The initiation of metabolic inflammation in childhood obesity

Introduction The prevalence of obesity and metabolic disease continues to increase from year to year in the US adult population (1) and generates an immense burden on quality of life and healthcare expenditures (2). More ominously, the rate of childhood obesity has increased in parallel with adult obesity, resulting in pediatric patients presenting with diseases traditionally associated with adulthood such as dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. Despite some reports to the contrary, the latest data show that the prevalence of childhood obesity between 1999 to 2014 has not declined and continues to increase in all age groups (17.4% of children have a BMI greater than the 95th percentile for their age and sex) (3). More alarmingly, 10.5% of adolescents meet the pediatric modified criteria for metabolic syndrome (4), a prevalence that exceeds that of diseases such as asthma and food allergies in children. The insidious effects of metabolic disease and the limited treatments to prevent the long-term morbidities of metabolic syndrome on cardiovascular disease (CVD) make obesity a threat to both child and adult health. Longitudinal studies demonstrate that the early onset of dyslipidemia and high blood pressure in children is associated with premature atherosclerosis in adults (5). Therefore, an understanding of the initiating events that occur in children that contribute to insulin resistance and CVD has the potential to positively influence how we treat and prevent metabolic disease and its morbidities in all ages. These problems are compounded by the fact that most pediatric caregivers are restricted in their abilities to manage metabolic disease and obesity due to limited resources for nutrition and exercise counseling, the need for multidisciplinary teams for intensive obesity treatment, and the lack of medical treatments available for pediatric obesity. The evidence above suggests that obesity-associated metabolic dysfunction can be framed as a disease of childhood in which growth, development, the environment, and genetic predisposition are intertwined. Such a framework provides a novel perspective on the potential mechanisms by which inflammation and metabolism interact over the lifespan and may change the face of metabolic disease treatment and prevention for decades to come. Many of the developmental windows that are sensitive to the patterning of metabolic physiology are also crucial in the patterning of the immune system and its responses. As such, in the setting of obesity, codependent interactions between metabolism and inflammation have been observed in the prenatal environment, infancy, early childhood, and adolescence. In this Review we highlight the evidence that metabolic inflammation (hereafter referred to as metainflammation) is initiated in childhood and discuss the mechanisms by which this is triggered in the context of child development.