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- A systemic disorder of energy regulation associated with ectopic fat deposition, immune activation, insulin resistance, and increased risk for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM)
- Recognized by central adiposity, dyslipidemia, hypertension, and abnormal glucose tolerance
- These metabolic parameters change with age, gender, race, and ethnicity, so no established pediatric thresholds have been defined.
- Extrapolation from adult criteria permits diagnosis when ≥3 of the following five elements are present (approximate levels):
- Waist circumference >90th percentile (waist to height ratio ≥0.5)
- Low high-density lipoprotein cholesterol (HDL-c) <10th percentile (<40 mg/dL)
- High triglycerides (TG) >90th percentile (≥90 mg/dL to age 9 years and then ≥110 mg/dL)
- Hypertension: systolic and/or diastolic blood pressure (BP) ≥95th percentile for age, height, and gender
- Elevated fasting blood sugar (>99 mg/dL) in youth with insulin resistance; hyperinsulinemia is more common than hyperglycemia.
- Uncommon in children of normal weight
- Up to 60% of obese children meet criteria for the metabolic syndrome.
- Rates correlate with visceral and other ectopic fat depots.
- Highest rates in Native Americans > Hispanics > non–Hispanic (NH) Whites ~ Asians > NH Blacks
- More prevalent with age and in males than females
- Prenatal and postnatal stressors
- Family history of T2DM and/or early CVD
- Diet high in processed foods, added sugars, trans fats
- Sedentary lifestyle
- Smoking or passive smoke exposure
Sequence and epigenetic modification of genes involved in energy regulation have been implicated in disease progression, including adipose tissue differentiation, insulin signaling, and circadian clock genes as well as the mitochondrial genome.
- Subcutaneous adipose capacity (which varies in individuals for both genetic and environmental reasons) is exceeded.
- Deposition of fat in hypertrophied adipose cells within nonadipose depots, notably visceral, hepatic, and muscular
- Triglyceride-engorged adipocytes trigger major histocompatibility complex (MHC) II response and immune activation. Antigen presentation may be endotoxin from microbial translocation.
- Stimulated monocyte/macrophage infiltration into ectopic adipose depots release tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1).
- Chronic low level inflammation
- Mitochondrial dysfunction and excessive intracellular oxidative stress
- Insulin resistance and systemic consequences
- Decreased mitochondrial reserve with age and physical inactivity
- Excessive caloric load, particularly a diet high in refined carbohydrate and/or trans fat
- Genetic and epigenetic predisposition
Commonly Associated Conditions
- Nonalcoholic fatty liver disease (NAFLD)
- Disordered sleep ± obstructive sleep apnea (OSA)
- Polycystic ovary syndrome (PCOS)
- Low 25-OH vitamin D level