It’s not the size that counts, it’s how you use it!

Before I do anything else, I want to let you know that Not Exactly Rocket Science has posted a really cool article on a robotic starfish! It can adapt to injury and self-assess. And it’s so cute! Anyone want to get me a robotic starfish? Anyone…?
And on a sad note: Tetrapod Zoology reports on strange giraffe deaths. This makes me so sad! The giraffe, in all it’s tall, necky, awkwardly graceful and nervous glory, is my totem! Though Coturnix also identifies with our favorite ungainly giant. Coturnix, watch out for trees.
ACK! Cool stuff keeps happening before I can finish this post! Tangled Bank is up over at Evolved and Rational, and yours truly is featured, tho’ we are misspelled are ‘Neutropia”. It’s almost the same, right?
Scienceblogs Book Club is back, with “Autism’s False Prophets” as it’s current book. I REALLY want this book. I think I might have to make it a special gift to me, since I’m so awesome.
Finally, and in keeping with today’s paper: Zooillogix has found fat dolphins. Regardless, I think they’re awfully cute. The second pic of the chubby one on the bottom is particularly so. But really, I had something real to write about today (though I think I’ve spent the entire day writing so far…). As I’m sure most of you are aware, doctors are very worried about an obesity epidemic in the United States and other countries. There are lots of possible causes, lack of activity due to sedentary lifestyles, genetic components, crappy food, etc. It’s not that doctors are worried about people being obese per se (though there is probably some societal vanity at work), it’s that there are strong correlations between obesity and several tough health problems, such as diabetes, cardiovascular problems, and cancer. A new essay out in PLoS Biology predicts that it may not be your actual size that counts, but what you do with the fat you have.
Virtue, S, Vidal-Puig, A. “It’s not how fat you are, it’s what you do with it that counts”. PLoS Biology, 6(9), Sept. 2008.

So right now there are three main theories as to why obesity contributes to insulin resistance, which is a precursor to diabetes. This paper looks at those theories and proposes that one of them, the adipose tissue expandability hypothesis, may be the correct model for why obesity predisposes people to diabetes.
A background for those not familiar with diabetes:
Basically, diabetes type I (which is also known as jeuvenile diabetes), is when your body is incapable of producing any insulin, and people with it must have insulin from outside sources to live. Diabetes type II is often referred to as adult onset or insulin resistant diabetes. The body is producing insulin, but either it cannot produce enough, or cells do not react to it very well. There are various drugs used to treat type II diabetes, but really severe cases require insulin replacement like Type I.
And on to the paper. There are three theories of how obesity can cause insulin resistance in humans. The first one is the Adipokine hypothesis, which is that large amounts of fat tissue (called adipose tissue) release a different amount of hormones than normal. The idea is that these hormones (adipokines), could cause insulin resistance. The sceond theory is the Inflammation hypothesis. This idea is that adipocytes (fat cells) secrete chemokines when they are large. Chemokines are chemicals that promote activation of macrophages, part of your body’s immune system. The theory is that these cytokines and the macrophages they activate decrease insulin sensitivity.
But the third hypothesis is the one this paper is concerned with, the Adipose Tissue Expandability Hypothesis. The idea behind this one is that your fat cells can only get so big. After fat cells have been filled up to their maximum expansion, fats can no longer be stored appropriately, and fats then get stored in other places like your liver and your muscle. The hypothesis is that storage in other places uses a lipotoxic mechanism to cause insulin resistance. I find their argument pretty convincing, but I do think it needs more studies in humans specifically to really be able to tell.
The authors start out by noting that obesity is on the rise, and ideas for treating it or reducing its incidence in the population do not appear to be working very well. So it makes sense that we have to come to a understanding of the diseases which are associated with obesity, particularly insulin resistant diabetes.
Insulin resistance diabetes is not always the result of obesity, and this has puzzled doctors and scientists for some time. For instance, some patients have a mutation which makes them unable to store fat at all, but they ALSO often suffer from insulin resistance diabetes. And obesity doesn’t necessarily mean you’ll get diabetes, there are many morbidly obese individuals with no insulin resistance or metabolic problems at all. So what is it about these groups of people? The authors think it can all explained by the adipose tissue expandability hypothesis.
Basically, you have a certain number of fat cells in your body, which scientists think right now are stabilized around puberty. From then on out, it’s very hard to grow new fat cells, so when you build up body fat, the fat cells you have mostly just get bigger. This type of fat is referred to as subcutaneous fat, which is located under the skin, but outside of the abdominal cavity, in places like your arms and legs. In the case of obesity, the fat cells you have get very large. Your body has a set-point, which can be influence by environmental and genetic factors, as to how much those fat cells can expand.
Once they’ve gotten to the point where they cannot expand anymore (usually when a patient is already obese), your body looks for places to put the excess fat that is still being taken in. The fat then starts getting deposited in places like muscle and in organs such as the liver. This also means that the amount of free fatty acids present in your blodo and tissues is going to increase. Fat in these places in called visceral white adipose tissue, and refers specifically to fat located inside the abdominal cavity. Fat inside the abdominal cavity is highly associated with metabolic problems associated with obesity, while subcutaneous fat is not.
Is is these free fatty acids causing problems? Is it the abdominal fat itself?
There are several mouse models out there of obesity, which have helped to answer these questions. First, there’s the “fatless” mouse, which has a mutation similar to that in humans who cannot store fat. These animals are REALLY skinny, but also are prone to type II diabetes. The mouse model and the human model both show that impaired fat tissue function can lend itself to insulin resistance, which implies that normal fat tissue is required for normal metabolism.

From Science Posts

(courtesy of the BBC)
But though some type II diabetics have this fat mutation (called lipodystrophy), the majority are obese. There are mouse models of obesity as well, the best known is the ob/ob mouse, which lacks the gene for leptin, a protein produced by fat cells which regulates appetite and food consumption. These mice are really fat (I imagine they’d be awfully easy to handle), and they are also insulin resistant. But if you limit the expansion of their adipose tissue (make them less able to store fat in subcutaneous fat stores), they are a little thinner, but their insulin resistance is worse! This really seems to back up the authors in their idea that problems with fat storage contribute to insulin resistance.

From Science Posts

(courtesy of Not Exactly Rocket Science)
So if it’s possible to have a mouse who is obese and insulin resistant, and one that is skinny and insulin resistant, what about an obese mouse with no insulin sensitivity? Sure enough, there’s a mouse model. This mouse overexpresses a gene which allows it limitless storage of fat, storing it almost entirely subcutaneously. And these mice are even BIGGER than the normal ob/ob mouse! 50% bigger! That’s the size of a small rat. They basically look like potatoes with legs. But because they can store fat limitlessly, they don’t become insulin resistant, and show none of the metabolic complications found in other obese mice.
Thus far, it looks like the author’s hypothesis, that problems with fat storage lead to insulin resistance, is looking pretty good. But how do these changes in mice translate to humans?
It turns out that scientists have done a few studies in humans, looking at adipose tissue from obese and non-obese people. What they found is that fat from obese patients couldn’t take up lipids (store fat) very well. Not only that, but insulin didn’t stop the release of fatty acids (one of its actions) as well at is was supposed to. None of these effects were present in non-obese humans. This problem with storing lipids could produce a lipotoxic profile which could lead to problems like insulin resistance and cardiovascular issues. It could be that, in obese individuals, the ability to store fat subcutaneously has reached maximal capacity. So this hypothesis could hold…some fat.
Of course, just because one hypothesis might be right, doesn’t mean other hypotheses are wrong. Conditions very from individual to individual. And the other hypotheses might fit in to the adipose tissue expansion hypothesis. Obesity does release increased cytokines, and problems with storage of subcutaneous fat could exacerbate the problems, leading to inflammation. Large fat cells secrete far more inflammatory agents than small fat cells, and the free fatty acids floating around, which the adipose tissue can’t store anymore, also activate inflammatory mechanisms.
The adipokine hypothesis may also contribute to the metabolic problems associated with obesity. Larger fat cells have different secretions of adipokines compared to their smaller neighbors, and insulin resistance itself could cause some of those changes, leading to a cycle of changed adipokine release. So all three hypotheses could have room under the adipose tissue expansion hypothesis.
Keep in mind that fat distribution here appears to be very important. Fat in your arms or feet doesn’t seem to be harmful, and might even be portective against metabolic problems, while the fat in your abdominal cavity and in your muscles and liver appears to be far more dangerous. This also means that your metabolic set point could be the point at which you stop storing body fat subcutaneously, and start storing it in the abdominal cavity, leading to metabolic problems. This metabolic set point could be very different for different people.
Of course a lot of studies need to be done, but I like this adipose tissue expansion hypothesis, and hopefully learning more about fat storage and distribution, as well as insulin sensitivity in individuals and adults, will lead to advances in treating the diseases that are becoming more common in our society.
Samuel Virtue, Antonio Vidal-Puig (2008). It’s Not How Fat You Are, It’s What You Do with It That Counts PLoS Biology, 6 (9) DOI: 10.1371/journal.pbio.0060237

2 Responses

  1. Fixed. Sorry – I haven’t been getting enough sleep lately. Curse you, /b/!

  2. S’all right. 🙂 I still misspell it sometimes, it’s not a good work for the typing figners. Great carnival, btw!

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