Adolescent Obesity and Insulin Resistance: Roles of Ectopic Fat Accumulation and Adipose Inflammation

Abstract

As a consequence of the global rise in the prevalence of adolescent obesity, an unprecedented phenomenon of type 2 diabetes has emerged in pediatrics. At the heart of the development of type 2 diabetes lies a key metabolic derangement: insulin resistance (IR). Despite the widespread occurrence of IR affecting an unmeasurable number of youths worldwide, its pathogenesis remains elusive. IR in obese youth is a complex phenomenon that defies explanation by a single pathway. In this review we first describe recent data on the prevalence, severity, and racial/ethnic differences in pediatric obesity. We follow by elucidating the initiating events associated with the onset of IR, and describe a distinct "endophenotype" in obese adolescents characterized by a thin superficial layer of abdominal subcutaneous adipose tissue, increased visceral adipose tissue, marked IR, dyslipidemia, and fatty liver. Further, we provide evidence for the cellular and molecular mechanisms associated with this peculiar endophenotype and its relations to IR in the obese adolescent.

Keywords: Adipose Tissue Distribution; Adipose Tissue Inflammation; Childhood and Adolescent Obesity; Fatty Liver; Inflammasome; Resistance.

Figure 1.

Cellular and molecular differences in the SAT in the obese adolescent with a low VAT/SAT ratio and a high VAT/SAT ratio.

Figure 2.

(A) Increased inflammatory gene expression and macrophage infiltration in abdominal SAT of the high VAT/VAT+SAT group. (B) Decreased lipogenic gene expression in abdominal SAT of the high VAT/VAT+SAT group. Subcutaneous expression of specific genes was normalized to the expression of 18S ribosomal RNA and based on the expression of a human control adipose tissue (2ΔΔCt). Expression values of the low VAT/VAT+SAT group (white bars) were set to 1, and values for the high VAT/VAT+SAT group (black bars) are expressed as fold changes compared with 1 (mean ± SD, n = 58). Macrophage infiltration (inset in A) was assessed by immunohistochemistry. *Indicates that the t test between the two groups was significant at the <.05 level.

Figure 3.

(A–L) Insulin-resistant obese adolescents have increased lipolysis and impaired suppression of HGP associated with increased WAT IL6 concentrations.

Figure 4.

Insulin-resistant obese adolescents. A model to explain the role of SAT Inflammation, activating lipolysis in AT, thereby increasing acetyl-CoA and pyruvate carboxylase activity in the liver, which ultimately enhances HGP in the obese insulin-resistant adolescent.