Einfluss von Ghrelin auf die neuronale Anpassung von Appetit-regulierenden Prozessen bei Diät-induzierter Adipositas
Zusammenfassung der Projektergebnisse
The obesity epidemic continues unabated and is associated with adverse health consequences ‐ diabetes, cardiovascular disease, disability, and increased cancer risk. Today, the only effective weight loss therapy involves bariatric surgery of the stomach, such as Roux‐en‐Y gastric bypass (RYGB), whereas the typical life‐style interventions failed to reduce obesity in long term and the currently available pharmacological treatments are less efficient. Therefore there is an urgent need to understand the neurobiological mechanisms how food intake and feeding behavior is controlled which can finally help to develop alternative therapies reducing body weight constantly. Originally it was planned to study the role of ghrelin in neuroadaption of appetite‐regulating brain networks in diet‐induced obesity, but due to unexpected difficulties during the first funding period it was decided to change the initial project and to design two separate studies that are also linked to the main goals of the project regarding how food intake is regulated. Firstly, it was investigated whether genetic predisposition has an impact on food‐reward behavior by phenotypical characterization of different strains of rats. Rats that differ in their susceptibility to develop obesity also differ in behavioral parameters like locomotor activity, anxiety‐like behavior and food reward prior they have started to diverge in their body weights. It could also be shown that the motivational properties for a palatable food are not increased in strains with a genetic predisposition to obesity, whereas the rewarding value of food (eg. chocolate) seems to be altered in these strains and demonstrates the striking impact of predisposing genetic factors for obesity development. One promising solution to treat diabesity is the development of polypharmaceutical approaches eg. targeting the incretin system by a GLP‐1‐estrogen (GE) conjugate. The anti‐obesity properties of GE were already demonstrated, but the direct site of action remained to be elucidated. Thus, the hypothesis of the second study was that the GE‐induced anorexia involves direct actions of GE on central receptors and may also involve changes in food‐motivated behavior. By targeting specific nuclei in the CNS it could be demonstrated that the body weight‐lowering efficacy of the conjugate GLP‐1‐estrogen is mediated through central effects and involves a change in food‐reward behavior. It was also possible to show which sub‐nuclei in the CNS are responsible for the anorexigenic properties of the GE conjugate and for the reduced food‐motivated behavior. In summary with the present studies the impact of genetic predisposition on food‐reward behavior and the action of a potential anti‐obesity drug was investigated. The new insights how genetic factors and polypharmaceutical substances can modulate food intake and food‐motivated behavior can facilitate the development of treatment strategies for diabesity.
Projektbezogene Publikationen (Auswahl)
- Ghrelin influences novelty seeking behavior in rodents and men. PLoS One. 2012; 7:e50409
Hansson C, Shirazi RH, Näslund J, Vogel H, Neuber C, Holm G, Anckarsäter H, Dickson SL, Eriksson E, Skibicka KP
- Acute sleep deprivation increases portion size and affects food choice in young men. Psychoneuroendocrinology. 2013; 381668‐74
Hogenkamp PS, Nilsson E, Nilsson VC, Chapman CD, Vogel H, Lundberg LS, Zarei S, Cedernaes J, Rångtell FH, Broman JE, Dickson SL, Brunstrom JM, Benedict C, Schiöth HB
- Divergent circuitry underlying food reward and intake effects of ghrelin: dopaminergic VTA‐accumbens projection mediates ghrelin's effect on food reward but not food intake. Neuropharmacology. 2013; 73:274‐83
Skibicka KP, Shirazi RH, Rabasa‐Papio C, Alvarez‐Crespo M, Neuber C, Vogel H, Dickson SL
- Glucagon‐like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL‐1 and IL‐6. Proc Natl Acad Sci USA. 2013; 110:16199‐204
Shirazi R, Palsdottir V, Collander J, Anesten F, Vogel H, Langlet F, Jaschke A, Schürmann A, Prévot V, Shao R, Jansson JO, Skibicka KP
(Siehe online unter https://doi.org/10.1073/pnas.1306799110)
