Understanding the mechanisms of food intake and obesity in down syndrome is supported by behavioral and neurochemical abnormalities
- Autores: Marta Fructuoso Castellar
- Directores de la Tesis: Mara Dierssen (dir. tes.), Jordi Alberch Vié (tut. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: Jean-Maurice Delabar (presid.), Roser Nadal Alemany (secret.), Fernando Fernández Aranda (voc.)
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
ABSTRACT Obesity prevalence is higher in Down syndrome (DS) than in the general population. Beyond metabolic alterations, individuals with DS present increased impulsivity, a trait observed in obese people and in compulsive eaters that may affect their control of food intake. In this Thesis, we used a trisomic DS mouse model (Ts65Dn) to understand the behavioral component of obesity in DS and explore some possible underlying mechanisms.
Our meal pattern analysis revealed longer and slowly meals in Ts65Dn mice, leading to reduced eating rate, which may be associated to the mandible hypoplasia described in both human and mice. When exposed to obesogenic environments, Ts65Dn mice showed higher preference for energy-dense food, gained more weight in specific conditions and scored higher in compulsivity and inflexibility tests than WT mice, as measured by binge eating during limited access and persistence of consumption of quine adulteration of energy-dense food. High performance liquid chromatography revealed reduced levels of dopamine in prefrontal cortex in Ts65Dn mice. This could lead to higher reward sensitivity that in turn would facilitate overeating as a compensatory response to restore optimal dopamine levels. Feeding behavior is also regulated by hormones and other circulating signals. We detected higher plasma leptin and glucose levels along with reduced insulin levels in Ts65Dn mice. Upon a glucose challenge, Ts65Dn mice showed reduced glucose-stimulated insulin response both in vivo and in vitro, suggesting a deficient insulin secretion or the reduced pancreatic mass. Indeed, we detected that Ts65Dn mice had altered plasma profile for some markers of inflammation and oxidative damage, in agreement with the high prevalence of autoimmune diseases and diabetes in DS people.
We also explored the involvement of the serine/threonine kinase DYRK1A, a candidate DS gene, in obesity and feeding behavior. Dyrk1A overexpression was sufficient to recapitulate some behavioral aspects associated to overeating in DS, but with a distinct profile. We conclude that increased obesity prevalence in DS is explained by both metabolic and behavioral alterations, in part driven by a hypodopaminergic status, and that Dyrk1A overexpression is only involved in specific DS obesity phenotypes.
