Glucagon Like Peptide 1 Receptor Agonists in the Treatment of Obesity

BACKGROUND: Obesity treatment based on glucagon-like peptide-1 receptor agonists (GLP-1 RAs) proved to limit morbidity and mortality in adult population. In children, optimizing lifestyle intervention and reducing culpable environmental exposures represents the mainstay strategy for obesity prevention and management. However, there remains a subset of children and adolescents whose obesity is resistant to lifestyle approach. For these poor responders, the need for safe and effective weight reducing agents is apparent. The purpose of this review is to provide an overview of the efficacy and safety of approved GLP-1 RA in the management of adult and paediatric obesity. SUMMARY: We presented the main outcomes of clinical trial programs called SCALE and STEP that supported a market authorization approval for liraglutide and semaglutide for the treatment of obesity in adult population. Then we summarised the studies on the efficacy of GLP-1 RA in paediatric obesity that have been accumulating from two larger studies with liraglutide and few other smaller studies with exenatide and liraglutide. The results indicate that GLP-1RA are safe, tolerable, and effective in reducing weight and also in improving cardiometabolic profile in children with obesity and poor response to lifestyle intervention alone. At present, liraglutide is the first and so far the only GLP-1 RA, that received FDA approval in 2020 for use in children age 12-17 years with obesity. New trials including semaglutide for paediatrics obesity are ongoing. KEY MESSAGES: There is a strong interest in current use and further development of obesity treatments based on GLP-1 agonism. In adolescents with obesity, who are poor responders to lifestyle approach, the use of GLP-1 RA as an adjunct to lifestyle intervention is effective and safe. Due to limited experience, a general recommendation is to prioritise long acting over short acting GLP-1 RA because they are approved for the treatment of obesity and have better tolerability, safety and treatment response effect. In the future research, more high-grade evidence including novel iterations of GLP-1 agonism and long-term follow-ups are needed in paediatrics population.

Paediatric obesity: a systematic review and pathway mapping of metabolic alterations underlying early disease processes

Background The alarming trend of paediatric obesity deserves our greatest awareness to hinder the early onset of metabolic complications impacting growth and functionality. Presently, insight into molecular mechanisms of childhood obesity and associated metabolic comorbidities is limited. Main body of the abstract This systematic review aimed at scrutinising what has been reported on putative metabolites distinctive for metabolic abnormalities manifesting at young age by searching three literature databases (Web of Science, Pubmed and EMBASE) during the last 6 years (January 2015–January 2021). Global metabolomic profiling of paediatric obesity was performed (multiple biological matrices: blood, urine, saliva and adipose tissue) to enable overarching pathway analysis and network mapping. Among 2792 screened Q1 articles, 40 met the eligibility criteria and were included to build a database on metabolite markers involved in the spectrum of childhood obesity. Differential alterations in multiple pathways linked to lipid, carbohydrate and amino acid metabolisms were observed. High levels of lactate, pyruvate, alanine and acetate marked a pronounced shift towards hypoxic conditions in children with obesity, and, together with distinct alterations in lipid metabolism, pointed towards dysbiosis and immunometabolism occurring early in life. Additionally, aberrant levels of several amino acids, most notably belonging to tryptophan metabolism including the kynurenine pathway and its relation to histidine, phenylalanine and purine metabolism were displayed. Moreover, branched-chain amino acids were linked to lipid, carbohydrate, amino acid and microbial metabolism, inferring a key role in obesity-associated insulin resistance. Conclusions This systematic review revealed that the main metabolites at the crossroad of dysregulated metabolic pathways underlying childhood obesity could be tracked down to one central disturbance, i.e. impending insulin resistance for which reference values and standardised measures still are lacking. In essence, glycolytic metabolism was evinced as driving energy source, coupled to impaired Krebs cycle flux and ß-oxidation. Applying metabolomics enabled to retrieve distinct metabolite alterations in childhood obesity(-related insulin resistance) and associated pathways at early age and thus could provide a timely indication of risk by elucidating early-stage biomarkers as hallmarks of future metabolically unhealthy phenotypes.

Stress Responsiveness and Emotional Eating Depend on Youngsters’ Chronic Stress Level and Overweight

The persistent coexistence of stress and paediatric obesity involves interrelated psychophysiological mechanisms, which are believed to function as a vicious circle. Here, a key mechanistic role is assumed for stress responsiveness and eating behaviour. After a stress induction by the Trier Social Stress Test in youngsters (n = 137, 50.4% boys, 6–18 years), specifically those high in chronic stress level and overweight (partial η2 = 0.03–0.07) exhibited increased stress vulnerability (stronger relative salivary cortisol reactivity and weaker happiness recovery) and higher fat/sweet snack intake, compared to the normal-weight and low-stress reference group. Stress responsiveness seems to stimulate unhealthy and emotional eating, i.e., strong cortisol reactivity was linked to higher fat/sweet snack intake (β = 0.22) and weak autonomic system recovery was linked to high total and fat/sweet snack intake (β = 0.2–0.3). Additionally, stress responsiveness acted as a moderator. As a result, stress responsiveness and emotional eating might be targets to prevent stress-induced overweight.

Obesity, oxidative DNA damage and vitamin D as predictors of genomic instability in children and adolescents

Background/objectives Epidemiological evidence indicates obesity in childhood and adolescence to be an independent risk factor for cancer and premature mortality in adulthood. Pathological implications from excess adiposity may begin early in life. Obesity is concurrent with a state of chronic inflammation, a well-known aetiological factor for DNA damage. In addition, obesity has been associated with micro-nutritional deficiencies. Vitamin D has attracted attention for its anti-inflammatory properties and role in genomic integrity and stability. The aim of this study was to determine a novel approach for predicting genomic instability via the combined assessment of adiposity, DNA damage, systemic inflammation, and vitamin D status. Subjects/methods We carried out a cross-sectional study with 132 participants, aged 10–18, recruited from schools and paediatric obesity clinics in London. Anthropometric assessments included BMI Z-score, waist and hip circumference, and body fat percentage via bioelectrical impedance. Inflammation and vitamin D levels in saliva were assessed by enzyme-linked immunosorbent assay. Oxidative DNA damage was determined via quantification of 8-hydroxy-2′-deoxyguanosine in urine. Exfoliated cells from the oral cavity were scored for genomic instability via the buccal cytome assay. Results As expected, comparisons between participants with obesity and normal range BMI showed significant differences in anthropometric measures (p < 0.001). Significant differences were also observed in some measures of genomic instability (p < 0.001). When examining relationships between variables for all participants, markers of adiposity positively correlated with acquired oxidative DNA damage (p < 0.01) and genomic instability (p < 0.001), and negatively correlated with vitamin D (p < 0.01). Multiple regression analyses identified obesity (p < 0.001), vitamin D (p < 0.001), and oxidative DNA damage (p < 0.05) as the three significant predictors of genomic instability. Conclusions Obesity, oxidative DNA damage, and vitamin D deficiency are significant predictors of genomic instability. Non-invasive biomonitoring and predictive modelling of genomic instability in young patients with obesity may contribute to the prioritisation and severity of clinical intervention measures.