Tanya L. Alderete

Subcutaneous Adipose Tissue Macrophage Infiltration Is Associated With Hepatic and Visceral Fat Deposition, Hyperinsulinemia, and Stimulation of NF-κB Stress Pathway

OBJECTIVE To examine in obese young adults the influence of ethnicity and subcutaneous adipose tissue (SAT) inflammation on hepatic fat fraction (HFF), visceral adipose tissue (VAT) deposition, insulin sensitivity (SI), β-cell function, and SAT gene expression. RESEARCH DESIGN AND METHODS SAT biopsies were obtained from 36 obese young adults (20 Hispanics, 16 African Americans) to measure crown-like structures (CLS), reflecting SAT inflammation. SAT, VAT, and HFF were measured by magnetic resonance imaging, and SI and β-cell function (disposition index [DI]) were measured by intravenous glucose tolerance test. SAT gene expression was assessed using Illumina microarrays. RESULTS Participants with CLS in SAT (n = 16) were similar to those without CLS in terms of ethnicity, sex, and total body fat. Individuals with CLS had greater VAT (3.7 ± 1.3 vs. 2.6 ± 1.6 L; P = 0.04), HFF (9.9 ± 7.3 vs. 5.8 ± 4.4%; P = 0.03), tumor necrosis factor-α (20.8 ± 4.8 vs. 16.2 ± 5.8 pg/mL; P = 0.01), fasting insulin (20.9 ± 10.6 vs. 9.7 ± 6.6 mU/mL; P < 0.001) and glucose (94.4 ± 9.3 vs. 86.8 ± 5.3 mg/dL; P = 0.005), and lower DI (1,559 ± 984 vs. 2,024 ± 829 ×10−4 min−1; P = 0.03). Individuals with CLS in SAT exhibited upregulation of matrix metalloproteinase-9 and monocyte antigen CD14 genes, as well as several other genes belonging to the nuclear factor-κB (NF-κB) stress pathway. CONCLUSIONS Adipose tissue inflammation was equally distributed between sexes and ethnicities. It was associated with partitioning of fat toward VAT and the liver and altered β-cell function, independent of total adiposity. Several genes belonging to the NF-κB stress pathway were upregulated, suggesting stimulation of proinflammatory mediators.

Associations between human milk oligosaccharides and infant body composition in the first 6 mo of life

BACKGROUND Evidence linking breastfeeding to reduced risk of developing childhood obesity is inconclusive, yet previous studies have not considered variation in specific components of breast milk that may affect early development. OBJECTIVE We examined whether differences in the composition of human milk oligosaccharides (HMOs) correlate with infant growth and body composition at 1 and 6 mo of age. DESIGN Twenty-five mother-infant dyads were recruited from the University Hospital at the University of Oklahoma Health Sciences Center. Infants were breastfed for 6 mo. Breast-milk and infant measures were obtained at 1 and 6 mo of infant age. HMO composition was analyzed by high-pressure liquid chromatography, and infant growth (length and weight) and body composition (percentage fat, total fat, lean mass) were measured by dual-energy X-ray absorptiometry. Relations between HMOs and infant growth and body composition were examined by using multiple linear regression. A priori covariates included maternal prepregnancy body mass index, pregnancy weight gain, and infant age and sex. RESULTS Higher HMO diversity and evenness at 1 mo were associated with lower total and percentage fat mass at 1 mo. At 1 mo, each 1-μg/mL increase in lacto-N-fucopentaose (LNFP) I was associated with a 0.40-kg lower infant weight (P = 0.03). At 6 mo, each 1-μg/mL increase in LNFPI was associated with a 1.11-kg lower weight (P = 0.03) and a 0.85-g lower lean mass (P = 0.01). At 6 mo, each 1-μg/mL increase in LNFPI was associated with a 0.79-g lower fat mass (P = 0.02), whereas disialyl-lacto-N-tetraose and LNFPII were associated with a 1.92-g (P = 0.02) and 0.42-g (P = 0.02) greater fat mass, respectively. At 6 mo, each 1-μg/mL increase in fucosyl-disialyl-lacto-N-hexaose and lacto-N-neotetraose was associated with 0.04% higher (P = 0.03) and 0.03% lower (P < 0.01) body fat, respectively. CONCLUSION These findings support the hypothesis that differences in HMO composition in mothers milk are associated with infant growth and body composition. This trial was registered at clinicaltrials.gov as NCT02535637.

Ectopic fat deposition in prediabetic overweight and obese minority adolescents.

CONTEXT Optimizing effective prevention and treatment of type 2 diabetes in youth is limited by incomplete understanding of its pathophysiology and how this varies across ethnicities with high risk. OBJECTIVE The aim of this study was to examine the contribution of visceral adipose tissue (VAT), hepatic fat fraction (HFF), and pancreatic fat fraction (PFF) to prediabetes in overweight/obese African American (AA) and Latino youth. DESIGN AND SETTING We conducted a cross-sectional study in an academic pediatric care facility. SUBJECTS A total of 148 healthy, overweight/obese adolescents (56 AA, 92 Latino; 72 males, 76 females; age, 15.5 ± 1.2 y; BMI z-score, 2.1 ± 0.5) participated in the study. They were normal glucose tolerant (n = 106) and prediabetic (n = 42), based on fasting glucose of 100-125 mg/dL and/or 2-hour glucose of 140-199 mg/dL, and/or hemoglobin A1C 6.0-6.4%. MAIN OUTCOME MEASURES We measured sc abdominal adipose tissue, VAT, HFF, and PFF by 3-Tesla magnetic resonance imaging and measured total body fat by dual-energy x-ray absorptiometry. RESULTS Adolescents with prediabetes had 30% higher HFF (P = .001) and 31% higher PFF (P = .042), compared to those with normal glucose tolerance after controlling for age, sex, pubertal stage, ethnicity, total percentage body fat, and VAT. Logistic regression showed that PFF predicted prediabetes in AAs and HFF predicted prediabetes in Latinos, with the odds of having prediabetes increased by 66% for every 1% increase in PFF in African Americans, and increased by 22% for every 1% increase in HFF in Latinos. CONCLUSION These data demonstrate that ectopic fat phenotypes associated with prediabetes are established by adolescence. Ethnic differences in the deposition of ectopic fat in adolescents with prediabetes may differ, with pancreatic fat in AAs, vs hepatic fat in Latino adolescents, being associated with diabetes risk.

Liver Fat Has a Stronger Association With Risk Factors for Type 2 Diabetes in African-American Compared With Hispanic Adolescents

CONTEXT Although overweight and obese African-Americans (AAs) have less visceral adipose tissue (VAT) and liver fat (LF) than Hispanics, they have a similar risk for type 2 diabetes. OBJECTIVE We examined ethnic differences in the association between VAT and LF with risk factors for type 2 diabetes to help explain this paradox. DESIGN We conducted a cross-sectional study in an academic pediatric care facility. SUBJECTS Subjects were overweight and obese AA (n = 131; 15.5 ± 3.3 years old) and Hispanic adolescents (n = 227; 14.7 ± 3.0 years old). MAIN OUTCOME MEASURES Outcome measures included insulin sensitivity (SI), acute insulin response (AIR), and disposition index (DI) by frequently sampled i.v. glucose tolerance test and minimal modeling. RESULTS LF, not VAT, was inversely associated with SI, and the effect of high LF compared with low was more pronounced in AAs (P(interaction) < .05). In Hispanics, high LF was associated with a 24% lower SI (P < .01) and a 31% increase in AIR (P < .01) and was not associated with DI (P = .35). In AAs, high LF was associated with a 49% lower SI (P < .001), was not associated with an increase in AIR (P = .25), and was associated with a 42% lower DI (P < .01), indicating failure of compensatory insulin secretion/clearance in response to insulin resistance. Prediabetes changed the relationship between high/low LF and DI in Hispanics (P(interaction) = .002) but not AAs such that prediabetic Hispanics with high LF had a 43% lower DI (P = .03) with no difference in those without prediabetes (P = .06). CONCLUSIONS LF has a stronger effect on SI compared with VAT. Our results suggest that the impact of high LF on poor β-cell compensation is more pronounced in AAs. In Hispanics, the combination of high LF and prediabetes contributes to poor β-cell compensation.

High Rates of Fructose Malabsorption Are Associated with Reduced Liver Fat in Obese African Americans

Objective: African Americans commonly have lower liver fat accumulation than Hispanics, despite a similar propensity for obesity. Both ethnicities exhibit high consumption of fructose-containing beverages, which has been associated with high liver fat owing to the lipogenic properties of fructose. Therefore, differences in fructose absorption may be an important factor in regulating liver fat deposition. We hypothesized that fructose malabsorption in African Americans may reduce hepatic delivery of fructose, thus contributing to lower liver fat deposition compared to Hispanics. Methods: Thirty-seven obese young adults aged 21.4 ± 2.1 years (16 African American, 21 Hispanic) underwent a 3-hour hydrogen (H2) breath test to assess fructose malabsorption. Magnetic resonance imaging was used to determine visceral and subcutaneous adipose tissue volume and liver fat. Fructose malabsorption was expressed as an area under the curve for H2 production (H2 AUC). Results: Compared to Hispanics, African Americans had lower liver fat (5.4% ± 5.0% vs 8.9% ± 2.3%, p = 0.02) and a higher prevalence of fructose malabsorption (75.0% vs 42.9%; p = 0.05). Liver fat was negatively related to the extent of fructose malabsorption in African Americans (r = −0.53, p = 0.03), and this relationship was independent of the volumes of total fat and subcutaneous and visceral adipose tissue. There were no significant relationships between liver fat and fructose malabsorption in Hispanics. Conclusion: African Americans have both a higher prevalence and a greater magnitude of fructose malabsorption than Hispanics. In African Americans, fructose malabsorption was negatively correlated with liver fat, which may be protective against fatty liver disease.

Relationships Between IGF‐1 and IGFBP‐1 and Adiposity in Obese African‐American and Latino Adolescents

The purpose of this study was to examine interrelationships between insulin‐like growth factor 1 (IGF‐1), IGF binding proteins (IGFBPs), and adiposity in 49 African‐American and 77 Latino obese adolescents (15.3 ± 0.1 and 15.4 ± 0.2 years; BMI: 33.0 ± 0.7 and 35.0 ± 1.0 kg/m2, respectively). Immunoradiometric assays were used to measure IGF‐1, IGFBP‐1, and IGFBP‐3. Total fat and soft lean tissue were measured by dual‐energy X‐ray absorptiometry and visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue (SAAT), and hepatic fat fraction (HFF) were measured by magnetic resonance imaging. IGF‐1 levels were 23.1% higher and IGFBP‐1 were 40.4% higher in African Americans compared to Latinos after adjustment for total lean and total fat mass. IGF‐1 and IGFBP‐1 were inversely correlated with BMI, total fat mass, VAT, and HFF (r = −0.20 to −0.33, P < 0.05) while IGFBP‐1 was inversely correlated with SAAT (r = −0.22, P < 0.05). These relationships did not differ by ethnicity, however, the relationship between IGF‐1 and SAAT, as well as IGFBP‐1 and HFF, differed by ethnicity. Predicted mean IGF‐1 levels were 30.7% higher for African Americans at the 75th compared to 25th percentile of SAAT and only 11.7% higher for Latinos. Predicted mean IGFBP‐1 levels were 158% higher for African Americans at the 25th compared to the 75th percentile of HFF while IGFBP‐1 levels were 1.7% higher for Latinos at the 75th compared to the 25th percentile. These results demonstrate that the relationship between IGF‐1 and SAAT as well as IGFBP‐1 and HFF are different in African‐American and Latino adolescents and may contribute to the higher IGF‐1 levels in African‐Americans.

Effects of Childhood Asthma on the Development of Obesity among School-aged Children

Rationale: Asthma and obesity often occur together in children. It is unknown whether asthma contributes to the childhood obesity epidemic. Objectives: We aimed to investigate the effects of asthma and asthma medication use on the development of childhood obesity. Methods: The primary analysis was conducted among 2,171 nonobese children who were 5‐8 years of age at study enrollment in the Southern California Childrens Health Study (CHS) and were followed for up to 10 years. A replication analysis was performed in an independent sample of 2,684 CHS children followed from a mean age of 9.7 to 17.8 years. Measurements and Main Results: Height and weight were measured annually to classify children into normal, overweight, and obese categories. Asthma status was ascertained by parent‐ or self‐reported physician‐diagnosed asthma. Cox proportional hazards models were fitted to assess associations of asthma history with obesity incidence during follow‐up. We found that children with a diagnosis of asthma at cohort entry were at 51% increased risk of developing obesity during childhood and adolescence compared with children without asthma at baseline (hazard ratio, 1.51; 95% confidence interval, 1.08‐2.10) after adjusting for confounders. Use of asthma rescue medications at cohort entry reduced the risk of developing obesity (hazard ratio, 0.57; 95% confidence interval, 0.33‐0.96). In addition, the significant association between a history of asthma and an increased risk of developing obesity was replicated in an independent CHS sample. Conclusions: Children with asthma may be at higher risk of obesity. Asthma rescue medication use appeared to reduce obesity risk independent of physical activity.

Metabolic Basis of Ethnic Differences in Diabetes Risk in Overweight and Obese Youth

The global pandemic of childhood obesity has led to increased risk for prediabetes and type 2 diabetes mellitus (T2DM). Studies have shown decreased insulin sensitivity and/or secretion with increasing adiposity and consistently observed greater risk for T2DM in obese, non-Caucasian youth. In the current review we describe recent advances in understanding how obesity and metabolic status in children and adolescents confers various risk profiles for T2DM among Latinos, African Americans, Caucasians, Asians, and Native Americans. These possible determinants include ectopic fat distribution, adipose tissue inflammation and fibrosis, and elevated plasma levels of nonesterified free fatty acids. Future work should aim to elucidate the ethnic-specific pathophysiology of T2DM in order to develop and implement appropriate prevention and treatment strategies based on different ethnic profiles of diabetes risk.

Fructose in Breast Milk Is Positively Associated with Infant Body Composition at 6 Months of Age

Dietary sugars have been shown to promote excess adiposity among children and adults; however, no study has examined fructose in human milk and its effects on body composition during infancy. Twenty-five mother–infant dyads attended clinical visits to the Oklahoma Health Sciences Center at 1 and 6 months of infant age. Infants were exclusively breastfed for 6 months and sugars in breast milk (i.e., fructose, glucose, lactose) were measured by Liquid chromatography-mass spectrometry (LC-MS/MS) and glucose oxidase. Infant body composition was assessed using dual-energy X-ray absorptiometry at 1 and 6 months. Multiple linear regression was used to examine associations between breast milk sugars and infant body composition at 6 months of age. Fructose, glucose, and lactose were present in breast milk and stable across visits (means = 6.7 μg/mL, 255.2 μg/mL, and 7.6 g/dL, respectively). Despite its very low concentration, fructose was the only sugar significantly associated with infant body composition. A 1-μg/mL higher breast milk fructose was associated with a 257 g higher body weight (p = 0.02), 170 g higher lean mass (p = 0.01), 131 g higher fat mass (p = 0.05), and 5 g higher bone mineral content (p = 0.03). In conclusion, fructose is detectable in human breast milk and is positively associated with all components of body composition at 6 months of age.

Subclinical Atherosclerosis in Latino Youth: Progression of Carotid Intima-Media Thickness and Its Relationship to Cardiometabolic Risk Factors

OBJECTIVE To assess carotid artery intima-media thickness (CIMT) change over 2 years in overweight Latino adolescents and examine its relationship to cardiometabolic risk. STUDY DESIGN Seventy-two healthy overweight male and female Latino adolescents (mean age, 14.5 ± 1.7 years; mean body mass index, 31.5 ± 6.9 kg/m(2)) were evaluated at baseline and 2 years later for CIMT by high-resolution B-mode ultrasound, the metabolic syndrome and its features, body composition by dual-energy x-ray absorptiometry and magnetic resonance imaging, glucose/insulin measures by fasting blood, and oral and intravenous glucose tolerance tests. RESULTS Baseline CIMT did not differ from 2-year follow-up; however, 38 participants increased CIMT (0.017 ± 0.003 mm; +2.8%) and 34 decreased or remained the same (-0.019 ± 0.002 mm; -3.1%). ANCOVA analyses showed that participants with CIMT progression had higher baseline low-density lipoprotein (LDL)-cholesterol and total cholesterol (91.3 ± 3.4 and 150.3 ± 3.9 mg/dL) compared with those with CIMT non-progression (78.1 ± 3.6 and 135.6 ± 4.2 mg/dL, P < .05), independent of sex, baseline CIMT, age, and height. In multivariate regression, LDL-cholesterol was the sole predictor of CIMT progression, but the effect was small (odds of CIMT progression increased by 3% for each 1 mg/dL higher baseline LDL-cholesterol; 95% CI, 1.004 to 1.006, P = .03). CONCLUSIONS These results indicate a high variability in the magnitude of CIMT change in growing overweight Latino youth and support the use of LDL-cholesterol to assess subclinical atherosclerosis risk in this population.