Abstract and Introduction
Abstract
Accumulation of fat mass in obesity may result from hypertrophy and/or hyperplasia and is frequently associated with adipose tissue (AT) dysfunction in adults. Here we assessed early alterations in AT biology and function by comprehensive experimental and clinical characterization of 171 AT samples from lean and obese children aged 0 to 18 years. We show an increase in adipocyte size and number in obese compared with lean children beginning in early childhood. These alterations in AT composition in obese children were accompanied by decreased basal lipolytic activity and significantly enhanced stromal vascular cell proliferation in vitro, potentially underlying the hypertrophy and hyperplasia seen in obese children, respectively. Furthermore, macrophage infiltration, including the formation of crown-like structures, was increased in AT of obese children from 6 years on and was associated with higher hs-CRP serum levels. Clinically, adipocyte hypertrophy was not only associated with leptin serum levels but was highly and independently correlated with HOMA-IR as a marker of insulin resistance in children. In summary, we show that adipocyte hypertrophy is linked to increased inflammation in AT in obese children, thereby providing evidence that obesity-associated AT dysfunction develops in early childhood and is related to insulin resistance.
Introduction
Obesity is characterized by the accumulation of fat mass and is often associated with adipose tissue (AT) dysfunction. Clinical data indicate that obesity already develops during early childhood between 2 and 6 years of age. Expansion of AT can be achieved by hyperplasia (increase in adipocyte number) or hypertrophy (increase in adipocyte size) or the combination of both. Early studies suggested that adipocyte number is determined in childhood and remains relatively constant during adulthood, implying that expansion of AT mass in (adult) obesity occurs via hypertrophy of adipocytes. On the other hand, the capability for cell renewal, achieved by differentiation of preadipocytes into mature adipocytes, persists throughout life. Whether AT expansion in the development of obesity occurs primarily by hyperplasia or hypertrophy and the time point when AT dysfunction emerges are still a matter of debate.
In addition to the mere accumulation of fat mass, obesity is often associated with changes in AT biology and function, including adipocyte cell death, autophagy, hypoxia, altered adipokine profile, remodeling of the extracellular matrix, and inflammation. This AT dysfunction is hypothesized to be a major contributor to the adverse metabolic and cardiovascular consequences of obesity seen clinically. Particularly, macrophage infiltration into AT and the ensuing orchestrated inflammatory response appear to play a role in the development of obesity-associated insulin resistance and cardiovascular disease. Noteworthy, obesity-related comorbidities, including insulin resistance, hypertension, and dyslipidemia, are already evident in children and adolescents.
So far, most studies focusing on obesity-associated AT dysfunction have been performed in adults. Considering the fact that obesity and the occurrence of first related comorbidities develop as early as in childhood, studies in children might allow better insight into the early processes occurring with normal development and progression of obesity at the level of AT. In addition, children usually represent earlier stages of disease, and studying the underlying mechanisms is less biased by preexisting comorbidities and their treatment.
The aim of this work was to evaluate obesity-associated alterations in AT biology in children and to evaluate their association with clinical parameters. In particular, we wanted to test the hypothesis that AT accumulation in childhood obesity is primarily associated with adipocyte hypertrophy and leads to AT inflammation and whether these alterations are linked to the early emergence of clinical comorbidities in children.