Mar. 29, 2012 Hunger has always threatened humankind. This makes it unsurprising that human bodies attempt to store all surplus nourishment in adipose tissue. In developed countries, this life-saving craving is turning into a problem and obesity -- adiposity -- is turning into a danger. Why, though, does excess fat the body ill? How does fat trigger diabetes? And can these superfluous fat reserves be turned into warmth and just as well burnt?
Marcel Scheideler from the Technical University of Graz has examined these questions intensively in a particular project of the Austrian genomic research programme GEN-AU; and he discovered that microRNAs are a part of the solution. It has been known for a while that these molecules, which are produced by the human body, play an important role in gene regulation and thus contribute to cancer genesis. Indeed, this is a research area to which Scheideler has already made valuable contributions as part of an interdisciplinary research team (1). The fact that microRNAs could also contribute to obesity and diabetes, however, is a new insight, to which Scheideler and his team have contributed significantly recently (2-4). The topic of RNA and adiposity thus played an important role at the current conference "9 Years of the GEN-AU Programme" in Innsbruck. The participating research teams were managed by the local Innsbruck company CEMIT.
Too much fat makes people diabetic as well as overweight
"Fatty acids that circulate freely in the blood stream are toxic. Thus, white adipose tissue is specialized at capturing fats from the blood stream and storing them," explained Scheideler. "However, if adipose tissue reaches capacity, chronic inflammatory reactions in this tissue are incurred and the free fatty acids must be taken on by other organs. These are then damaged, which leads to subsequent conditions such as type-2-diabetes. One possible way of fighting diabetes is thus to sustain the capacity of adipose tissue to store fatty acids."
The discovery of "good" and "bad" microRNA
MicroRNA can inhibit the construction of proteins by blocking the building instructions, namely messenger RNA (mRNA). MicroRNA attaches itself to particular positions on the mRNA and thus prevents its translation into proteins. The order to construct proteins is thus not carried out; the amount of proteins in the cell decreases. Michael Karbiener from Scheideler's team discovered the first microRNA to hamper adipose cells production (2).
MicroRNA-27b blocks the building instructions of the protein PPARgamma. PPARgamma has been known for a while to increase the capacity of adipose tissue to absorb fatty acids. Consequently, there are already diabetes drugs on the market that work by activating this protein. However they do not help all relevant patients and, furthermore, they are riddled with side effects. The research conducted by the researchers from Graz offers a possible explanation for this: the way that Micro RNA-27b inhibits PPARGamma might be responsible for these shortcomings and, furthermore, an inhibition of microRNA-27b in turn might unfold the effects of the drug at low doses without side effects.
After all, it has already been observed that microRNA-27b is produced in elevated quantities in adipose tissue of diabetic rats -- a further clue for this connection between microRNA and diabetes. Above all, however, the effect of microRNA-27b on PPARgamma that the scientists from Graz have discovered seems to be another piece of the jigsaw in explaining the development of diabetes itself and in finding new avenues in fighting said disease. At the end of 2011 Scheideler's team discovered a further type of microRNA of opposite effect. MicroRNA-30c supports the production of adipose cells by simultaneously blocking two different proteins (3). One of these proteins is known for its influence on the development of diabetes. A pharmacological regulation of both microRNAs discovered by the researchers from Graz could thus further therapies for diabetes as well as adiposity.
Fat metabolism in brown fat -- new hope in fighting adiposity
Not very many years ago it was discovered that adults (as well as just infants) possess brown fat tissue, which the body uses to produce heat. If it were possible to transform parts of "normal" white adipose tissue into brown tissue and to activate it, excess fat deposits could practically be burnt off -- a totally new therapeutic avenue in fighting obesity and diabetes. In cooperation with scientists from Nice in France, Scheideler and his team have recently developed a cellular model on which, for the first time, it is possible to study this transformation of energy-storing white into energy-burning brown fat cells (4). This GEN-AU sponsored research by the researchers of Graz was so successful that it was included in the recently-started large EU project DIABAT, which researches the transformation of white into brown fat tissue in the treatment of diabetes.
A GEN-AU project on non-coding RNA, within which Scheideler's research was conducted, examined RNA from parts of the genome that were long considered "junk DNA," since the RNA it produces is not mRNA and thus does not provide any building instructions for proteins. By now it has become clear to the entire scientific community that precisely these regions of the genome are extremely important particularly for complex organisms and that this constitutes one of the most significant biological insights of the last decade. This further underlines how timely and relevant the work of the GEN-AU project on noncoding RNA is. "The work of Scheideler's group is one of the success stories of the GEN-AU project on non-coding RNA," say both of the scientific coordinators of the project, Alexander Hüttenhofer and Norbert Nolacek. The success of this work has not just been reflected in academic publications but also in a patent registration. Furthermore, Scheideler's colleague Karbiener won two prizes for his excellent doctoral thesis, respectively from the Technical University of Graz and the Friedrich Schmiedl Foundation.
(1) Merkel et al (2010). "Identification of differential and functionally active miRNAs in both ALK+ and ALK- anaplastic large cell lymphoma." Proceedings of the National Academy of Science USA 107(37):16228-33.
(2) Karbiener et al. (2009) "microRNA miR-27b impairs human adipocyte differentiation and targets PPARgamma," Biochemical and Biophysical Research Communications 390:247-251.
(3) Karbiener et al. (2011) "MicroRNA-30c promotes human adipocyte differentiation and co-represses PAI-1 and ALK2." RNA Biology 8(5):850-860.
(4) Pisani et al. (2011) "Differentiation of human adipose-derived stem cells into 'brite' (brown-in-white) adipocytes." Cellular Endocrinology, Frontiers in Cellular Endocrinology 2(87):1-9
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