PPAR gamma 2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism.
Back in this post I made the point that the transcription factor PPAR(gamma) was critical for the development of obesity. And that this is probably how insulin makes you fat, because ultimately insulin stimulates PPAR(gamma) in adipose tissue.
PPAR(gamma) exists with 2 isoforms, PPARg1 is expressed in alot of different tissues, but PPARg2 is primarily expressed in adipose tissue. Theres a funny study from back in 1997 that looked at different ways you can activate PPARg, we know that thiazolidinediones activate PPARg but this study from 1997 shows activation by non-ligand means. This occurs at the N-terminus, whatever the fuck that is.
This is gonna get a bit technical now, hopefully you can keep up,
The below graph shows how strongly each isoform of PPARg is activated when you poke its N-terminus.
As you can see in the graph, PPARg2 shoots up like a rocket when you activate its N-terminus.
Next we activate the N-terminus with and without insulin. We use something called GAL4 to activate the N-terminus, and at the same time we incubate the cells with and without 10nM insulin.
Graph B is our focus. This graph shows that insulin alone cannot activate PPARg2, as evidenced by "Empty Gal 4" column. But look at the very end, when you have both GAL4 and insulin, PPARg2 goes to the moon.
So basically, this study shows that activation of PPARg2 is dependent on something poking its N-terminus, but if you have insulin when this happens, the affects are multiplied.
Interesting bits next, I promise
We go back to the study I linked at the top of this post, its title is quite revealing, remove the lipotoxicity part and you have "PPARg2 controls adipose tissue expandability". I.E. PPARg2 controls how fat your ass gets.
Here the researchers generated ob/ob mice ( leptin deficient mice ) but also without PPARg2. Now, we know that ob/ob get massively obese and eat everything in site, they also refuse to move. Next picture shows the characteristics of ob/ob mice that also dont have PPARg2.....
Look at the bodyweight and food consumption graphs, the double knockout leptin/PPARg2 mice eat just as much as the ob/ob mice, but stay as lean as the wild type mice!. Imagine that..... ( Note there was a slight increase in weight in the female double knockout mice, but the male double knockout mice weighed the same as controls. Not surprisingly really as we know that sex hormones play an important part in bodyfat status. )
Next lets check out this quote....
Furthermore insulin resistance in adipose tissue was demonstrated by the extremely low levels of glucose transporter4 (GLUT4) protein in POKO adipose tissue when compared with GLUT4 levels in adipose tissue from ob/ob mice
This ties in with the GLUT4 and how it influences obesity. With this data in mind, my model for obesity goes like this......
insulin acts on adipocyte -> multiplied PPARg2 activity -> increased GLUT4 expression -> adipocyte hyperplasia.
- Obesity is dependent on PPARg2 activity, not food intake ( there is evidence you can still hypertrophy adipocytes without PPARg2, but you cannot hyperplasia adipocytes ).
- Insulin alone does not increase PPARg2
- Insulin along with something that activates N-termnius in PPARg2 greatly increases PPARg2 activity.
P.S. there is one final interesting comment in the paper that caught my eye...
However POKO had similar total locomotor activity compared with ob/ob mice
POKO are the double knockout mice, and despite them weighing the same as controls, they had reduced urge to move like ob/ob mice. This fits in with something I saw in another paper about how PPARg might control urge to move. As strange as that sounds.
I hope to make a short followup post that suggests laziness is a response to be obesity, and not a cause of obesity.