The Secret(e) Life of Fat Cells
Evan David Rosen, M.D., Ph.D.

Assistant Professor of Medicine, Harvard Medical School

As a fat cell maven, I am immensely gratified to see my favorite tissue finally get some respect. For years it was felt that fat cells were simply inert storage containers, loading up on fat when times were good and letting it go when times were hard. Adipose (fatty) tissue does, in fact, do this. It just does a whole lot more.

Research over the past few years has revealed that fat, far from just lying around looking yellow and flabby, plays a critical role in regulating energy balance throughout the whole body. Additionally, fat secretes hormones and other factors that help control such diverse bodily functions as appetite, reproduction, bone density, blood clotting, inflammation, and blood pressure. The inflammation aspect is a fascinating story in its own right that may have a lot to do with how diabetes develops, but I’ll save that for a future Diabetes In Control feature.

The story today concerns a protein that is produced and secreted exclusively by fat cells. It was identified almost five years ago by several different groups of researchers, all of whom independently exercised their naming rights. The confusing result is that this protein is known in the scientific literature by at least five different names, adipoQ, adiponectin, apM1, GBP28, and Acrp30. For the sake of this Viewpoint we’ll use the name Acrp30, because it’s the name chosen by the first group to publish their findings on the new protein, and priority ought to count for something. Acrp30 stands for adipocyte complement-related protein of 30 kilodaltons in size, which points out that this molecule bears resemblance to certain molecules of the immune system, specifically the complement proteins that we employ to help kill some bacteria. As far as we know, Acrp30 doesn’t participate in immune function, although that possibility hasn’t been explicitly ruled out yet.

According to several new studies, Acrp30 is involved in regulating the way tissues handle sugar and fat. Several observations point to this result in dramatic fashion. First of all, Acrp30 levels are reduced in obesity. This is the opposite of what would be expected of a protein made by fat cells, as common sense would dictate that more adipocytes should make more Acrp30. This opened speculation that reduced Acrp30 levels might be a link between obesity and diabetes, which led investigators to give Acrp30 to obese mice with type 2 diabetes. Amazingly (because the hypothesis seemed too simple to actually be true) Acrp30 reduced blood sugar levels in these animals, and in many cases reduced serum insulin levels as well. This result points out that Acrp30 is not likely to act like sulfonylurea drugs, which increase insulin levels, but more like a thiazolidinedione (TZD), which sensitizes the body to its own insulin. This is particularly salient, because the new studies show that TZDs act to increase Acrp30 levels in fat cells and in the blood. Perhaps, then, control of Acrp30 is one way in which TZD drugs exert their antidiabetic effects.

Another interesting result is that Acrp30 reduces fat accumulation in tissues other than adipose, including muscle and liver. Fat tends to build up in these organs in diabetes, and current theories predict that this fat acts to disturb the normal insulin sensitivity there. Reducing fat content in muscle and liver would be predicted to improve whole body insulin sensitivity, which is in fact what is seen when Acrp30 is administered to diabetic mice. Acrp30 also reduces triglyceride (fat) levels in the blood; these effects seem to occur because Acrp30 turns on enzymes that cause tissues to burn the fat they contain. The net result of all this fat burning is weight loss in mice that are treated for several days.

There are other interesting findings as well. For example, there has been a great deal of activity trying to locate the genetic determinants of type 2 diabetes in humans, and researchers have located a number of areas on our chromosomes that may play a role in the development of this disease. One of these regions is on the same part of chromosome 3 that contains the Acrp30 gene, suggesting that variations in Acrp30 levels may help to determine who gets diabetes and who does not.

Another interesting result concerns a rare disease called lipodystrophy. People (and mice) with this disease have little or no adipose tissue, which may sound like a good thing, but it’s not. There are many problems in lipodystrophy, but the worst may be the severe diabetes that develops. As it turns out, replacing Acrp30 in mice with lipodystrophy partially corrects their diabetes, and adding leptin to the mix (another hormone secreted by fat cells) seems to completely fix the problem.

There’s still a lot to be learned about Acrp30, including how it exerts its effects, and how fat cells regulate its production in leanness and obesity. Nonetheless, I think it’s likely that several drug companies will put Acrp30 high on their priority list. On the one hand, Acrp30 is a protein, which means that it will probably have to be injected like insulin. On the other hand, there is a lot of work going on in drug delivery, focused hard on the possibilities of administering proteins like Acrp30 and insulin orally, or via inhalation, or through a skin patch. The main reason why I believe Acrp30 is going to be big news is that it causes weight loss in mice. If this holds true in humans it will be very exciting, because virtually all other medications for diabetes cause weight gain as an incidental effect. And for the average patient with obesity and type 2 diabetes, weight gain is a side effect they would rather avoid.

References:
1. Anders H. Berg, Terry P. Combs, Xueliang Du, Michael Brownlee & Philipp E. Scherer. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nature Medicine August 2001 Volume 7 Number 8 pp 947 - 953.
2. T. Yamauchi, J. Kamon1, H. Waki, Y. Terauchi, N. Kubota, K. Hara, Y. Mori, T. Ide, K. Murakami, N. Tsuboyama-Kasaoka, O. Ezaki, Y. Akanuma, O. Gavrilova, C. Vinson, M.L. Reitman, H. Kagechika, K. Shudo, M. Yoda, Y. Nakano, K. Tobe1, R. Nagai1, S. Kimura1, M. Tomita, P. Froguel & T. Kadowaki. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Medicine August 2001 Volume 7 Number 8 pp 941 - 946.
3. Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proceedings of the National Academy of Sciences USA. 2001 Feb 13;98(4):2005-10.

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