I believe that obesity is a fuel partitioning disorder. I’ve argued that when you pack on fat, you essentially “lose” that fuel into your fat tissue. If you don’t have access to fuel, you become hungry and you eat more.
In my last article, I started to delve into the mechanism of this. One thing that is shared between obese humans and animals fattening for winter is elevated PDK4 in skeletal muscle. This blocks the ability of muscle tissue to utilize glucose. So blood glucose is high but you can’t USE it!
The paper1 from the last article has a gem of a chart illustrating this in practice.
There are four groups of mice. The red squares are “normal” mice eating low fat diet. The red triangles are normal mice eating a diet with 60% of calories as high-PUFA lard with some soybean oil. The green triangles are mice who lack PPAR gamma – who therefore will not become torpid – eating a low fat diet. The green diamonds are the mice lacking PPAR gamma on the high fat diet.
And here are the weights of the mice. Remember again that these mice aren’t really normal, this is a special straim (C57BL/6) that is known to reliably become fat when fed a high fat diet.
Here are the weights of the mice. The “normal” mice on the high fat diet is the solid black line and they are easily the fattest. The mice lacking PPAR gamma – dashed black line – also become fat, but not nearly so much. The ROS Theory Of Obesity would predict that an obesity prone organism on a mixed diet of starch and mostly unsaturated fat will gain weight while remaining glucose tolerant and this is what we see.
Let’s think about the two groups of mice on the high fat diet. For the first 6 weeks their food consumption is similar. From that point on the food consumption of both groups of mice rises steadily, but the food consumption of the torpid, insulin resistant mice with a functional PPAR gamma gene far surpasses the consumption of all other mice. They are overeating.
Why are they overeating? Is it because their food is too palatable and too low in fiber and they lack willpower? If that was the issue, the mice lacking PPAR gamma would overeat just as much. But they don’t.
Interestingly, their food consumption rises in parallel with their blood glucose – an indirect indicator of their degree of torpor. Torpid hibernating animals become hyperphagic in the fall -they overeat.
So as the skeletal muscles of the mice become torpid and lose access to glucose as a fuel the mice consume more food. Lipogenic genes are turned on in the liver and so the glucose is being turned into fat in the liver rather than burned as glucose in the muscle.
We could argue about the exact mechanism by which the appetite of the torpid mice is increased, but what is clear is this: the mice increased their caloric intake in response to the activation of PPAR gamma by oxidized PUFA. They are overeating because they have a torpid metabolism and not the other way around.
- 1.Sikder K, Shukla SK, Patel N, Singh H, Rafiq K. High Fat Diet Upregulates Fatty Acid Oxidation and Ketogenesis via Intervention of PPAR-γ. Cell Physiol Biochem. Published online 2018:1317-1331. doi:10.1159/000492091