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 were 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 (60% 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.
Citations
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. http://dx.doi.org/10.1016/j.mce.2012.06.0185.
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.