Metabotyping of Overweight and Obese Children

Metabolic Disease, Obesity, Infant

metabolomics, mass spectrometry

Today's children are increasingly facing metabolic-related health issues, among which the worldwide prevalence of overweight and obesity is rising at an alarming pace. Childhood obesity is associated with the early onset of chronic diseases including an emergence of prediabetes and diabetes mellitus type 2. The decline of insulin sensitivity already years before puberty, exposes children to long- term complications prior the appearance of clinical symptoms and time of diagnosis. The shortened life expectancy and large economic burden imposed underlines the need for the identification of metabotypes at risk at an early stage. One's genetics, microbial gut composition and every aspect of the environment in which children are raised have been implicated in diet-related obesity rendering metabolomics a very powerful tool towards precision medicine. Yet, the excellence of stool in reflecting the intertwining thereof is completely unexplored for pediatric purposes, whereas blood sampling causing pain and stress for child and parent only captures a narrow fraction of the metabolome. As such, rectal sampling using a customised medical swab for optimal gut metabolome coverage is envisioned. Ambient laser desorption ionisation will be hyphenated to high-resolution mass spectrometry-based metabolomics to provide a framework for elucidating predictive and/or prognostic biomarkers for ever-increasing pediatric metabolic diseases such as obesity and (pre)diabetes.

The impetus for this research proposal stems from the ever-increasing metabolic-related health issues impacting today's children. Particularly, the high prevalence of childhood obesity accompanied by substantial progression to 'prediabetic state' at teen age and full-blown DMT2, the most prevailing endocrine disease worldwide, at early adulthood. Several risk factors for the development of overt DMT2 and crescent atherogenic processes, including unhealthy lifestyle patterns, decreased physical activity and (subsequent) obesity, that may be considered markers of metabolic abnormalities, such as insulin resistance, are already well-established in children with impaired glucose tolerance prior to time of diagnosis around early adolescence. Moreover, even in individuals with normal glucose tolerance, insulin resistance has been pointed out a major risk factor and predictor for the development of DMT2. Conversely, the micro- and macrovascular events do not readily appear until maturity, thereby predisposing obese children to the development of several long-term complications urging the quest for diagnostic, prognostic and/or predictive biomarkers for insulin resistance and related metabolic diseases. Hence, intervening in the pre-pubertal life stage becomes of paramount importance. As a pivotal component in precision medicine, and unlike routine measurements that only include a narrow set of blood chemistry analytes, metabolomics reveals a far more comprehensive metabolic signature. Taken together that DM and related comorbidities are considered metabolic diseases with a dysregulated lipid metabolism being a central factor in the pathogenesis, metabolomics (and in particular lipidomics) is of key importance in this research proposal. Furthermore, given the collision between genes, gut microbiota and environmental changes preceding the development of DM and, in addition, the excellence of stool in reflecting the metabolic interactions and outcomes thereof, an innovative rectal sampler using a medical swab with customized surface tip for optimal gut metabolome coverage will be used. REIMS significantly reduces time (\< 10 s) and workload (minimal sample preparation), enhancing research output and efficiency. The aim is the early identification of children who are destined to develop obesity-related chronic diseases.

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