What is metabolic syndrome, and why are children getting it?

Abstract

Metabolic syndrome comprises a cluster of cardiovascular risk factors (hypertension, altered glucose metabolism, dyslipidemia, and abdominal obesity) that occur in obese children. However, metabolic syndrome can also occur in lean individuals, suggesting that obesity is a marker for the syndrome, not a cause. Metabolic syndrome is difficult to define, due to its nonuniform classification and reliance on hard cutoffs in the evaluation of disorders with non-Gaussian distributions. Defining the syndrome is even more difficult in children, owing to racial and pubertal differences and lack of cardiovascular events. Lipid partitioning among specific fat depots is associated with insulin resistance, which can lead to mitochondrial overload and dysfunctional subcellular energy use and drive the various elements of metabolic syndrome. Multiple environmental factors, in particular a typical Western diet, drive mitochondrial overload, while other changes in Western society, such as stress and sleep deprivation, increase insulin resistance and the propensity for food intake. These culminate in an adverse biochemical phenotype, including development of altered glucose metabolism and early atherogenesis during childhood and early adulthood.

Figure 1

An hypothesis on the relationship between obesity and metabolic syndrome. The metabolic impact of obesity is determined by the pattern of lipid partitioning. Lipid storage in insulin-sensitive tissues, such as liver or muscle, and in the visceral compartment is associated with a typical metabolic profile characterized by elevated free fatty acids and inflammatory cytokines alongside reduced levels of adiponectin. This combination can independently lead to peripheral insulin resistance and to endothelial dysfunction. The combination of insulin resistance and early atherogenesis (manifested as endothelial dysfunction) drives the development of altered glucose metabolism and of cardiovascular disease. (With permission from Ref. 184.)

Figure 2

Mechanisms of subcellular metabolic dysfunction, using fructose as an example. The formation of acetyl-CoA leads to lipid deposition and activation of inflammatory pathways, including serine phosphorylation of IRS-1, which leads to insulin resistance. Furthermore, metabolic processing in the mitochondria, the glycation of protein ɛ-amino groups via the Maillard reaction, and circulating inflammatory cytokines due to their receptor-mediated activation of NADPH oxidase, all increase intracellular levels of ROS. In the absence of sufficient peroxisomal quenching and degradation, the ROS moieties lead to endoplasmic reticulum stress, promoting the unfolded protein response, and cause either cell death (apoptosis) or cellular/metabolic dysfunction. (With permission from Ref. 18.) Courtesy of the American Academy of Pediatrics. Abbreviations: ATP, adenosine triphosphate; CoA, coenzyme A; JNK-1, c-jun N-terminal kinase 1; NADPH, nicotinamide adenine dinucleotide phosphate; PKCɛ, protein kinase C-ɛ; pSer-IRS-1, serine phosphorylated IRS-1; ROS, reactive oxygen species; UPR, unfolded protein response.

Figure 3

Hepatic fructose metabolism. In contrast to glucose, fructose induces (1) substrate-dependent hepatocellular phosphate depletion, which increases uric acid and contributes to hypertension through inhibition of endothelial nitric oxide synthase and reduction of nitric oxide (NO); (2) excess citrate production; (3) stimulation of de novo lipogenesis and excess production of VLDL and serum TG, promoting dyslipidemia; (4) accumulation of intrahepatic lipid droplets, promoting hepatic steatosis; (5) lack of phosphorylation of FoxO1, leading to increased gluconeogenesis; (6) delivery of triglycerides to muscle, promoting muscle insulin resistance; (7) CNS hyperinsulinemia, which antagonizes leptin signaling and promotes continued energy intake; (8) JNK-1 activation, which causes serine phosphorylation of the hepatic insulin receptor rendering it inactive and contributing to hepatic insulin resistance; and (9) production of reactive oxygen species (ROS), which lead to protein instability.