Evidence of Early Alterations in Adipose Tissue Biology and Function and Its Association With Obesity-Related Inflammation and Insulin Resistance in Children

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 crownlike 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.Obesity is characterized by the accumulation of fat mass and is often associated with adipose tissue (AT) dysfunction (1). Clinical data indicate that obesity already develops during early childhood between 2 and 6 years of age (2). Expansion of AT can be achieved by hyperplasia (increase in adipocyte number) or hypertrophy (increase in adipocyte size) or the combination of both (3). 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 (4,5). On the other hand, the capability for cell renewal, achieved by differentiation of preadipocytes into mature adipocytes, persists throughout life (6). 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

Adipocyte hypertrophy-hyperplasia balance contributes to weight loss after bariatric surgery

“…11,12 Moreover, consistent with our findings here and in previously published work 6 others have shown that larger adipocytes are associated with greater insulin resistance in humans. 7,13,14 Of interest, we found that adipocyte hypertrophy in DM affects specific subpopulations of adipocytes based on size, with decreased adipocytes »700-3,300 mM 2 and increased adipocytes »5,600-8,700 mM. 2 Others have shown that greater improvements in insulin sensitivity are associated with a reduction of large and very large adipocyte subfractions in DM patients after caloric restriction and exerciseinduced weight loss.…”

Enhanced leptin synthesis and secretion in vitro by human adipocytes from type 2 diabetic donors occurs only under hyperinsulinaemic conditions

“…It is possible that prolonged exposure of adipocytes to insulin may increase leptin secretion by a combination of such mechanisms. Furthermore, it has been suggested that a delayed effect of insulin treatment on leptin secretion in adipocytes is compatible with the effect being indirect 12 and additional physiological factors may be involved in vivo with strong candidates being hormonal 34 and inflammatory 35,36 influences, and a role for the hypothalamus. 23 Should the delayed effect of insulin treatment on leptin secretion in adipocytes from type 2 diabetic donors be proven in subsequent studies, the phenomenon may be analogous to the biphasic response of insulin secretion to glucose 37 where impairment of early and late phase insulin secretion leads to different clinical outcomes.…”

Inflammation and insulin resistance according to body composition in European adolescents: the HELENA study.

“…The relation between traditional inflammatory cells, cytokines, and chemokines and insulin resistance has been studied in adult populations (10). In children, obesity-related adipose tissue dysfunction develops early in childhood and is related to IR (11). In a previous study in adolescents, an association between IR and some inflammatory biomarkers was observed, and these relationships were stronger in obese subjects (12).…”