YOUNG RESEARCHERS. Discoveries about the hormone GLP-1 can by extension lead to a new pharmaceutical treatment against obesity – and an alternative to obesity surgery. Karolina Skibicka has conducted pioneering studies of the nervous system’s reward mechanisms and is now continuing her research at the Wallenberg Centre for Molecular and Translational Medicine.
Obesity is a widespread disease, which is more common in the world today than starvation. It is a serious disease that affects the entire body; it is associated with an increased risk for diabetes, cardiovascular disease and certain cancers, and can lead to premature death. In 2014, one out of three Swedes over the age of 16 were overweight and more than one out of ten were obese, according to the WHO definition of obesity.
Obesity is a complex disease with many different causes, which have proven difficult to pinpoint and treat. The results of available treatments are disappointing. For example, as many as 90 percent of those trying to loose body weight by dieting do not succeed at maintaining their weight loss.
“With extreme obesity, only gastric bypass has proven to provide a lasting weight loss, but it’s an extensive surgical procedure that isn’t risk free. The medications available on the market today do not provide a sufficiently good effect,” says Karolina Skibicka.
A hormone with an effect in the brain
Karolina Skibicka is interested in a hormone called GLP-1, the most well-known function of which is to keep our blood sugar in check. Consequently, GLP-1 was previously mainly been studied by diabetes researchers, and an analogue of this hormone has long been a part of medication for diabetics. But GLP-1 also has effects in the brain. Karolina Skibicka and her colleagues were the first to show that the hormone targets the brain’s reward system to reduce reward behavior for food.
“It was a revolutionary discovery, and the review process was lengthy. Nearly everyone who reviewed our paper had a hard time believing what we showed was true, and it took a whole year before the article was accepted. But there were actually advantages with the long process before publication. At that stage, two other teams had also been able to show the same thing so other researchers immediately confirmed our results and could take them to the next level,” says Karolina Skibicka.
Seeking amplifiers
GLP-1 has proven to reduce appetite and provide weight loss, and it is possible that the hormone could be developed into an alternative to obesity surgery, which today is the only truly effective treatment against extreme obesity. In the U.S., obesity medication with GLP-1 has already been approved, but the effects of the hormone as a weight loss medication are very modest to-date.
“People with extreme obesity can lose 10 percent of their weight with the medications. It’s a respectable weight loss that can already help to improve some metabolic parameters, but it’s not enough. This is why now we are expanding considerable effort focusing on ways to amplify the effects of GLP-1 so that we can get a more effective medication against extreme obesity,” says Karolina Skibicka.
One possible way to strengthen the effect of GLP-1 is to combine the hormone with another hormone, for example with the female sex hormone estrogen.
“After menopause, women have a greater tendency to gain weight, something that seems to be connected to the levels of estrogens, which drop significantly,” she says.
Estrogens increase the risk of breast cancer, but this can be circumvented in several ways. One way is to create a composite molecule where the estrogen is bound together with GLP-1 to be released only when the molecule has reached the specific cell where GLP-1 will have its effect.
“I’m collaborating with a team in Germany that can create such molecules. The idea is that GLP-1 holds on to the estrogen so that we get a very selective estrogen signaling,” says Karolina Skibicka, who also..orbritannien och en med forskargrupper i USA, Schweitz .ch tsom framkallar sjukdom, snarare collaborates with research teams in the U.S., the UK and Switzerland.
Fascinating brain
Karolina is originally from Warsaw, Poland, but moved to the U.S. early on where she lived in several different states. She completed her undergraduate studies in microbiology at the University of South Florida. She had first intended to conduct research in microbiology, working on bacteria and viruses, but a course in neuroscience incited her interest in the brain:
“The enormous complexity of the nervous system and how its function is translated into behavior immediately sparked my interest. It is a perfect marriage of Biology, Chemistry, and Psychology, three subjects I was pursuing during my undergraduate studies. This topic was a perfect fit for me! I decided to apply for doctoral studies in neurosciences and to my surprise received several offers. After all my research to date was focused on bacteria, I didn’t have any prior experience in the field of neuroscience,” says Karolina and continues:
“I chose the University of Pennsylvania for my doctorate. My PhD supervisor, Professor Harvey Grill, a preeminent scientist known for his pioneering work on the neural control of energy balance, really inspired me to focus my work on trying to decipher how the brain controls eating behavior and body weight.”
Happy to collaborate locally
Karolina Skibicka has been active at the University of Gothenburg for the past seven years.
“I am a part of a somewhat recently established Section for Metabolic Physiology, headed by Patrik Rorsman. We are a fast expanding section and now take up the entire top floor of the Physiology building. I think it’s a vibrant and creative environment. Many of the team leaders are relatively young and we easily collaborate across the teams. We’re all interested in obesity, but focus on different organs. This gives us a holistic perspective in our research,” says Karolina Skibicka, who really enjoys cooperating within the department:
“I notice that many researchers value international collaboration more than local collaboration. I think it’s very important to have international contacts, but finding the really good local collaborative relationships also contributes a great deal.”
Obesity also linked to depression
The research is experimental and demands both space and many hands. Karolina Skibicka uses mice and rats as model animals, and they take up two whole rooms at the Laboratory of Experimental Biomedicine (EBM).
“We’re interested in how appetite changes various aspects of animal behavior.When studying appetite or feeding behavior some question we are always asking are: How often do animals eat? How much do they eat? How rewarding do they find meals of various compositions? We need to understand the distinct brain neurocircuits that underlies each of these aspects of feeding. We’re also studying the link between obesity and depression. If we understand the link between them, we also increase the understanding of obesity and depression separately,” she says.
Right now, her team consists of six very hard working and dedicated junior scientists, most at the post-doc level, and she expects to have to expand the team further.
The brain’s ability to adapt never ceases to fascinate Karolina Skibicka, and it is also this ability that is her greatest challenge:
“If we downregulate one system in the brain and successfully manage to reduce appetite and body weight, often it doesn’t take long until another system is upregulated and begins to compensate. I expect the reward system to keep me busy my entire life in research.”
TEXT: ELIN LINDSTRÖM CLAESSEN
PHOTO: JOHAN WINGBORG
