Why a Calorie is not a Calorie: Part 1 AMPK

Yesterday, I came upon the annual “Obesity” issue in the medical journal Lancet about how obesity is accelerating across the world.  They estimate that 1 in 2 people will be obese, not just overweight, by 2030.  In addition, we all will be paying $66 billion a year to treat obesity-associated medical problems by the same time.  This blew my mind, and I wanted to document this prediction on my blog.  The world is failing miserably with preventing and treating obesity.  I believe that central to this failure is the persistence of the “calories in minus calories out” myth.  I want to provide a comprehensive series of blog posts that explain the cellular machinery changes that occur in response to the type of calories the body is exposed to.  I will provide an explanation into weight regulation hormones and how those hormones change in response to various macronutrients, stresses, and situations.  I hope to supply a working hypothesis regarding why I believe carbohydrates cause obesity.

The people that know me are aware of my belief that carbohydrate causes excess weight accumulation and metabolic dysregulation.  I am interested in the mechanism through which carbohydrates exert those changes; until now it’s usually explained by “carbs cause increased insulin” and “insulin is the storage hormone.”   However, I am going to try and explain the cellular machinery that responds to insulin and other hormones to cause weight gain and fat accumulation.  Then I will make the link that carbohydrates create a hormonal environment that tips the body towards metabolic disaster.

Enter AMPK

Adenosine monophosphate-activated protein kinase (AMPK) is an enzyme that is conserved through most metabolic tissues in the body including the brain, muscle, liver, fat, and heart.   What is interesting is that the enzyme is a kinase, meaning that when it is activated, it goes on to turn many other enzymes on or off.  In this way, AMPK can control many different aspects of the energy balance machinery.  AMPK is like the air traffic controller, though planes can determine their own path, one master switch controls a vast number of planes.  The more I read about the enzyme, I am convinced it plays a crucial role as the “metabolic master switch” for the body by regulating glucose uptake and fat oxidation (burning).  It responds to many of the “energy regulation hormones” including leptin, adiponectin, cortisol, insulin, ghrelin, and cannabanoid molecules.  (The next post will cover these hormones and give an overview of their roles and sources).  AMPK has specific energy regulation actions, that differ in response to different hormones, both in the brain (appetite determination) and in the periphery (fat storage/usage); I think it is crucial to cover both.  For this discussion, I will refer to hypothalamus (brain) AMPK as “brain AMPK” and I will refer to fat cell/liver cell/heart cell AMPK as “body AMPK.”

Brain AMPK

In the brain, AMPK activity is determined by the hormones mentioned above including Leptin, Insulin, Adiponectin, Ghrelin and Corticosteroids.  AMPK has been found throughout the brain but is most important in the determination of appetite through its activity in the hypothalamus and hindbrain.  Bottom line, activation of AMPK in the brain, specifically in these two areas, results in increased appetite and food intake.   Similarly, low AMPK activity will cause “anorexigenic” behavior with lower food intake and appetite.  A fasted state is known to cause high AMPK activity in the  brain while increased feeding will suppress AMPK behavior.  In this way, AMPK activity is determined by multiple hormones and is the “sensor” of the brain in determining the feeling of appetite.  This is why low-fat, low-calorie diets ultimately fail; you can’t fight the AMPK “master switch” of appetite unless you know how to periodically eat to decrease AMPK activity in the brain. I will go on to discuss how to control brain AMPK with specific macronutrient intake to maximize weight loss in part 3 of this series.

Body AMPK

AMPK is ubiquitous in the body with high concentrations in the fat, heart, muscles, and liver.  Generally, AMPK activation results in the initiation of catabolic (“energy burning”) processes while inhibition of AMPK results in anabolic processes (“energy storing”).  Some examples: AMPK activation in the liver causes decreased fat synthesis, increased fat breakdown and decreased cholesterol synthesis.  In the muscle, AMPK activation cause increased uptake of glucose from the blood, decreased glycogen (storage form of carbohydrate) synthesis, increased glycogen breakdown, and decreased glucose production in the liver.  Finally AMPK activity causes cells to make more mitochondria, the “cellular power plants,” which go on to make energy through using up glucose, fat, and ketones that are in the cell.  More mitochondria, more energy burning.

Metformin Structure (From Wikipedia)

For a quick clinical correlation, Metformin (Glucophage) is usually the first anti-diabetes drug that a Type II diabetic patient is started on to control blood sugars.  The vast majority of patients experience weight loss, decreased appetite, and increased insulin sensitivity with the drug.  Metformin is a “body AMPK” activator, working at the liver, fat, and muscle to burn energy.  Contrast that to the patients who have such bad insulin resistance at presentation that they require insulin therapy to manage their sugars.  Nearly all patients treated with insulin gain weight.  As we will see in the next part of the series, insulin is “body AMPK” inhibitor, and we should do everything we can to minimize insulin prevalence in the body’s hormonal environment…most of the time.

This primer on AMPK aims to show you why calories themselves aren’t the whole story, it is the hormonal effects of those calories that count.  The next post will focus on hormonal influences on AMPK and Part 3 of the series will discuss how different macronutrients in diet alter hormones to ultimately determine AMPK activity.   Please comment if you have questions, thoughts or opinions.