Anna M.G. Cali

Obesity in Children and Adolescents

CONTEXT Although the prevalence rates of childhood obesity have seemingly been stable over the past few years, far too many children and adolescents are still obese. Childhood obesity, and its associated metabolic complications, is rapidly emerging as one of the greatest global challenges of the 21st century. About 110 million children are now classified as overweight or obese. EVIDENCE ACQUISITION In this review we first describe the most recent data on the prevalence, severity, and racial/ethnic differences in childhood obesity. Obesity is associated with significant health problems in the pediatric age group and is an important early risk factor for much of adult morbidity and mortality. EVIDENCE SYNTHESIS We review the metabolic complications associated with childhood obesity. Particular emphasis is given to the description of studies regarding the impact of varying degrees of obesity on the cardiometabolic risk factors in youth. We further describe studies in obese adolescents that have examined the importance of ectopic lipid deposition in the visceral abdominal depot and in insulin sensitive tissues in relation to the presence of insulin resistance. We end by describing studies that have examined beta-cell function in obese adolescents with normal glucose tolerance. CONCLUSIONS The growing number of obese children and adolescents worldwide is of great concern. Many obese children and adolescents already manifest some metabolic complications, and these children are at high risk for the development of early morbidity. Understanding the underlying pathogenesis of this peculiar phenotype is of critical importance.

High Visceral and Low Abdominal Subcutaneous Fat Stores in the Obese Adolescent A Determinant of an Adverse Metabolic Phenotype

OBJECTIVE— To explore whether an imbalance between the visceral and subcutaneous fat depots and a corresponding dysregulation of the adipokine milieu is associated with excessive accumulation of fat in the liver and muscle and ultimately with insulin resistance and the metabolic syndrome. RESEARCH DESIGN AND METHODS— We stratified our multi-ethnic cohort of 118 obese adolescents into tertiles based on the proportion of abdominal fat in the visceral depot. Abdominal and liver fat were measured by magnetic resonance imaging and muscle lipid (intramyocellular lipid) by proton magnetic resonance spectroscopy. RESULTS— There were no differences in age, BMI Z score, or fat-free mass across tertiles. However, as the proportion of visceral fat increased across tertiles, BMI and percentage of fat and subcutaneous fat decreased, while hepatic fat increased. In addition, there was an increase in 2-h glucose, insulin, c-peptide, triglyceride levels, and insulin resistance. Notably, both leptin and total adiponectin were significantly lower in tertile 3 than 1, while C-reactive protein and interleukin-6 were not different across tertiles. There was a significant increase in the odds ratio for the metabolic syndrome, with subjects in tertile 3 5.2 times more likely to have the metabolic syndrome than those in tertile 1. CONCLUSIONS— Obese adolescents with a high proportion of visceral fat and relatively low abdominal subcutaneous fat have a phenotype reminiscent of partial lipodystrophy. These adolescents are not necessarily the most severely obese, yet they suffer from severe metabolic complications and are at a high risk of having the metabolic syndrome.

A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents†‡

The genetic factors associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in pediatric obesity remain largely unknown. Recently, a nonsynonymous single‐nucleotide polymorphism (rs738409), in the patatin‐like phospholipase 3 gene (PNPLA3) has been associated with hepatic steatosis in adults. In a multiethnic group of 85 obese youths, we genotyped the PNLPA3 single‐nucleotide polymorphism, measured hepatic fat content by magnetic resonance imaging and insulin sensitivity by the insulin clamp. Because PNPLA3 might affect adipogenesis/lipogenesis, we explored the putative association with the distribution of adipose cell size and the expression of some adipogenic/lipogenic genes in a subset of subjects who underwent a subcutaneous fat biopsy. Steatosis was present in 41% of Caucasians, 23% of African Americans, and 66% of Hispanics. The frequency of PNPLA3(rs738409) G allele was 0.324 in Caucasians, 0.183 in African Americans, and 0.483 in Hispanics. The prevalence of the G allele was higher in subjects showing hepatic steatosis. Surprisingly, subjects carrying the G allele showed comparable hepatic glucose production rates, peripheral glucose disposal rate, and glycerol turnover as the CC homozygotes. Carriers of the G allele showed smaller adipocytes than those with CC genotype (P = 0.005). Although the expression of PNPLA3, PNPLA2, PPARγ2(peroxisome proliferator‐activated receptor gamma 2), SREBP1c(sterol regulatory element binding protein 1c), and ACACA(acetyl coenzyme A carboxylase) was not different between genotypes, carriers of the G allele showed lower leptin (LEP)(P = 0.03) and sirtuin 1 (SIRT1) expression (P = 0.04). Conclusion: A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance. The rs738409 PNPLA3 G allele is associated with morphological changes in adipocyte cell size. (HEPATOLOGY 2010.)

Central Role of Fatty Liver in the Pathogenesis of Insulin Resistance in Obese Adolescents

OBJECTIVE We evaluated the role of fatty liver in the alteration of insulin sensitivity and β-cell function in two groups of obese adolescents, differing in hepatic fat content (hepatic fat fraction [HFF]) but with similar intrabdominal intramyocellular lipid content (IMCL) and overall degree of obesity. RESEARCH DESIGN AND METHODS We studied 23 obese adolescents with high HFF (HFF >5.5%) and 20 obese adolescents with low HFF (HFF <5.5%), matched for age, Tanner stage, BMI z score, and percentages of body fat, visceral fat, and IMCL. All subjects underwent an oral glucose tolerance test and a two-step hyperinsulinemic-euglycemic clamp, magnetic resonance imaging and 1H nuclear magnetic resonance to assess abdominal fat distribution, HFF, and IMCL, respectively. RESULTS The high HFF group showed significantly lower whole-body insulin sensitivity index (P = 0.001) and estimates of insulin secretion (P = 0.03). The baseline hepatic glucose production (EGP) rate was not different between the two groups. Suppression of EGP was significantly lower (P = 0.04) in the high HFF group during low-dose insulin; no differences were observed during the second step. Baseline fatty acids, glycerol concentrations, and clamp suppression of glycerol turnover did not differ between the groups. During the second step, the glucose disposal rate was significantly lower (P = 0.01) in the high HFF group. CONCLUSIONS Fatty liver, independent of visceral fat and IMCL, plays a central role in the insulin-resistant state in obese adolescents.

Glucose dysregulation and hepatic steatosis in obese adolescents: is there a link?

Fatty liver is increasingly common in obese adolescents. We determined its association with glucose dysregulation in 118 (37M/81F) obese adolescents of similar age and percent total fat. Fast‐magnetic resonance imaging (MRI) and simple MRI were used to quantify hepatic fat content and abdominal fat distribution. All subjects had a standard oral glucose tolerance test. Insulin sensitivity was estimated by the Matsuda Index and homeostasis model assessment of insulin resistance. Baseline total and high molecular weight (HMW)‐adiponectin and interleukin (IL)‐6 levels were measured. The cohort was stratified according to tertiles of hepatic fat content. Whereas age and %fat were comparable across tertiles, ethnicity differed in that fewer Blacks and more Whites and Hispanics were in the moderate and high category of hepatic fat fraction (HFF). Visceral and the visceral‐to‐subcutaneous fat ratio increased and insulin sensitivity decreased across tertiles. Two‐hour plasma glucose rose with increasing hepatic steatosis (P < 0.008). 73.7% of the subjects in the high HFF had the metabolic syndrome compared to 19.5% and 30.6%, respectively, in the low and moderate categories. Both total and HMW‐adiponectin decreased, and IL‐6 increased with increasing hepatic steatosis. Conclusion: In obese adolescents, independent of total fat, increasing severity of fatty liver is associated with glucose dysregulation, metabolic syndrome, and with a proinflammatory milieu. (HEPATOLOGY 2009.)

Interethnic Differences in Muscle, Liver and Abdominal Fat Partitioning in Obese Adolescents

The prevalence of insulin resistance and type 2 diabetes (T2D) in obese youth is rapidly increasing, especially in Hispanics and African Americans compared to Caucasians. Insulin resistance is known to be associated with increases in intramyocellular (IMCL) and hepatic fat content. We determined if there are ethnic differences in IMCL and hepatic fat content in a multiethnic cohort of 55 obese adolescents. We used 1H magnetic resonance spectroscopy (MRS) to quantify IMCL levels in the soleus muscle, oral glucose tolerance testing to estimate insulin sensitivity, magnetic resonance imaging (MRI) to measure abdominal fat distribution. Liver fat content was measured by fast–MRI. Despite similar age and % total body fat among the groups, IMCL was significantly higher in the Hispanics (1.71% [1.43%, 2.0%]) than in the African-Americans (1.04% [0.75%, 1.34%], p = 0.013) and the Caucasians (1.2% [0.94%, 1.5%], p = 0.04). Liver fat content was undetectable in the African Americans whereas it was two fold higher than normal in both Caucasians and Hispanics. Visceral fat was significantly lower in African Americans (41.5 cm2 [34.6, 49.6]) and was similar in Caucasians (65.2 cm2 [55.9, 76.0]) and Hispanics (70.5 cm2 [59.9, 83.1]). In a multiple regression analysis, we found that ethnicity independent of age, gender and % body fat accounts for 10% of the difference in IMCL. Our study indicates that obese Hispanic adolescents have a greater IMCL lipid content than both Caucasians and African Americans, of comparable weight, age and gender. Excessive accumulation of fat in the liver was found in both Caucasian and Hispanic groups as opposed to virtually undetectable levels in the African Americans. Thus, irrespective of obesity, there seem to be some clear ethnic differences in the amount of lipid accumulated in skeletal muscle, liver and abdominal cavity.

Primary Defects in β-Cell Function Further Exacerbated by Worsening of Insulin Resistance Mark the Development of Impaired Glucose Tolerance in Obese Adolescents

OBJECTIVE—Impaired glucose tolerance (IGT) is a pre-diabetic state of increasing prevalence among obese adolescents. The purpose of this study was to determine the natural history of progression from normal glucose tolerance (NGT) to IGT in obese adolescents. RESEARCH DESIGN AND METHODS—We determined the evolution of β-cell function, insulin sensitivity (SI), and glucose tolerance in a multiethnic group of 60 obese adolescents over the course of approximately 30 months. Each subject underwent three serial 3-h oral glucose tolerance tests. Dynamic, static, and total β-cell responsivity (Φd, Φs, and Φtot, respectively) and Si were assessed by oral C-peptide and glucose minimal models. The disposition index (DI), which adjusts insulin secretion for Si, was calculated. RESULTS—At baseline, all 60 subjects had NGT. Seventy-seven percent (46 subjects) maintained NGT over the three testing periods (nonprogressors), whereas 23% (14 subjects) developed IGT over time (progressors). At baseline, percent fat and BMI Z score were comparable between the groups. Fasting plasma glucose, 2-h glucose, glucose area under the curve at 180 min, and Φd were significantly different between the two groups at baseline, whereas Si was comparable between the two groups. Over time, although Si remained unchanged in nonprogressors, it steadily worsened by ∼45% (P > 0.04) in progressors. β-Cell responsivity decreased by 20% in progressors, whereas it remained stable in nonprogressors. The DI showed a progressive decline in progressors compared with a modest improvement in nonprogressors (P = 0.02). CONCLUSIONS—Obese adolescents who progress to IGT may manifest primary defects in β-cell function. In addition, progressive decline in Si further aggravates β-cell function, contributing to the worsening of glucose intolerance.

Evidence for Early Defects in Insulin Sensitivity and Secretion Before the Onset of Glucose Dysregulation in Obese Youths: A Longitudinal Study

We sought to determine whether obese adolescents with high-“normal” 2-h post-oral glucose tolerance test glucose levels display defects in insulin secretion and sensitivity associated with future development of impaired glucose tolerance (IGT). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and insulin secretion by applying mathematical modeling during the hyperglycemic clamp in 60 normal glucose tolerance (NGT) obese adolescents, divided into three groups based on the 2-h glucose values (<100, 100–119, 120–139 mg/dL), and in 21 IGT obese adolescents. Glucose tolerance was reevaluated after 2 years. Insulin sensitivity decreased significantly across 2-h glucose NGT categories, while the highest NGT category and IGT group were similar. First-phase insulin secretion decreased across NGT categories, while no difference was found between the highest NGT group and IGT subjects. Second-phase secretion was similar across all NGT and IGT groups. The disposition index (CDI) decreased across NGT categories, while no difference was observed between the highest NGT and IGT subjects. Age and CDI were the best predictors of 2-h glucose after two years. Across rising categories of normal 2-h glucose levels, NGT obese adolescents exhibit significant impairment of β-cell function relative to insulin sensitivity associated with the development of IGT.

Metabolic Abnormalities Underlying the Different Prediabetic Phenotypes in Obese Adolescents

OBJECTIVE The aim of this study was to define the metabolic abnormalities underlying the prediabetic status of isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), and combined IFG/IGT in obese youth. RESEARCH DESIGN AND METHODS We used state-of-the-art techniques (hyperinsulinemic-euglycemic and hyperglycemic clamps), applying a model of glucose-stimulated insulin secretion to the glucose and C-peptide concentration, in 40 normal glucose tolerance (NGT), 17 IFG, 23 IGT, and 11 IFG/IGT obese adolescents. Percent fat (by dual-energy x-ray absorptiometry), age, gender and ethnicity were comparable among groups. RESULTS Peripheral insulin sensitivity was similar between the IFG and NGT groups. In contrast, the IGT and IFG/IGT groups showed marked reductions in peripheral insulin sensitivity (P < 0.002). Basal hepatic insulin resistance index (basal hepatic glucose production x fasting plasma insulin) was significantly increased in IFG, IGT, and IFG/IGT (P < 0.009) compared with NGT. Glucose sensitivity of first-phase insulin secretion was progressively lower in IFG, IGT, and IFG/IGT compared with NGT. Glucose sensitivity of second-phase secretion showed a statistically significant defect only in the IFG/IGT group. In a multivariate regression analysis, glucose sensitivity of first-phase secretion and basal insulin secretion rate were significant independent predictors of FPG (total r(2) = 25.9%). CONCLUSIONS IFG, in obese adolescents, is linked primarily to alterations in glucose sensitivity of first-phase insulin secretion and liver insulin sensitivity. The IGT group is affected by a more severe degree of peripheral insulin resistance and reduction in first-phase secretion. IFG/IGT is hallmarked by a profound insulin resistance and by a new additional defect in second-phase insulin secretion.

Intrahepatic Fat Accumulation and Alterations in Lipoprotein Composition in Obese Adolescents A perfect proatherogenic state

OBJECTIVE—Among other metabolic consequences, a dyslipidemic profile often accompanies childhood obesity. In adults, type 2 diabetes and hepatic steatosis have been shown to alter lipoprotein subclass distribution and size; however, these alterations have not yet been shown in children or adolescents. Therefore, our objective was to determine the effect of hepatic steatosis on lipoprotein concentration and size in obese adolescents. RESEARCH DESIGN AND METHODS—Using fast magnetic resonance imaging, we measured intrahepatic fat content in 49 obese adolescents with normal glucose tolerance. The presence or absence of hepatic steatosis was determined by a threshold value for hepatic fat fraction (HFF) of 5.5%; therefore, the cohort was divided into two groups (HFF > or <5.5%). Fasting lipoprotein subclasses were determined using nuclear magnetic resonance spectroscopy. RESULTS—Overall, the high-HFF group had 88% higher concentrations of large VLDL compared with the low-HFF group (P < 0.001). Likewise, the high-HFF group had significantly higher concentrations of small dense LDL (P < 0.007); however, the low-HFF group had significantly higher concentrations of large HDL (P < 0.001). Stepwise multiple regression analysis revealed that high HFF was the strongest single correlate, accounting for 32.6% of the variance in large VLDL concentrations (P < 0.002). CONCLUSIONS—The presence of fatty liver was associated with a pronounced dyslipidemic profile characterized by large VLDL, small dense LDL, and decreased large HDL concentrations. This proatherogenic phenotype was strongly related to the intrahepatic lipid content.