pounds short and stayed there for five years despite steady low carbing for the past ten years and excellent lab reports. Am I right in thinking Metformin might budge that extra weight?
    I dislike taking unnecessary meds, but I would ask for a trial prescription.
    So glad you’re back posting again!

      1. Thank you! I cut some calories and actually have lost five pounds in four weeks. Some of those calories, of necessity, were protein and I’ve dropped below my former minimum of 70g. I have hopes!

          1. Eight more pounds gone. It’s slow, but going in the right direction. Still tweaking. Protein is variable, but rarely under 70g.

    1. Thanks for the link. Interesting. If Metformin makes the brain cells grow via the activation of AMPK, then the low-carb diet should do the same. Perhaps that’s why low-carb dieters are so smart. 🙂

  46. Dear Dr M.E.,
    Thanks, this was a really educational post – enjoyed it thoroughly. Also, it’s great to see fresh activity on the website site. The citation “Coenzyme Q10 and Statin-Induced Mitochondrial Dysfunction “was especially interesting.
    In conjunction with following a low-carb regime, I’ve been on a self-imposed statin/HCT ban since last October – against the advice of my primary care physician. Even though I’ve lost 33 lbs (insert any/all gratuitous praise here) and all key bio-indicators/risk factors have improved with the exception of T-C (230) my PCP is still insistent on prescribing Simvastatin based solely on T-C > 200 (Triglycerides = 53, Fasting glucose=80, HDL=72, VLDL=10.6, T-C/HDL=3.72, T-G/HDL=.736, BP=128/76, Non-smoker, No history CVD, metcon or strength conditioning daily).
    So it was with a wry smile that I read in the summary of the CoQ10 citation:
    “Given the low risk of toxicity and the potential benefit in treating statin-induced myopathy, a trial of 200 mg of coenzyme Q10 daily should be considered for these patients.”
    We couldn’t possibly recommend ending CoQ10 inhibiting statin therapy with a low carb diet to regain function; the solution is “Damn the torpedoes – More Pharmaceuticals”. Ouch!

    1. Statin-induced depletion of coenzyme Q10 has many adverse consequences and for many years was thought to be the cause of statin-induced myopathy. The article you cited noted that CoQ10 supplements did not consistently resolve myopathy.
      A recent study from Japan attributes “statin-induced contractile dysfunction of skeletal muscle” (myopathy?) to another isoprenoid, geranylgeranylpyrophosphate GGPP), which is blocked by the statin blockade of the mevalonate pathway.
      A Harvard study (pubmed ID 19754385) attempts to portray the statin inhibition of mevalonate pathway as a GOOD thing because it inhibits GGPP synthesis which in turn reduces Rho thereby reducing inflammation. There are less toxic ways to reduce rho such as reducing triglycerides, quiting smoking and reducing intake of LA.
      Your lipid profile looks very good to me.

  47. Very interesting article. But I mainly wanted to thank ‘Leslie’ for posting the link on the development of Metformin. I’m a type 2 diabetic, so of course, they have me on Metformin. I found the story of the drug intriguing.
    So anyway, thank you for the information. ^_^

  48. Glad to see you’re posting again. Welcome back! Interesting info and it seems to explain why low carb works, right down to the molecular level. Thanks for providing this review.
    Question: do you know if there is any down side to metformin?
    Again, thanks!

    1. Other than the expense, not really. And if you don’t have elevated blood sugar, you may have to watch it a bit to make sure it doesn’t go too low.

      1. In that case, is Metformin a reasonable thing to consider if you’re trying to lose 50lbs on a low carb eating plan, assuming no blood sugar dysregulation?

        1. I’ve never used it on a patient in those circumstances, so I can’t comment from experience. Theoretically, it would seem to make sense, and I’m sure some do. Probably wouldn’t hurt to try it out if you can get your doc to prescribe.

      2. Just an update on metformin, ShopRite will fill any diabetic prescriptiion for FREE. My wife’s been doing it for years (she’s diabetic), and I started using metformin some months ago, largely motivated by this posting. It does control blood sugar, but you still have to watch what you eat. I have my own prescription. Also, Jimmie Moore has been blogging about an herbal supplement called berberine (marketed as glycosolve), and he swears by it. I was thinking of giving it a try. But metformin is free, remember (at ShopRite). Hope this is helpful.

  49. Some calorie restriction studies did not show increased lifespan, including a recent primate study. Some rat studies even showed reduced life span. Seems like it depended on what strain of rat was used for the study, some lived longer, some showed no change, and some died sooner. It might also depend on the makeup of the food ingested. Despite much hoopla to the contrary, the concept of living longer via caloric restriction is not well substantiated at this point by science. I also suspect carb restriction would not be so important if we only ate healthier sources of carbs instead of wheat, high fructose corn syrup, chemicals, etc.

  50. Hey Dr Eades, I just came across this video “The Diet Wars” by high carb low fat advocate Dr John McDougall. Apparently it was filmed live in September of this year. He argues against the Paleo Diet. He cites the work of Cordain quite frequently towards the beginning of the presentation and even includes a current photo of Cordain and the one used on Cordain’s updated Paleo Diet book, which clearly shows that his current weight is heavier than the phone used on his book.

    1. Whether Dr. Cordain has gained weight or not has nothing to do with his argument re the Paleo diet. I haven’t laid eyes on Loren in over a year, so I can’t comment on his alleged weight gain. But if he has, it doesn’t prove or disprove his dietary theories. They stand on their own.

  51. Dr. Mike,
    As I’ve commented before, I have been eating exclusively fatty meats of all kind now for 4-5 years….and when experimenting with fat intake, I can confirm the notion that eating more fat (saturated in particular) always has the effect of “boosting” my continuous energy (very stable throughout the day).
    When I know that I have a sporting event coming up (usually basketball…and at the age of 44, low carbing has been an absolute asset to continue my hobby) I will eat an extremely high fatty meal (sometimes eating cooked ground beef and drinking the “grease”) 12 hours before….low and behold, I feel like there is an adreneline rush!
    So in summary, for me….the more fat (with almost zero carbs for 4.5 years) the better!!
    Good health to all!!

  52. Very interesting article. But I mainly wanted to thank ‘Leslie’ for posting the link on the development of Metformin. I’m a type 2 diabetic, so of course, they have me on Metformin. I found the story of the drug intriguing.
    So anyway, thank you for the information. ^_^

    1. I’ve heard good things about berberine but I’ve never used it myself or with patients so can’t comment from first-hand experience. The studies look good, though. Don’t know if it acts by activating AMPK or not.

        1. Thanks for the link. I would think it would have additive benefits, but wouldn’t know without studying. Probably wouldn’t hurt to take it, though.

  53. Metformin comments
    You do have to watch your B-12 levels on metformin. It depletes them.
    And take it with PROTEIN, carbs are fine to take it with too, but you have to take it with PROTEIN. For alot of ppl thats the ticket to getting rid of the GI distress that it can cause, that and of course titrating your dosage.
    I am in fact, using it without being diabetic while I lowcarb a la Metabolism Diet. Step Two of this is in fact roughly 15% carb so I found it interesting that that could be a factor maybe in increased AMPK activation. Very interesting. Would love to know when someone studies that aspect of this topic.

  54. Real cheese (as opposed to processed ‘American cheese’) is made by using rennet or acid to curdle the casein into ‘curds’, from which the cheese is made. The liquid surrounding the curds is the ‘whey’, which consists of the acid-soluble ‘whey protein’, most of the lactose (also acid soluble), and some of the minerals (potassium, calcium, and magnesium). In traditional cheese-making cultures, the whey liquid was either drunk as a beveage by poor folks or fed as part of the waste slop to hogs. In the modern ag-industry world, the whey is used as a food additive or sold as a purported muscle-building protein to buffed guys in the gym.
    Either way, natural cheese made from curds starts out life containing relatively little lactose — maybe one gram per ounce. When cheese is aged, however, be it soft like St. Andre or hard like cheddar, the lactobacilli charactertistic of those cheeses all turn lactose into lactate (ie, sweet into sour). Thus aged cheddar becomes ‘sharp’ due to its decreased lactose and increased lactate content.
    When one thumbs thru a food composition manual such as “Pennington & Church”, aged cheeses characteristically contain between 0.6 and 0.2 grams of ‘carbohydrate’ per ounce, and much of what they list as carbohydrate is actually lactic acid, which does not stimulate insulin release unless ingested (or produced endogenously) in very large quantity. Thus the consumption of 4 ounces of aged cheese will add about 2 grams of carbohydrate to one’s daily tally. This is at least an order of magnitude short of “buggering up ones ketogenic state”.
    Our colleagues who advocate a ‘paleo diet’ tell us we should avoid all dairy products, be it fresh milk, yogurt, or cheese. Their argument seems to be that our ancestors didn’t start collecting and consuming milk from ungulates until maybe 10K years ago. Therefore anything containing milk products must be bad for our genes (be they 50 thousand or 2 million years old). The counter argument that over these last ten thousand years our ancesters might have figured out how to detoxify milk always seems to fall on deaf ears.
    Would you think please Sir that the cheese of the goats falls into this description ???
    Rgds to you and MDMD

    1. As you pointed out, a debate rages among the Paleo crowd as to what constitutes ‘real’ Paleo food with one group accepting dairy and the other rejecting it. I, myself, come down on the side of dairy, although I don’t particularly like cheese, other than soft cheeses, which I love. I couldn’t imagine doing without butter.
      My problem with cheeses in general is that they are so calorically dense yet contain very few carbohydrates. As a consequence, people can eat a ton of cheese yet keep their carb intake well within the limit. The huge amount of calories thus consumed can often slow or even halt weight loss. The three foods we’ve found that commonly do this are cheese, nuts and nut butters – all calorically dense, yet low in carb. So, for people who can tolerate it, I don’t have a problem with their eating cheese as long as they’re not overdoing it while trying to lose weight.

  55. Dr. Eades,
    What do you recommend as a source of vitamin K2 for those who do not eat cheese?
    A good reason to eat fermented cheese is the high vitamin K2 content. Deficiency of vitamin K2 is almost universal and many of the sources of vitamin K2 that were available when I was a kid, such as brains and kidneys, are very hard to come by these days. Cheese provides about half of dietary vitamin K2 in the western world and about two thirds of the vitamin K2 among those it the highest quartile of vitamin K2 intake.
    I generally eat about 3 ounces of aged cheese daily which provides about two thirds of the recommended 100 mcg/day of vitamin K2. I get raw milk cheese from pastured cows because it has better nutrient content than cheese made from milk of grain fed cows and because federal regulations require that raw milk cheese be aged at least 60 in order to be shipped across state lines. The balance of my dietary K2 comes from butter (3 ounces per day), eggs and meat.
    I prefer eating aged cheese for vitamin K2 rather than the alternatives of eating natto, which is not paleo either, or taking supplements.

    1. If you don’t want to supplement, the best sources are eggs and meat, especially organ meats, which I eat as often as I can.

  56. Great Stuff Dr. Eades. I’ve been obsessed with reading studies and articles centered around AMPK, Chrebp, Srebp1c and the like lately, and how AMPK inactivates these transcription factors, thus giving a mechanism for a the low carb diet to have such an effect on all the markers we like to see, like improved blood lipids, body fat decrease, etc. Also interesting to see that Glucagon and long chain fatty acids, even the omega 6 (not in the presence of insulin though) activate AMPK as well. Fascinating stuff! Glad to see some posts from you again!

  57. It does not see like you have the right education to draw conclusions from this small piece of research. Am I correct?
    What is shown is that the lack of carbohydrates induces more AMPK since more adaption is needed.
    On higher carbohydrates however, change is not very big since the same amount of fat is used by the body (easily drained from fat cells in obese individuals), and no special adaption is needed in only 5 days!
    The thing that makes losing weight difficult is long term hormonal changes (leptin etc) taking over your brain.
    Not saying high carb is better, but drawing conclusions from these 2 inadequate studies and what AMPK is a MARKER for is absurd.

    1. Not sure exactly what you’re trying to say, but go read a biochemistry book my friend. Carbohydrate and insulin give all the signals for body fat storage and de-novo lipogenesis. Fatty acids, low levels of bood glucose, increased levels of glucagon all give the signal to burn fat for fuel, through the activation of AMPK. It is well established that the transcription factors chrebp and srebp 1c both supress AMPK activity, both which are activated by an excessive amount of glucose, which would lead to an excessive amount of insulin. So on a high carb diet, AMPK expression would undoubtedly be lower and not surprisingly weight loss as well. I don’t think Dr. Eades was drawing conclusions at all. I believe the title of the post was “CAN your food make you fit?” and not “Your food CAN make you fit”…….

  58. My query may somewhat off the mark. I am very much interested in people of cultures who eat non-western (recommended by FDA and MDs; i.e., diets that contain no fruit or vegetables.
    So interested, that I would like to research and perhaps write a Journal Article, or book, which points out the baffling phenomenon of people who eat almost all meat (animal protein) and live just as long as Western Society people who eat a “balanced” meal as recommended by FDA and MDs.
    When I earned my M.A. in anthropology, we had no M.Ds. on our faculty, or I would have written up this fascinating subject in my Thesis.
    I would like your comments how these people can be healthy. Perhaps you could recommend some source information?
    TKOs, Len

    1. It’s really pretty simple. Meat is a perfect food. We are essentially meat ourselves, so dietary meat provides us with anything we might need. Stefansson showed that meat – as long as it’s not overcooked – is an antiscorbutic (prevents scurvy), so a meat diet even takes care of that.

    2. A good example might be the Eskimo peoples, Inuit and Yupik, who historically subsisted almost entirely on meat. Seal and whale.

  59. I’m new to your blog and just discovered this excellent article. Thank you for what you do.
    I think it should be explicitly said that this very exciting overfeeding study is not of meaningful carbohydrate restriction, but rather of increased dietary fat. (Of course, those of us eating low carb and not restricting calories ARE eating more fat.)
    An example is probably the best way to show this: Say a participant’s baseline diet was 2,000 calories. Then, the overfeeding diet would be 2,800 calories. Carbs would decrease only from 1000 to 840 calories, or from 250 to 210 grams — neither low carb nor a drastic change. Meanwhile fat would increase from 600 calories to 1,400 calories.
    A study that shows fat is healthful! Horrors! I predict it will get zero mainstream attention. Even as an MD I find it hard to get people to listen to my reassurances about fat.

  60. This is pretty hot off the press and looks important, although I have only seen the abstract:
    I hope it might be of interest. I found it by searching on one of the author’s names (Wojtaszewski JF), and I had already noticed that he has done a lot of research relating to the topic of your blog post.

    1. Interesting paper. Thanks.
      I’ve got to ask. Did you just randomly pick the name Wojtaszewski JF to search? 🙂

      1. No, not at all randomly. When I first begin to associate a significant researcher with a particular area of study by reading a first paper on which he or she is an author and which I find of interest and of good quality, I tend to then start to search more on the author’s name.
        I am having a tough time remembering what that first paper was in Wojtaszewski’s case, though. But I think that I found it as a reference in an article by Jeff Volek. It was something like five years old I think, but it clued me in as to what this particular researcher tended to focus upon.
        I then thought of the above blog post of yours that I had read some time ago — it was quite an interesting story with the researchers who could not totally divulge what they were doing in the end, and I thought that the new study by Wojtaszewski et al MIGHT be related so I thought I would alert you.

      2. P. S. I think that I was perusing mitochondria-related stuff, as I often do. I am very interested in the theories of Douglas Wallace regarding the relationship between mitochondria and modern/chronic diseases — this makes a lot of sense to me and it seems almost impossible to imagine that there is not a “unifying” cause to the modern diseases. At the endocrinological level Taubes has captured things pretty well, but my guess is that the ultimate cause is at the cellular level and any specific disease in an individual is simply the result of the unifying cause (probably related to ROS overstress) and the individual’s own inherited genetics and accumulated mtDNA damage in the particular degenerating tissue.
        I find M. Brownlee’s theory of macrovascular atherosclerosis degeneration (i.e. vascular IR and excess ROS) interesting, and a case in point. It seems to be consistent with the epidemiological data and other research. It is related, but quite different from his well accepted theory of microvascular disease (i.e. diabetic complications of chronic hyperglycemia).
        The mtDNA factor makes things more complex and difficult to research, of course. And also more difficult or impossible to “treat” with drugs. Hence, I suspect, the general lack of interest in Wallace’s work. But I think that makes it even more compelling. The interaction of energy and anatomy seems a more likely accurate explanation of modern disease than the anatomy alone, but due to the recently developed genetic research tools the possibility for excuses for research grants based upon anatomy is basically infinite. I think that Taubes is appropriately skeptical of molecular research for this reason, as are some evolutionary biologists such as M. Rose.
        But I am just a biologically untrained person with a health-induced interest in following some of the medical research. These are the kind of things that interest me.

          1. Hah 🙂 , I DO own that book and also “Oxygen” but I have not really been able to thoroughly digest either one as yet. I read a lot but probably not anywhere nearly as fast as you evidently must. But thanks for the recommendation — I first learned about Nick Lane reading the Hyperlipid blog that I know you also follow. Peter/Petro is a big fan of Lane, and of course is heavily interested in everything mitochondrial.
            Despite not being trained in biology I am an engineer and scientist and so probably somewhat better equipped to self-educate on scientific topics than many. And, like so many others, I have had my eyes opened in recent years to the relationship between nutrition and health and longevity and physical degeneration (I like WAP’s phrase better than “chronic disease”) by my own middle-aged developing problems. Hence, all of this stuff no longer seems “arcane” at all, although I appreciate your point.
            Your blog is just GREAT — please keep up the super work.

          2. Since you are an engineer, you may find the work of Aubrey de Grey interesting, especially since he focuses much attention on the mitochondria.
            If you haven’t already, you can get your feet wet here. Gives you a lot of info and many links to branch out from.

        1. Dr Bell in Lyndonville, NY hypothesized a decade ago mitochondria were the problem in fibromyalgia. Trying to get grant money is a huge obstacle for him also and he’s put alot of his own money into it. But now we have Dr Terry Wahl and her success with MS and other diseases, all focusing on the mitochondria.
          Minding Your Mitochondria (her first book) seems to be the evolving theme here LOL

  61. my ex does not eat any vegs or fruits, nor drink juice. i always wondered why he didnt develop scurvy or get constipated, altho its hard for him to go, for sure. he eats lots of grains and potatoes and some pinto beans along with lots of junk & sugar; horrific diet. now i see cooked meat prevents scurvy? i assumed the inuits, etc were fermenting roots or eating dried seaweeds. hmmmmmmm

    1. Stefansson figured out that there was something in fresh meat that prevented scurvy because the Inuit pretty much at nothing but for months at a time and did not get scurvy. Also, Stefansson, himself, lived among the Inuit for years, following their diet, and did not get scurvy. So fresh meat contains some sort of anti scorbutic.

    1. Most of the references I’ve seen indicate the Inuit ate cooked meat primarily with some raw and some dried.

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