„Gastro-intestinal Peptides in Obesity (GIPIO)” was a 4-year collaborative research project, funded by the European Union FP7 programme to the value of 4 million Euros, which brings together a consortium of 4 leading academic institutions and 2 small and medium enterprises. The project was coordinated by the University of Leipzig and studied gastro-intestinal peptides and their nutritional signals after food-intake and develop drugs against obesity based on this knowledge.
Obesity is the fastest growing health problem in the Western World. In the United States, obesity as a cause of preventable mortality (365,000 deaths in 2000) will soon overtake tobacco (435,000 deaths) and already has overtaken alcohol consumption (85,000 deaths), infectious diseases (75,000) and motor vehicle crashes (43,000). More importantly, it is also a problem in children and adolescents, and accordingly is, one of the major future health problems.
We hypothesize that the reduction of hormones/signals, released or blocked after food intake, significantly contributes to the feed-back upon food intake, and subsequently to the onset in obesity. Accordingly, the focus of this project was to better understand the contribution of gastro-intestinal peptides to the onset of obesity. It aimed to identify the most relevant hormones or combinations of hormones, and subsequently to develop anti-obesity drugs that are based on endogenous hormone agonists or antagonists.
The starting points for the GIPIO project was the question: “How does bariatric surgery really work?” – and can this be mimicked by novel pharmaceutical agents modifying the signal transduction between gut and brain with the help the peptide hormone? It was originally believed that the main function of the gastrointestinal bypass was to ensure that the small stomach would limit food intake and that the food would not get appropriately absorbed. However, the malabsorbtion only lasts for few weeks as the intestine adapts to the shorter length; whereas decreased appetite continues for years. In our opinion, the reason for this is that hunger and satiety signals from the GI-tract to the CNS have been altered and do not adapt to the situation. In gut and pancreas there are multiple forms of endocrine, sensory cells which release mainly peptide hormones, which signal to other parts of the GI-tract and to the CNS, mainly through areas where there is a leaky blood brain barrier – i.e. the brain stem and arcuate nucleus of the hypothalamus. These satiety and hunger hormones are secreted in response to nutritional signals and they and their receptors are potential targets for development of anti-obesity and anti-diabetes agents. Although it is to some degree a matter of debate, it has consistently been reported that many of these hormones are decreased in obesity, for example PYY and PP. Thus treatment with these hormones or improved versions of these could in some cases be considered to be hormone replacement. Importantly, there are many reports of increased levels of at least certain satiety hormones, GLP-1 and PYY, and decreased levels of the hunger hormone, ghrelin, after intestinal bypass operations. Accordingly, the focus of the project was to identify the most relevant hormones and combinations of hormones, understand their mode of release and activity, and to use this knowledge and these peptide hormones as the basis for the development of novel anti-obesity drugs in the form of agonists, inverse-agonists or antagonists – providing the benefits of bariatric surgery without the risk.
Within the project, we made critical steps towards understanding the structural conformations of the investigated peptide hormones and established advanced production methods for these compounds. We optimized native hormones to make them more stable and increased their bioavailability. Furthermore, we developed bioassays to analyse activity in different tissues and under different conditions in animals and man. Important steps were standardization tasks to assure comparability in the testing conditions of novel compounds. The elucidation of the cellular and molecular pathophysiological mechanisms involved in obesity and its correlation with nutrition-dependent hormone release has been investigated.
GIPIO was funded by the European Union's Seventh Framework Programme (Grant Agreement No. 223057) and coordinated by University of Leipzig, Germany.