Obesity is a major public health issue in Brazil, affecting 17% of all Brazilians over the age of 20. In addition, half of the country’s population is overweight, according to the most recent data issued by the Brazilian Institute of Geography and Statistics (IBGE). On a global scale, an estimated 500 million people are obese and there is no reliable, drug-based treatment with lasting results against the disease. In an effort to discover an effective drug to fight obesity, a group of researchers from Brazil and Germany signed an international cooperation agreement in the first half of 2013. Their studies will focus mainly on kinins, a family of peptides produced in the blood and tissues. These peptides play a direct role in human appetite, as well as other clinical parameters such as inflammation and blood pressure. The scientists want to confirm the role and effectiveness of kinin antagonists as potential anti-obesity drugs. An antagonist is a molecule that can block the activities of a given substance – in this case, kinins.
“The agreement includes collaboration between our team and that of Professor Michael Bader from the Max Delbrück Center for Molecular Medicine (MDC), in Germany. We want to look more thoroughly into animal models that can confirm the importance of kinins in obesity,” says molecular biologist João Bosco Pesquero, professor at the Federal University of São Paulo (Unifesp). Collaboration between the two groups involves a regular line of research project award from FAPESP and a similar project funded by the Helmholtz Association of German Research Centers, a German scientific organization with an annual budget of €3.76 billion and 18 member research institutes. The agreement was drawn up at the initiative of the researchers themselves, without any prior arrangement between FAPESP and Helmholtz. Most of the grants and fellowships awarded by the Brazilian foundation – such as the regular line of research award requested by Pesquero – include funds that can be used at the principal investigator’s discretion for international research collaboration (according to the conditions laid out by FAPESP). This is the first project involving a collaboration between researchers supported by these two institutions in particular.
“Cooperation between Brazil and Germany has been growing over the years, and when Helmholtz president Jürgen Mlynek visited Brazil in 2011, he showed great interest in scientific collaboration between the two countries,” says Pesquero. “Professor Bader and I decided that we would begin collaborating. Because there had been no prior arrangement between the two research foundations, and therefore no pre-established rules, I applied for a regular line of research award from FAPESP as a means to kick off the project. We got approval for the project here and Professor Bader did the same in Germany, with Helmholtz.” The same project – Kinins as novel targets in obesity – was submitted in both countries to apply for two separate research grants. Helmholtz awarded it a three-year grant with annual payments of €50,000, while FAPESP granted R$267,000 payable over the course of two years.
Genetically modified mice
In the studies to be performed by the two research groups, animal models play a central role – more specifically, genetically modified mice whose B1 receptor genes have been deactivated, or, in the scientific jargon, knocked out. These receptors are responsible for transmitting signals triggered by kinins. Past studies by the two research groups have shown that the B1 receptor is closely involved in the signaling of leptin, an appetite-modulating hormone. High levels of this substance in the blood will reduce a person’s appetite. The B1 receptor knockout mice raised by the group in the past were resistant to obesity induced by a fatty diet (see Pesquisa FAPESP Issue No. 189).
Chance in the nervous system
The idea now is to look deeper to try to pinpoint the exact type of B1 receptor that has a direct role in obesity, as this type of receptor is present not only in fatty tissue, but also in various organs. In previous joint research projects, the researchers saw that the nervous systems of genetically modified animals with knocked out B1 receptors undergo a change that leads to increased expression of an appetite-controlling hormone called CART (Cocaine and Amphetamine-Related Transcript). “Since the B1 receptor is present in different tissues and cells, including the brain, the purpose of this model will be to test the hypothesis that the phenotype we observed in animals that don’t get fat, in other words their resistance to obesity, is caused by removing the receptor expressed in the cells of the nervous system,” Pesquero explains. “This means that if the hypothesis is correct, we will see the opposite effect when we increase the expression of B1 receptors in these cells. These are different ways of genetically testing a hypothesis.” A direct result of this new investigation – if the proposed hypothesis proves accurate – will be the creation of potential anti-obesity drugs based on B1 receptor antagonists that can work more effectively by acting on the brain. “In order to do this, the new drug will have to have a structure that enables it to cross the blood-brain barrier,” says Pesquero.
In the recently signed international agreement, expected to be in place for three to four years, the role of the German group will be to raise the new genetically modified animals. “My group works with several hormonal systems that are involved in cardiovascular control, including the kinin system,” says molecular biologist Michael Bader. “We generate rat and mice models with modifications to the genes involved in these processes. By analyzing these animals, we can discover new, often therapeutically relevant functions associated with these systems.” As soon as the genetically modified mice are produced and characterized at the MDC’s laboratories, the Unifesp researchers will begin their work of performing the physiological experiments on the animals. “We will feed them a hyperlipidic diet and evaluate several parameters, like body mass, amount and concentration of fat, and response to a range of metabolism-related hormones,” explains the Unifesp professor.
This is not the first time that Bader and Pesquero have worked together. Their first collaboration dates back to 1992, when the Brazilian went to Germany for a post-doctorate at MDC, where he met his German colleague. Pesquero spent four years in the country – two on a grant from the Coordinating Agency for the Improvement of Higher Education Personnel (Capes) and another two funded by the German government – and has kept in touch with Bader ever since. Upon returning to Brazil, Pesquero was hired as a professor by Unifesp’s Biophysics Department. “For several years, many of my students who are now researchers or faculty members at Unifesp or other Brazilian institutions have had the opportunity to develop part of their work at the Max Delbrück Center with Professor Bader’s group.” In 2003, the two researchers, together with other researchers from their respective teams, filed a patent in Brazil under the title Mechanisms and Drugs Used for the Treatment of Diabetes and Obesity and for the Control of Eating Disorders.
Kinins as novel targets in obesity (nº 2011/12909-8); Grant Mechanism Regular Line of Research Project Award; Coordinator João Bosco Pesquero – Unifesp; Investment R$ 147,025.00 and $50,000.00 (FAPESP).