Another study showing that obese people have rapid and increased glucose absorption from the duodenum due to increased glucose transporters. This rapid glucose absorption facilitates hyperglycemia and hyperinsulinemia, because as we know, faster digesting carbs spike blood sugar and insulin more aggressively.
Although it has long been thought that the hyperglycemia and hyperinsulinemia in obese people is due to insulin resistance, the authors here question this, and speculate that rapid glucose absorption could instead easily account for this.
Further there is an imbalance of postprandial incretin hormones, obese people exhibit reduced GLP-1 secretion in response to carbs, ( which is also seen in the graphs here ), the authors here mention that reduced GLP-1 secretion allows glucagon secretion to be enhanced in the postprandial state, which is very inconvenient when combined with the hyperglycemia from the food ingested, because the job of glucagon is to raise blood sugar ( and its already raised from the food ) The combination of enhanced glucagon levels AND the carbs results in even HIGHER blood glucose, and you need even HIGHER insulin to deal with it. Something of a vicious cycle.
We know way back from the powdered carbs study that there is something about the digestibility of carbohydrates that can SERIOUSLY enhance how fattening they are. Indeed it seems to be refinement of carbs that makes them more easily and quickly digested that is the devil. The obesity epidemic has risen in parallel with refined carb consumption.
How hard would it be to believe that...
refined carbs -> morphological changes to intestine** -> hyperglycemia + hyperinsulinemia in response to carbs -> adipogenesis + histone acetylation in fat tissue -> elevated fat mass setpoint -> obesity + resistance to weight loss
**to the best of my knowledge, this has never been investigated, so we dont know if its true, or false. I.E. if the refinement of dietary carbs can directly cause elevated glucose transporters in the duodenum.
I want to come back to this question at the end of the post, after we have examined some research results.
For those not aware a "pre-adipcoyte" is just a cell that has the potential to turn into a proper adipocyte, and is not really an "adipocyte" in the pure sense, it also does not store much fat.
Here's some pictures to do the talking, ( stolen from google )
Something we have to ask ourselves, is, why is the adipocyte storing large amounts of fat, and why is the "pre-adipocyte" not storing hardly any fat? Something to do with calories and energy balance? The adipocytes eat more than they burn, and are in positive energy balance, meanwhile the pre-adipocytes are in perfect energy balance, they eat as much as they burn and stay slim. Calories in, calories out, second law of thermodynamics. Matter cannot be created or destroyed, only transferred.
Is any of this making any sense yet?
Dont dare ask WHY the adipocyte is eating more than it burns. Thats IRRELEVANT................or it might have something to do with its poor impulse control and lack of willpower when faced with tasty food. mmmmmmm cake.
Meanwhile, back in the lab, I came across this paper recently, which looks at epigenetics of the PPARγ gene. A question that has bugged me and should hopefully of bugged anyone else in obesity research is, why are obese people always drawn to regain weight after weight loss. Somehow it seems that the fat tissue is slowly and surely sucking up fat to regain its original mass. I think we've discussed to death on this blog the possible causes of this. Adipocyte hyperplasia and low leptin being the leading culprits. Aswell as catecholamine resistance, particularly in the subcutaneous depot.
However, I think the answer to the question of why fat tends to return to its original size lies in the answer to the question of how it got to that size in the first place.
1. What determines how much fat a fat cell stores?
2. What turns a pre-adipocyte into a mature adipocyte? ( Adipocyte hyperplasia )
Actually we have already seen the answer to the first question, back in this post. The idea put forward was that the histone H3 acetylation of the PPAR-gamma promoter region increased the transcriptional activity of this gene, and thus resulted in increased fat accumulation in the adipocyte.
I Advise you to watch this video which easily and quickly explains what all this histone H3 acetylation stuff is about
So in short, The histone H3 acetylation uncoils the DNA and allows the PPARγ gene to be read, with increasing permissiveness. The next question is,
Why would increased PPARγ lead to increased fat storage?
While I dont have hard conclusive evidence of this, my guess would be because PPARγ targets the gene transcription of proteins involved in the formation and maintenance of lipid droplets. If you want to build a huge single lipid droplet in the middle of the adipocyte ( which is the defining feature of the adipose ), you need proteins to do that. Fatty acids and triglycerides dont just magically like to clump together in large solid balls.
As an example, PPARγ targets and expresses perilipin1 , which is a lipid droplet protein involved in whole body energy balance. One of the crucial functions of perilipin1 is to coat the lipid droplet surface and stop hormone-sensitive lipase entering the droplet and chopping up triglycerides into fatty acids. (lipolysis )
Infact atleast one team are looking to make an inhibitor of perilipin1 to treat obesity. It has also been discovered that the weight loss associated with anti-retroviral drugs is due to their actions in degrading perilipin1. FSP27, is another lipid droplet protein controlled by PPARγ. The function of FSP27 is to make small lipid droplets fuse together into larger ones.
So, in essence, higher PPARγ -> more lipid droplet proteins being manufactured and floating around -> increased ability to build large lipid droplets.
I would propose that PPARγ IS the "vacuum" that is sucking up fat from the blood and causing it to be stored and maintained in the large central lipid droplets of adipocytes.
There is *some* evidence for this, because forced expression of PPAR gamma in fibroblasts and myoblasts is sufficient to differentiate these cells into adipocytes. Its almost as if PPARγ is itself entirely responsible the adipocyte phenotype. Basically, once PPARγ becomes active in a cell, that cell BECOMES an adipocyte. And with that, this is a good time to move on to the second question....
What turns a pre-adipocyte into a mature adipocyte?
Again you can read pubmed[22991504] for an in depth description of the very complex multi-step process that is adipocyte differentiation, But basically....
the transcriptional activation of PPARγ during adipogenesis correlates with an epigenetic switch at the PPARγ gene. For instance, adipocyte differentiation is associated with a strong increase in levels of histone activation marks at the two PPARγ promoters.
in essence, PPARγ is not expressed in pre-adipocytes, then, modifications to the chromatin and promoter regions causes the DNA that codes for PPARγ to unwind from the nucleosome, this allows access by RNA polymerase II to start transcribing PPARγ. PPARγ itself then starts off a cascade that involves unwinding the DNA in its gene target regions. An important ingredient in adipogenic differentiation media is high glucose and insulin. For some reason, ( and this is what the title of the post refers to ) pre-adipocytes regard high glucose and high insulin levels as a signal to epigenetically modify the DNA to expose the PPARγ promoter region, to start transcribing this gene, and ultimately become an adipocyte. There are other key ingredients in adipogenic media, indeed glucose and insulin exclusively may not be sufficient. (shrug, glucose and insulin appears to be enough to make me fat in vivo )
Whats the real reason sugary drinks make you fat? It may because, the hyperglycemia and insulin these drinks promote causes epigenetic changes to DNA in cells that ultimately result in increased and sustained expression of PPARγ. There is already evidence out there that diet and hyperglycemia cause chromatin remodeling to DNA.
Is histone acetylation of PPARγ the reason obese people have elevated fat mass set point?
Its important to point out PPARγ is regulated both at the nutritional and hormonal level, aswell as at the genetic level by chromatin modelling acetylation/methylation. The ligands for PPARγ arefatty acids and prostaglandins. Further, PPARγ is strongly upregulated by insulin.
A curious study from 1997 found increased mRNA of PPARγ in adipose tissue of obese people ( 14.25 obese vs 9.9 lean ), whats more, the increased mRNA of PPARγ positively correlated with the BMI of the subject. The fatter you are, the more likely your PPARγ is to be higher. Given what we have learned above, that would be expected. But the most curious part of the the study was that they made the obese people lose 10% bodyweight on a 800 calorie diet, and PPARγ decreased by 25%. This was then followed by a 4 week intervention of weight maintenance, during this time, PPARγ increased back topre-treatment levels! Isnt that funny? Suddenly my brain is flooded with images and notions of weight regain following weight loss. Its entirely possible these obese people, like pretty much the vast majority of obese people, have chromatin modifications to their PPARγ promoter regions thus encouraging increased basal levels of PPARγ. Going on a diet temporarily suppresses PPARγ, because as discussed, PPARγ is also regulated by nutrition and insulin. But returning to normal eating patterns would see metabolic hormones return to normal. The PPARγ levels return to normal, and their weight will probably return to normal. ( normal being the pre-treatment obese state ).
Adipocyte dedifferentiation.
As eluded to in the fat cell size regulation post.... it would appear adipocytes are actually capable of de-differentiating back into pre-cursor cells, losing their lipid content in the process. Indeed they appear to take on stem cell properties.
As such it may not be necessary to cause any kind of apoptosis to reduce obesity, instead it may only be necessary to silence the PPARγ gene in the adipocyte. Through either DNA methylation or de-acetylation of the histone H3, , or some other complex restructuring of the chromatin, . Once the PPAR gene is silenced, lipid droplet proteins will no longer be manufactured, the adipocyte will have no way to build the large lipid droplet and lipid stores should exhibit a net flow out of the cell.
Whether this can happen in vivo in humans to produce practical weight loss is anyones guess however, and this subject would require another post.
