Increased levels of inflammatory plasma markers and obesity risk in a mouse model of Down syndrome

Fructuoso, Marta; Rachdi, Latif; Philippe, Erwann; Denis, Raphaël; Magnan, Christophe; Stunff, Hervé Le; Janel, Nathalie; Dierssen, Mara

doi:10.1016/j.freeradbiomed.2017.09.021

Cited by 28 publications

(31 citation statements)

References 62 publications

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“…Supporting this idea, it has been shown that hyperglycemia is presented in Ts65Dn and Dp16 DS mouse models but not in Tc1 and Ts1Rhr mice (Peiris et al, 2016;Fructuoso et al, 2018), allowing the dissection of the region of chromosome 21 containing genes related to hyperglycemia (Figure 1). More specifically, this phenotype has been attributed to RCAN1, since transgenic mice overexpressing the human RCAN1-1 isoform present age-dependent hyperglycemia, impaired glucose tolerance, hypoinsulinemia, reduced β-cell secretion, reduced β-cell number, decreased insulin granule filling, and reduced mitochondria size in β-cell along with an aberrant mitochondrial reactive oxygen species production (Peiris et al, 2012).…”

Section: Peripheral Metabolic Alterations In Ds and Possible Genetic mentioning

confidence: 97%

“…Animal models provide a suitable alternative to investigate the impact of the HSA21 genes on the metabolic alterations in DS controlling for environmental factors. Recently, we investigated the effect of the trisomy in the metabolic-inflammatory axis and their relation with energy expenditure, energy intake, and fat accumulation in Ts65Dn mice, a partial trisomy DS model (Fructuoso et al, 2018; Figure 1). Ts65Dn mice presented increased fat mass and energy intake, along with increased leptin levels compared to WT (Fructuoso et al, 2018; Figure 1).…”

Section: Peripheral Metabolic Alterations In Ds and Possible Genetic mentioning

confidence: 99%

“…Recently, we investigated the effect of the trisomy in the metabolic-inflammatory axis and their relation with energy expenditure, energy intake, and fat accumulation in Ts65Dn mice, a partial trisomy DS model (Fructuoso et al, 2018; Figure 1). Ts65Dn mice presented increased fat mass and energy intake, along with increased leptin levels compared to WT (Fructuoso et al, 2018; Figure 1). Even so, Ts65Dn mice consumed more calories, suggesting that leptin would be ineffective in controlling the satiety.…”

Section: Peripheral Metabolic Alterations In Ds and Possible Genetic mentioning

confidence: 99%

“…In cell cultures, it has been shown that fetal T21 islets have fragmented mitochondria and present abnormal intracellular accumulation of pro-insulin and islet amyloid polypeptide (IAPP). The results illustrated came from Helguera et al (2013), Peiris et al (2016), and Fructuoso et al (2018).…”

Section: Peripheral Metabolic Alterations In Ds and Possible Genetic mentioning

confidence: 99%

“…As compared to WT, Ts65Dn mice present lower levels of ghrelin in plasma, which in the general population has been associated with obesity ( Buss et al, 2014 ). Ts65Dn mice also show increased glucose-stimulated response of the adipokine resistin and increase of plasma galectin-3 and HSP72 ( Fructuoso et al, 2018 ; Figure 1 ), which are associated with autoimmunity ( Krause et al, 2014 ; De Oliveira et al, 2015 ). Recently, higher levels of C-reactive protein (CRP), C3, and C4 complement factors have been reported in DS adolescents ( Gutierrez-Hervas et al, 2020 ).…”

Section: Peripheral Metabolic Alterations In Ds and Possible Genetic mentioning

confidence: 99%

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Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

et al. 2020

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Down syndrome (DS) is the most frequent chromosomal abnormality that causes intellectual disability, resulting from the presence of an extra complete or segment of chromosome 21 (HSA21). In addition, trisomy of HSA21 contributes to altered energy metabolism that appears to be a strong determinant in the development of pathological phenotypes associated with DS. Alterations include, among others, mitochondrial defects, increased oxidative stress levels, impaired glucose, and lipid metabolism, finally resulting in reduced energy production and cellular dysfunctions. These molecular defects seem to account for a high incidence of metabolic disorders, i.e., diabetes and/or obesity, as well as a higher risk of developing Alzheimer's disease (AD) in DS. A dysregulation of the insulin signaling with reduced downstream pathways represents a common pathophysiological aspect in the development of both peripheral and central alterations leading to diabetes/obesity and AD. This is further strengthened by evidence showing that the molecular mechanisms responsible for such alterations appear to be similar between peripheral organs and brain. Considering that DS subjects are at high risk to develop either peripheral or brain metabolic defects, this review will discuss current knowledge about the link between trisomy of HSA21 and defects of insulin and insulin-related pathways in DS. Drawing the molecular signature underlying these processes in DS is a key challenge to identify novel drug targets and set up new prevention strategies aimed to reduce the impact of metabolic disorders and cognitive decline.

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Section: Peripheral Metabolic Alterations In Ds and Possible Genetic mentioning

confidence: 97%

Section: Peripheral Metabolic Alterations In Ds and Possible Genetic mentioning

confidence: 99%

Section: Peripheral Metabolic Alterations In Ds and Possible Genetic mentioning

confidence: 99%

Section: Peripheral Metabolic Alterations In Ds and Possible Genetic mentioning

confidence: 99%

Section: Peripheral Metabolic Alterations In Ds and Possible Genetic mentioning

confidence: 99%

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Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

et al. 2020

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Exploring the link between hedonic overeating and prefrontal cortex dysfunction in the Ts65Dn trisomic mouse model

Fructuoso,

Fernández-Blanco,

Gallego-Román

et al. 2023

Cell. Mol. Life Sci.

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Individuals with Down syndrome (DS) have a higher prevalence of obesity compared to the general population. Conventionally, this has been attributed to endocrine issues and lack of exercise. However, recent research suggests that de cits in neural reward responses and dopaminergic disturbances in DS may be contributing factors. To investigate further, we focused on a mouse model (Ts65Dn) bearing some triplicated genes homologous to trisomy 21. Through detailed meal pattern analysis in Ts65Dn mice, we observed an increased preference for energy-dense food, pointing towards a potential "hedonic" overeating behavior. Moreover, trisomic mice exhibited higher scores in compulsivity and in exibility tests when limited access to energy-dense food and quinine hydrochloride adulteration were introduced, compared to euploid controls. Interestingly, when we activated prelimbic-to-nucleus accumbens projections in Ts65Dn mice using a chemogenetic approach, impulsive and compulsive behaviors signi cantly decreased, shedding light on a promising intervention avenue. Our ndings uncover a novel mechanism behind the vulnerability to overeating and offer potential new pathways for tackling obesity through innovative interventions. However, it is important to acknowledge that the observed phenotype in Ts65Dn mice may be in uenced by the presence of triplicated non-HSA21 genes, which is a limitation worth considering for future investigations.

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Alzheimer’s disease and Down syndrome

Pelt

Head

Schmitt

et al. 2020

Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease

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Increased levels of inflammatory plasma markers and obesity risk in a mouse model of Down syndrome

Cited by 28 publications

References 62 publications

Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

Exploring the link between hedonic overeating and prefrontal cortex dysfunction in the Ts65Dn trisomic mouse model

Alzheimer’s disease and Down syndrome

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