Understanding the mechanisms of food intake and obesity in Down syndrome is supported by behavioral and neurochemical abnormalities

[eng] 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.[spa] La prevalencia de obesidad es más alta en el síndrome de Down (SD) que en la población general. Más allá de las alteraciones metabólicas, los individuos con SD tienen mayor impulsividad, rasgo común en personas obesas y en comedores compulsivos, que pueden afectar el control de la ingesta de alimentos. En esta Tesis, se ha utilizado un modelo de ratón trisómico (Ts65Dn) para comprender el componente de comportamiento en el desarrollo de la obesidad en SD. Nuestro análisis del patrón de ingesta mostró que los ratones Ts65Dn comen más lento que los euploides, lo que podría estar asociado con la hipoplasia mandibular descrita en ratones y humanos con SD. Cuando los ratones Ts65Dn son expuestos a ambientes obesogénicos, comen mayores cantidades de dietas hipercalóricas, engordan más en determinadas condiciones y puntúan más alto en pruebas de compulsividad e inflexibilidad que los ratones euploides. La cuantificación de los niveles de monoaminas mediante cromatografía líquida reveló que los ratones Ts65Dn presentan niveles más bajos de dopamina en corteza prefrontal. Dado que las dietas hipercalóricas promueven la liberación del neurotransmisor en el circuito de recompensa, el sobre consumo de las mismas podría indicar un intento de restaurar los niveles óptimos de dopamina. La regulación de la ingesta también depende de otras señales circulantes. Detectamos que los ratones Ts65Dn tienen mayores niveles de leptina y glucosa en plasma y niveles más bajos de insulina que los euploides. La administración exógena de glucosa produjo una menor respuesta secretoria de insulina en los ratones Ts65Dn in vivo e in vitro. Además, diversos marcadores de inflamación y estrés oxidativo son más elevados en los ratones Ts65Dn, en consonancia con la mayor incidencia de enfermedades autoinmunes y diabetes en personas con SD. En esta Tesis también se ha explorado la contribución de la proteína serina / treonina quinasa DYRK1A, un gen candidato para SD en la obesidad e ingesta. La sobreexpresión de Dyrk1A es suficiente para recapitular algunos comportamientos asociados a la ingesta compulsiva, pero con un perfil distinto al observado en el modelo trisómico. Concluimos que la prevalencia de la obesidad en SD se explica por alteraciones tanto metabólicas como conductuales, en parte como consecuencia de un estado de hipodopaminergia, y que la sobreexpresión de Dyrk1A está implicada en fenotipos específicos de la obesidad en SD

Ts66Yah, a mouse model of Down syndrome with improved construct and face validity

International audienceDown syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). The understanding of genotype–phenotype relationships, the identification of driver genes and various proofs of concept for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to human DS features. It carries an additional minichromosome with the Mir155 to Zbtb21 region of mouse chromosome 16, homologous to Hsa21, encompassing around 90 genes, fused to the centromeric part of mouse chromosome 17 from Pisd-ps2/Scaf8 to Pde10a, containing 46 genes not related to Hsa21. Here, we report the investigation of a new model, Ts66Yah, generated by CRISPR/Cas9 without the genomic region unrelated to Hsa21 on the minichromosome. As expected, Ts66Yah replicated DS cognitive features. However, certain phenotypes related to increased activity, spatial learning and molecular signatures were changed, suggesting genetic interactions between the Mir155-Zbtb21 and Scaf8-Pde10a intervals. Thus, Ts66Yah mice have stronger construct and face validity than Ts65Dn mice for mimicking consequences of DS genetic overdosage. Furthermore, this study is the first to demonstrate genetic interactions between triplicated regions homologous to Hsa21 and others unrelated to Hsa21. This article has an associated First Person interview with the first author of the paper