So like I was saying, biology is weird. AMPK and SCD1 are a literal teeter totter.
This matters because, as I pointed out in the last post, AMPK can help to keep us out of torpor.
In hibernating animals and obese humans, SCD1 wins the teeter totter war. (The analogy is kind of backwards because to win at teeter totter you need to be low to the ground. Think of winning at teeter totter because you have “more of”.)
SCD1 Turns Off AMPK
In this study1, there were mice who had their SCD1 gene genetically removed and a there were mice who produced extra SCD1 in their muscle tissues. Mice who can’t make SCD1 are protected against obesity and mice who make extra SCD1 are very obesity prone.
The mice were put on either a normal “chow” mouse diet or a high fat, high sugar diet known to make mice fat. Look what happens to their AMPK levels. AMPK isn’t activated until it gets “phosphorylated”. That’s the little p. So “pAMPK” is the one we care about.
This image is a “Western Blot”. Don’t worry about the details other than that a darker band means more. There are two individual mice under each scenario. So the first two columns of the first block are normal mice on a normal mouse diet. They have a little bit of pAMPK. The next two columns are two different normal mice on a high fat diet. They make a little less pAMPK. The fifth and sixth columns are two mice on a normal diet who have had their SCD1 gene removed. They make a LOT of pAMPK. When SCD1 goes down, pAMPK goes up. Columns 7 and 8 show two mice who can’t make SCD1 on a high fat, high sugar diet. They have less pAMPK than the mice in columns 5 and 6, but still way more than mice who can make SCD1.
ACC is a target protein of pAMPK. It is responsible for lipogenesis: fat making. when it gets phosphorylated it is turned OFF. So the mice in columns 5 and 6, with the most pAMPK, have turned OFF a lot of the enzymes involved in fat making.
The second block shows mice who make EXTRA SCD1 in their muscle tissues. You can’t compare the darkness of the bands in the second block to the ones in the first block, the exposure time is longer. The first four columns are the same as in the first block – normal mice on a normal or high fat diet. Columns 5 and 6 are again where things get interesting. In the mice making EXTRA SCD1, pAMPK levels go DOWN 60%. This is true whether the mice are on a normal or high fat diet. But the mice with extra SCD1 on a high fat, high sugar diet have the least pAMPK activity as measured by their lack of pACC. They can’t turn lipogensis off.
AMPK Turns Off SCD1
This study2 also used a high-fat diet to fatten up mice. The high fat diet caused a huge increase in SCD1 levels and the mice got fat. This fattening was preventing by berberine, which activates AMPK. Another group of mice were given a pharamcological activator of AMPK. Mice on a high fat diet given either berberine (gray bar) of the AMPK activator (labeled) had their SCD1 levels returned to almost baseline. When pAMPK goes UP, SCD1 goes DOWN.
Then they took it one step further. In the next graph the red bar is a mouse on a normal diet. The black bar is a mouse on a high fat diet – SCD1 goes UP. They light gray bar is a mouse on a high fat diet supplemented with the AMPK activator berberine. AMPK goes up and SCD1 goes down. The very dark gray bar all the way on the right is a mouse on a hi-fat diet with berberine fed a pharmaceutical that blocks the activation of AMPK. SCD1 goes UP because AMPK activity went DOWN.
AMPK in Humans
This is relevant in human obesity. One of the many things that can activate AMPK is adiponectin, which rises after a meal. Except that a moderate dose of adiponectin fails to stimulate AMPK in the muscle tissue of obese humans.3
We’ve already seen that the muscle tissue of obese humans has a lower rate of fat burning than the muscle tissue of lean humans and that increasing the amount of SCD1 in the muscle tissue of lean humans causes it to behave like the muscle tissue of obese humans: it burns less fat.
pAMPK increases the amount of something called CPT1, which controls how fast fat can be shuttled into the mitochondria to be burned. So when you increase SCD1, pAMPK goes down, CPT1 goes down, fat is burned slower.
Why would we evolve to have two genes that are critical for controlling metabolic rate, each of which suppresses the other? No human would design a system like this.
The answer is that this creates a type of meta-stable binary system. The normal state of mammals is to have relatively low levels of SCD1 which allows them to quickly switch into fat burning mode when insulin levels are low – two hours or so after a meal. This happens because AMPK is quickly activated into pAMPK. pAMPK will suppress SCD1 expression and ensure that SCD1 levels remain low. In this state, mammals burn fat efficiently and remain lean.
In response to diets high in PUFA and/or sugar, mammals upregulate SCD1. In this alternate state, mammals do not switch into fat burning mode when insulin drops after a meal. They are in fat storing mode. Fat storing mode is critical if one is trying to fatten up for winter. Once SCD1 is upregulated the mammal stays in fat storing mode because SCD1 inhibits the activation of AMPK.
It’s like a teeter totter and you don’t want SCD1 to win.
In the next post I’ll look at the underlying mechanisms that control the relationship between AMPK and SCD1. There will also be a some posts about ways to increase AMPK activation but you want to do some research, I’ll give you some hints: Vitamin D, Vitamin K2, berberine, metformin, resveratrol.
- 3.Chen MB, McAinch AJ, Macaulay SL, et al. Impaired Activation of AMP-Kinase and Fatty Acid Oxidation by Globular Adiponectin in Cultured Human Skeletal Muscle of Obese Type 2 Diabetics. The Journal of Clinical Endocrinology & Metabolism. Published online June 2005:3665-3672. doi:10.1210/jc.2004-1980