With American children on course to grow into the most obese generation of adults in history, Sonia Caprio argues that it is critical to develop more effective strategies for preventing childhood obesity and treating serious obesity-related health complications. She notes that although pediatricians are concerned about the obesity problem, most are ineffective in addressing it. Treatment should begin, Caprio explains, with a thorough medical exam, an assessment of nutrition and physical activity, an appraisal of the degree of obesity and associated health complications, a family history, and full information about current medications. Caprio also summarizes the current use of medications and surgery in treating child obesity and argues, that for severe forms of obesity, the future lies in developing new and more effective drugs. Caprio explains that today's most effective obesity treatment programs have been carried out in academic centers through an approach that combines a dietary component, behavioral modification, physical activity, and parental involvement. Such programs, however, have yet to be translated to primary pediatric care centers. Successfully treating obesity, she argues, will require a major shift in pediatric care that builds on the findings of these academic centers regarding structured intervention programs. To ensure that pediatricians are well trained in implementing such programs, the American Medical Association is working with federal agencies, medical specialty societies, and public health organizations to teach doctors how to prevent and manage obesity in both children and adults. Such training should be a part of undergraduate and graduate medical education and of continuing medical education programs. Caprio also addresses the problem of reimbursement for obesity treatment. Despite the health risks of obesity, patients get little support from health insurers, thus putting long-term weight-management programs beyond the reach of most. Caprio argues that obesity should be recognized as a disease and receive coverage for its treatment just as other diseases do.
We examined the impact of varying degrees of obesity on the prevalence of the metabolic syndrome and its relation to ectopic fat deposition in a large, multi-ethnic cohort of children and adolescents.A standard glucose tolerance test was administered to 438 obese, 31 overweight and 20 nonobese children and adolescents. Baseline measures included blood pressure and plasma lipid and insulin levels. In a subset of 118 subjects, abdominal fat distribution was measured by magnetic resonance imaging (MRI) and further stratified into tertiles based on the proportion of abdominal fat in the visceral depot. Liver fat was measured by fast MRI and intramyocellular fat by proton magnetic resonance spectroscopy.Overall, the prevalence of the metabolic syndrome increased with the severity of obesity. In the subset of 118 obese adolescents undergoing MRI, there were no differences in age or body mass index z-scores across tertiles. However, as the proportion of visceral fat increased, subcutaneous fat decreased. There were significant increases in the occurrence of hepatic steatosis, insulin resistance and metabolic syndrome, with subjects in tertile 3 being 5.2-times more likely to have the metabolic syndrome than those in tertile 1.The prevalence of the metabolic syndrome is high in obese children and adolescents and increases with worsening obesity. Obese adolescents with a high proportion of visceral fat and relatively low abdominal subcutaneous fat have a phenotype reminiscent of partial lipodystrophy: hepatic steatosis, profound insulin resistance and an increased risk of the metabolic syndrome.
OBJECTIVE Macrophage recruitment to adipose tissue is a reproducible feature of obesity. However, the events that result in chemokine production and macrophage recruitment to adipose tissue during states of energetic excess are not clear. Sirtuin 1 (SirT1) is an essential nutrient-sensing histone deacetylase, which is increased by caloric restriction and reduced by overfeeding. We discovered that SirT1 depletion causes anorexia by stimulating production of inflammatory factors in white adipose tissue and thus posit that decreases in SirT1 link overnutrition and adipose tissue inflammation. RESEARCH DESIGN AND METHODS We used antisense oligonucleotides to reduce SirT1 to levels similar to those seen during overnutrition and studied SirT1-overexpressing transgenic mice and fat-specific SirT1 knockout animals. Finally, we analyzed subcutaneous adipose tissue biopsies from two independent cohorts of human subjects. RESULTS We found that inducible or genetic reduction of SirT1 in vivo causes macrophage recruitment to adipose tissue, whereas overexpression of SirT1 prevents adipose tissue macrophage accumulation caused by chronic high-fat feeding. We also found that SirT1 expression in human subcutaneous fat is inversely related to adipose tissue macrophage infiltration. CONCLUSIONS Reduction of adipose tissue SirT1 expression, which leads to histone hyperacetylation and ectopic inflammatory gene expression, is identified as a key regulatory component of macrophage influx into adipose tissue during overnutrition in rodents and humans. Our results suggest that SirT1 regulates adipose tissue inflammation by controlling the gain of proinflammatory transcription in response to inducers such as fatty acids, hypoxia, and endoplasmic reticulum stress.
OBJECTIVE—The MiniMed Continuous Glucose Monitoring System (CGMS) measures subcutaneous interstitial glucose levels that are calibrated against three or more fingerstick glucose levels daily. The objective of the present study was to examine whether the relationship between plasma and interstitial fluid glucose is altered by changes in plasma glucose and insulin levels and how such alterations might influence CGMS performance. RESEARCH DESIGN AND METHODS—Arterialized plasma glucose, sensor glucose, and interstitial fluid glucose were measured by microdialysis in 11 healthy subjects during a 1.0 mU · kg−1 · min−1 stepped euglycemic-hypoglycemic-hyperglycemic (plasma glucose ∼5, 3.1, and 8.6 mmol/l, respectively) insulin clamp that raised plasma insulin to ∼360–390 pmol/l. RESULTS—When the CGMS was calibrated versus plasma glucose levels before insulin infusion, basal sensor and plasma glucose were similar (5.0 ± 0.3 vs. 5.2 ± 0.3 mmol/l, respectively); dialysate glucose was 3.3 ± 0.9 mmol/l. During the hyperinsulinemic-euglycemia study (plasma glucose 4.9 ± 0.3 mmol/l), dialysate glucose fell by 30–35%, accompanied by a significant reduction in sensor glucose (to 3.7 ± 0.6 mmol/l; P < 0.001 vs. plasma). Subsequently, sensor levels remained lower than plasma values during mild hypoglycemia (2.5 ± 0.6 vs. 3.1 ± 0.3 mmol/l; P < 0.01) and during recovery from hypoglycemia (7.3 ± 1.2 vs. 8.6 ± 0.6; P < 0.01). However, when the CGMS was calibrated against plasma glucose levels before and during each step of the clamp, sensor glucose levels increased throughout the study and did not differ from plasma glucose values during hypoglycemia. CONCLUSIONS—Although hyperinsulinemia may contribute to modest discrepancies between plasma and sensor glucose levels, the CGMS is able to accurately track acute changes in plasma glucose when calibrated across a range of plasma glucose and insulin levels.
Obesity in peripubertal girls is associated with hyperandrogenemia (HA), which can represent a forerunner of polycystic ovary syndrome (PCOS). However, not all obese girls demonstrate HA, and determinants of HA in obese girls remain unclear. We hypothesized that insulin and luteinizing hormone (LH) are independent predictors of free testosterone (T) concentration in obese girls. To assess this further, fasting morning blood samples were collected from 92 obese (BMI-for-age percentile ≥95) girls in various stages of puberty. A multivariate regression model was then constructed using free T (dependent variable), LH, insulin, pubertal group (early, mid-, or late puberty), BMI z-score, and age. Free testosterone (T) concentrations were highly variable among obese girls in each pubertal group. The regression model accounted for roughly half of the variability of free T in obese girls (adjusted R(2) = 0.53, P < 0.001). LH was found to have the greatest independent ability to predict free T, followed by insulin, then age and BMI z-score. Pubertal group was not an independent predictor of free T. We conclude that morning LH and fasting insulin are significant predictors of free T in obese girls, even after adjusting for potential confounders (age, pubertal group, adiposity). We suggest that abnormal LH secretion and hyperinsulinemia can promote HA in some peripubertal girls with obesity.
Pediatric obesity is associated with insulin resistance, which, in turn, impacts glucose and lipid metabolism. This study sought to assess how glucose variability relates to intrahepatic fat content, β cell insulin sensitivity, and glycolysis in youth with obesity.
Insulin resistance associated with altered fat partitioning in liver and adipose tissues is a prediabetic condition in obese adolescents. We investigated interactions between glucose tolerance, insulin sensitivity, and the expression of lipogenic genes in abdominal subcutaneous adipose and liver tissue in 53 obese adolescents. Based on their 2-h glucose tests they were stratified in the following groups: group 1, 2-h glucose level <120 mg/dL; group 2, 2-h glucose level between 120 and 140 mg/dL; and group 3, 2-h glucose level >140 mg/dL. Liver and adipose tissue insulin sensitivity were greater in group 1 than in group 2 and group 3, and muscle insulin sensitivity progressively decreased from group 1 to group 3. The expression of the carbohydrate-responsive element-binding protein (ChREBP) was decreased in adipose tissue but increased in the liver (eight subjects) in adolescents with impaired glucose tolerance or type 2 diabetes. The expression of adipose ChREBPα and ChREBPβ was inversely related to 2-h glucose level and positively correlated to insulin sensitivity. Improvement of glucose tolerance in four subjects was associated with an increase of ChREBP/GLUT4 expression in the adipose tissue. In conclusion, early in the development of prediabetes/type 2 diabetes in youth, ChREBPβ expression in adipose tissue predicts insulin resistance and, therefore, might play a role in the regulation of glucose tolerance.
