Maternal Diet Quality During Pregnancy and Offspring Hepatic Fat in Early Childhood: The Healthy Start Study.

BACKGROUND: Overnutrition in utero may increase offspring risk of nonalcoholic fatty liver disease (NAFLD), but the specific contribution of maternal diet quality during pregnancy to this association remains understudied in humans. OBJECTIVES: This study aimed to examine the associations of maternal diet quality during pregnancy with offspring hepatic fat in early childhood (median: 5 y old, range: 4-8 y old). METHODS: Data were from 278 mother-child pairs in the longitudinal, Colorado-based Healthy Start Study. Multiple 24-h recalls were collected from mothers during pregnancy on a monthly basis (median: 3 recalls, range: 1-8 recalls starting after enrollment), and used to estimate maternal usual nutrient intakes and dietary pattern scores [Healthy Eating Index-2010 (HEI-2010), Dietary Inflammatory Index (DII), and Relative Mediterranean Diet Score (rMED)]. Offspring hepatic fat was measured in early childhood by MRI. Associations of maternal dietary predictors during pregnancy with offspring log-transformed hepatic fat were assessed using linear regression models adjusted for offspring demographics, maternal/perinatal confounders, and maternal total energy intake. RESULTS: Higher maternal fiber intake and rMED scores during pregnancy were associated with lower offspring hepatic fat in early childhood in fully adjusted models [Back-transformed ß (95% CI): 0.82 (0.72, 0.94) per 5 g/1000 kcal fiber; 0.93 (0.88, 0.99) per 1 SD for rMED]. In contrast, higher maternal total sugar and added sugar intakes, and DII scores were associated with higher offspring hepatic fat [Back-transformed ß (95% CI): 1.18 (1.05, 1.32) per 5% kcal/d added sugar; 1.08 (0.99, 1.18) per 1 SD for DII]. Analyses of dietary pattern subcomponents also revealed that lower maternal intakes of green vegetables and legumes and higher intake of "empty calories" were associated with higher offspring hepatic fat in early childhood. CONCLUSIONS: Poorer maternal diet quality during pregnancy was associated with greater offspring susceptibility to hepatic fat in early childhood. Our findings provide insights into potential perinatal targets for the primordial prevention of pediatric NAFLD.

Antiretroviral Therapy Initiation Is Associated With Decreased Visceral and Subcutaneous Adipose Tissue Density in People Living With Human Immunodeficiency Virus.

BACKGROUND: Adipose tissue (AT) alterations are common in people living with human immunodeficiency virus (PLWH). Decreases in AT density suggest disrupted adipocyte function/hypertrophy. We assessed changes in AT density after antiretroviral therapy (ART) initiation and associations with immunometabolic parameters. METHODS: In a prospective randomized clinical trial of ART initiation, L4-L5 abdominal CT scans measured subcutaneous AT (SAT) and visceral AT (VAT) area and density in treatment-naive PLWH randomized to tenofovir-emtricitabine plus ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or raltegravir. Linear regression models compared week 0 and week 96 levels, and 96-week changes, in SAT and VAT density (in Hounsfield units [HU]). Spearman correlations assessed relationships between AT density and immunometabolic parameters. RESULTS: Of the 228 participants, 89% were male and 44% were white non-Hispanic. Median age was 36 years, baseline HIV-1 RNA was 4.6 log10 copies/mL, and CD4+ T-cell count was 344 cells/µL. Over 96 weeks, SAT and VAT HU decreased significantly in all arms. Less dense week 96 SAT and VAT density correlated with higher high-density lipoprotein (HDL) cholesterol and adiponectin (r = 0.19-0.30) levels and lower interleukin 6, non-HDL cholesterol, triglyceride, leptin, and homeostatic model assessment of insulin resistance (r = -0.23 to -0.68) levels at week 96 after adjusting for baseline CD4+ T-cell count, HIV-1 RNA, and baseline AT area. CONCLUSIONS: Following virologic suppression, lower SAT and VAT density was associated with greater plasma measures of systemic inflammation, lipid disturbances, and insulin resistance independent of AT area, suggesting that changes in AT density with ART may lead to adverse health outcomes independent of AT quantity. CLINICAL TRIALS REGISTRATION: NCT00851799.

Associations of Nutrient Intake Changes During Childhood with Adolescent Hepatic Fat: The Exploring Perinatal Outcomes Among CHildren Study.

OBJECTIVE: To examine associations of dietary changes from childhood to adolescence with adolescent hepatic fat and whether the PNPLA3 rs738409 risk allele, a strong genetic risk factor for hepatic fat, modifies associations. STUDY DESIGN: Data were from 358 participants in the Exploring Perinatal Outcomes among CHildren (EPOCH) study, a longitudinal cohort in Colorado. Diet was assessed by food frequency questionnaire in childhood (approximately 10 years of age) and adolescence (approximately 16 years of age) and converted to nutrient densities. Hepatic fat was assessed in adolescence by magnetic resonance imaging. Linear regression was used to test associations of dietary changes from childhood to adolescence with adolescent hepatic fat. RESULTS: Increases in fiber, vegetable protein, and polyunsaturated fat intake from childhood to adolescence were associated with lower adolescent hepatic fat, and increases in animal protein were associated with higher hepatic fat (ß per 5-unit increase on log-hepatic fat: -0.12 [95% CI, -0.21 to -0.02] for ▵fiber; -0.26 [95% CI, -0.45 to -0.07] for ▵vegetable protein; -0.18 [95% CI, -0.35 to -0.02] for ▵polyunsaturated fat; 0.13 [95% CI, 0.04-0.22] for ▵animal protein). There was evidence of effect modification by PNPLA3 variant, whereby inverse associations of ▵fiber and ▵vegetable protein and positive associations of ▵saturated fat with adolescent hepatic fat were stronger in risk allele carriers. Most conclusions were similar after adjusting for obesity in adolescence, but associations of ▵saturated fat with hepatic fat were attenuated toward the null. CONCLUSIONS: Our results suggest that nutrient intake changes between childhood and adolescence, particularly decreases in fiber and vegetable protein and increases in saturated fat intake, interact with the PNPLA3 variant to predict higher hepatic fat in adolescence, and may be targets for reducing hepatic fat in high-risk youth.

Persistent effects of in utero overnutrition on offspring adiposity: the Exploring Perinatal Outcomes among Children (EPOCH) study.

AIMS/HYPOTHESIS: We previously showed that intrauterine exposure to gestational diabetes mellitus (GDM) increases selected markers of adiposity in pre-pubertal adolescents. In the present study, we examined these associations in adolescence, and explored whether they are strengthened as the participants transition through puberty. METHODS: Data from 597 individuals (505 unexposed, 92 exposed) participating in the longitudinal Exploring Perinatal Outcomes among Children (EPOCH) study in Colorado were collected at two research visits when the participants were, on average, 10.4 and 16.7 years old. Adiposity measures included BMI, waist/height ratio, and visceral and subcutaneous adipose tissue (as determined by MRI). Separate general linear mixed models were used to assess the longitudinal relationships between exposure to maternal GDM and each adiposity outcome. We tested whether the effect changed over time by including an interaction term between exposure and age in our models, and whether the associations were explained by postnatal behaviours. RESULTS: Compared with unexposed participants, those exposed to maternal GDM had higher BMI (ß = 1.28; 95% CI 0.35, 2.21; p < 0.007), waist/height ratio (ß = 0.03; 95% CI 0.01, 0.04; p = 0.0004), visceral adipose tissue (ß = 4.81; 95% CI 1.08, 8.54; p = 0.01) and subcutaneous adipose tissue (ß = 35.15; 95% CI 12.43, 57.87; p < 0.003). The magnitude of these differences did not change over time and the associations did not appear to be explained by postnatal behaviours. CONCLUSIONS/INTERPRETATION: Our data provide further evidence that intrauterine exposure to maternal GDM is associated with increased offspring adiposity, an effect that appears early in life and tracks throughout adolescence. Efforts to prevent childhood obesity following intrauterine exposure to maternal GDM should target the prenatal or early life periods.

Youth with type 2 diabetes have hepatic, peripheral, and adipose insulin resistance.

Adolescents with type 2 diabetes (T2D) have severe insulin resistance (IR) secondary to obesity, genetics, and puberty, and IR predicts metabolic comorbidities. Adults with T2D have multitissue IR, which has guided therapeutic developments, but this is not established in youth. We sought to assess adipose, hepatic, and peripheral insulin sensitivity in adolescents with and without T2D. Twenty-seven youth with T2D [age: 15.6 ± 0.4 yr; female: 78%; body mass index (BMI) percentile: 96.1 (52.6, 95.9), late puberty; hemoglobin A1c (HbA1c) 7.3% (6.2, 10.1)] and 21 controls of similar BMI, pubertal stage, and habitual activity were enrolled. Insulin action was measured with a four-phase hyperinsulinemic-euglycemic clamp (basal, 10, 16, and 80 mU·m-2·min-1 for studying adipose, hepatic, and peripheral IR, respectively) with glucose and glycerol isotope tracers. Total fat mass, fat-free mass, liver fat fraction, and visceral fat were measured with dual-energy x-ray absorptiometry (DXA) and MRI, respectively. Free fatty acids (FFAs), lipid profile, and inflammatory markers were also measured. Adolescents with T2D had higher lipolysis ( P = 0.012), endogenous glucose production ( P < 0.0001), and lower glucose clearance ( P = 0.002) during hyperinsulinemia than controls. In T2D, peripheral IR positively correlated to FFA ( P < 0.001), inflammatory markers, visceral ( P = 0.004) and hepatic fat ( P = 0.007); hepatic IR correlated with central obesity ( P = 0.004) and adipose IR ( P = 0.003). Youth with T2D have profound multitissue IR compared with BMI-equivalent youth without T2D. The development of multitissue interactions appears crucial to the pathogenesis of T2D. Therapeutic targets on multitissue IR may be of benefit, deserving of further research.

Clinical prediction score of nonalcoholic fatty liver disease in adolescent girls with polycystic ovary syndrome (PCOS-HS index).

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is common in obese adolescents with polycystic ovary syndrome (PCOS), but there are no inexpensive ways to accurately identify NAFLD in PCOS. The objective was to develop a simple clinical score to screen for NAFLD risk in obese adolescents with PCOS. DESIGN: This is a secondary analysis of 3 cross-sectional studies on metabolic characterization of obese adolescents with PCOS. 108 overweight and obese adolescents with PCOS (BMI > 90th percentile, age 12-19 years) were enrolled from 2012 to 2018. METHODS: Magnetic resonance imaging was used to quantify hepatic fat fraction (HFF). A development cohort of 87 girls were divided by presence of NAFLD (HFF > 5.5%). A logistic regression model with the outcome of NAFLD and candidate predictor variables was fit. A simplified model (PCOS-HS index) was created using backwards stepdown elimination. Validation was performed using 200 bootstrapped sample and in a second cohort of 21 PCOS participants. RESULTS: 52% of the development cohort had NAFLD. The PCOS-HS index that included BMI percentile, waist circumference, ALT and SHBG had an AUCROC of 0.81, sensitivity 82%, specificity 69%, negative predictive value (NPV) 78% and positive predictive value 74%, using a threshold of 0.44 to predict HS. A threshold of 0.15 ruled out NAFLD with a NPV 90%. In the validation cohort, the model showed an accuracy of 81%, sensitivity of 91% and specificity of 70%. CONCLUSIONS: We developed a clinical index to identify NAFLD in girls with PCOS who would need further evaluation and treatment.

Investigation of Low-Dose CT Lung Cancer Screening Scan "Over-Range" Issue Using Machine Learning Methods.

Low-dose computed tomography (CT) lung cancer screening is recommended by the US Preventive Services Task Force for high lung cancer-risk populations. In this study, we investigated an important factor affecting the CT dose-the scan length, for this CT exam. A neural network model based on the "UNET" framework was established to segment the lung region in the CT scout images. It was trained initially with 247 chest X-ray images and then with 40 CT scout images. The mean Intersection over Union (IOU) and Dice coefficient were reported to be 0.954 and 0.976, respectively. Lung scan boundaries were determined from this segmentation and compared with the boundaries marked by an expert for 150 validation images, resulting an average 4.7% difference. Seven hundred seventy CT low-dose lung screening exams were retrospectively analyzed with the validated model. The average "desired" scan length was 252 mm with a standard deviation of 28 mm. The average "over-range" was 58.5 mm or 24%. The upper boundary (superior) on average had an "over-range" of 17 mm, and the lower boundary (inferior) on average had an "over-range" of 41 mm. Further analysis of this data showed that the extent of "over-range" was independent of acquisition date, acquisition time, acquisition station, and patient age, but dependent on technologist and patient weight. We concluded that this machine learning method could effectively support quality control on the scan length for CT low-dose screening scans, enabling the eliminations of unnecessary patient dose.

Fetal Overnutrition and Adolescent Hepatic Fat Fraction: the Exploring Perinatal Outcomes in Children Study.

OBJECTIVE: To determine if fetal overnutrition resulting from maternal obesity or gestational diabetes mellitus (GDM) is associated with increased liver fat during adolescence, adjusting for past and current metabolic risk factors. STUDY DESIGN: Data come from a historical prospective cohort study (Exploring Perinatal Outcomes in Children) of 254 mother-child pairs in Colorado who participated in 2 research visits at T1 (mean age 10.4, SD = 1.5 years) and at T2 (mean age 16.4, SD = 1.5 years), and had complete exposure and outcome data. Multiple linear regression was used to evaluate the effects of pre-pregnancy body mass index (BMI) and GDM on hepatic fat fraction (HFF) by magnetic resonance imaging at T2. RESULTS: Maternal pre-pregnancy obesity (BMI 30+) was significantly associated (ß = 1.59, CI = 0.66, 2.52) with increased HFF relative to mothers with normal pre-pregnancy weight (BMI <25) independent of maternal GDM and sociodemographic factors. Moreover, this association was independent of T2 and T1 metabolic risk factors (acanthosis nigricans, BMI, fasting glucose) (ß = 1.03, CI = 0.10, 1.97). Prenatal GDM exposure was not associated with HFF in either unadjusted or adjusted models. CONCLUSIONS: Maternal pre-pregnancy obesity was associated with increased HFF in offspring independent of childhood and adolescent adiposity. Intervention studies are needed to test the hypothesis that maternal obesity is a modifiable risk factor for childhood fatty liver disease.

Imaging acquisition display performance: an evaluation and discussion of performance metrics and procedures.

When The Joint Commission updated its Requirements for Diagnostic Imaging Services for hospitals and ambulatory care facilities on July 1, 2015, among the new requirements was an annual performance evaluation for acquisition workstation displays. The purpose of this work was to evaluate a large cohort of acquisition displays used in a clinical environment and compare the results with existing performance standards provided by the American College of Radiology (ACR) and the American Association of Physicists in Medicine (AAPM). Measurements of the minimum luminance, maximum luminance, and luminance uniformity, were performed on 42 acquisition displays across multiple imaging modalities. The mean values, standard deviations, and ranges were calculated for these metrics. Additionally, visual evaluations of contrast, spatial resolution, and distortion were performed using either the Society of Motion Pictures and Television Engineers test pattern or the TG-18-QC test pattern. Finally, an evaluation of local nonuniformities was performed using either a uniform white display or the TG-18-UN80 test pattern. Displays tested were flat panel, liquid crystal displays that ranged from less than 1 to up to 10 years of use and had been built by a wide variety of manufacturers. The mean values for Lmin and Lmax for the displays tested were 0.28 ± 0.13 cd/m2 and 135.07 ± 33.35 cd/m2, respectively. The mean maximum luminance deviation for both ultrasound and non-ultrasound displays was 12.61% ± 4.85% and 14.47% ± 5.36%, respectively. Visual evaluation of display performance varied depending on several factors including brightness and contrast settings and the test pattern used for image quality assessment. This work provides a snapshot of the performance of 42 acquisition displays across several imaging modalities in clinical use at a large medical center. Comparison with existing performance standards reveals that changes in display technology and the move from cathode ray tube displays to flat panel displays may have rendered some of the tests inappropriate for modern use.

ADP-Ribosylation Factor-Interacting Protein 2 Acts as a Novel Regulator of Mitophagy and Autophagy in Podocytes in Diabetic Nephropathy.

(1) Background: Differentiated podocytes are particularly vulnerable to oxidative stress and cellular waste products. The disease-related loss of postmitotic podocytes is a direct indicator of renal disease progression and aging. Podocytes use highly specific regulated networks of autophagy and endocytosis that counteract the increasing number of damaged protein aggregates and help maintain cellular homeostasis. Here, we demonstrate that ARFIP2 is a regulator of autophagy and mitophagy in podocytes both in vitro and in vivo. (2) Methods: In a recent molecular regulatory network analysis of mouse glomeruli, we identified ADP-ribosylation factor-interacting protein 2 (Arfip2), a cytoskeletal regulator and cofactor of ATG9-mediated autophagosome formation, to be differentially expressed with age. We generated an Arfip2-deficient immortalized podocyte cell line using the CRISPR/Cas technique to investigate the significance of Arfip2 for renal homeostasis in vitro. For the in vivo analyses of Arfip2 deficiency, we used a mouse model of Streptozotozin-induced type I diabetes and investigated physiological data and (patho)histological (ultra)structural modifications. (3) Results: ARFIP2 deficiency in immortalized human podocytes impedes autophagy. Beyond this, ARFIP2 deficiency in human podocytes interferes with ATG9A trafficking and the PINK1-Parkin pathway, leading to the compromised fission of mitochondria and short-term increase in mitochondrial respiration and induction of mitophagy. In diabetic mice, Arfip2 deficiency deteriorates autophagy and leads to foot process effacement, histopathological changes, and early albuminuria. (4) Conclusions: In summary, we show that ARFIP2 is a novel regulator of autophagy and mitochondrial homeostasis in podocytes by facilitating ATG9A trafficking during PINK1/Parkin-regulated mitophagy.

Intrahepatic fat is increased in the neonatal offspring of obese women with gestational diabetes.

OBJECTIVES: To assess precision magnetic resonance imaging in the neonate and determine whether there is an early maternal influence on the pattern of neonatal fat deposition in the offspring of mothers with gestational diabetes mellitus (GDM) and obesity compared with the offspring of normal-weight women. STUDY DESIGN: A total of 25 neonates born to normal weight mothers (n = 13) and to obese mothers with GDM (n = 12) underwent magnetic resonance imaging for the measurement of subcutaneous and intra-abdominal fat and magnetic resonance spectroscopy for the measurement of intrahepatocellular lipid (IHCL) fat at 1-3 weeks of age. RESULTS: Infants born to obese/GDM mothers had a mean 68% increase in IHCL compared with infants born to normal-weight mothers. For all infants, IHCL correlated with maternal prepregnancy body mass index but not with subcutaneous adiposity. CONCLUSION: Deposition of liver fat in the neonate correlates highly with maternal body mass index. This finding may have implications for understanding the developmental origins of childhood nonalcoholic fatty liver disease.

Adiposity, fat patterning, and the metabolic syndrome among diverse youth: the EPOCH study.

OBJECTIVES: To assess fat distribution, prevalence of obesity, and the metabolic syndrome among diverse 6-13-year-old Colorado youth to better understand racial/ethnic influences on adiposity and metabolic syndrome. STUDY DESIGN: We measured body mass index, subscapular-to-triceps skinfold ratio, waist circumference, dietary fat, and physical activity in 422 youth (47% non-Hispanic White, 44% Hispanic, and 9% African-American). Visceral adipose tissue, subcutaneous adipose tissue, and intramyocellular lipid were measured with magnetic resonance techniques. Multiple-linear regression was used to assess associations between race/ethnicity and adiposity patterns. RESULTS: Hispanic and African-American youth had a higher prevalence of obesity and metabolic syndrome compared with non-Hispanic White youth. Both groups displayed a more centralized fat distribution and larger volumes of subcutaneous tissue, compared with non-Hispanic White youth. After controlling for body mass index, these differences were attenuated, and for a given body size, African-American youth showed significantly lower visceral adipose tissue than non-Hispanic White youth. However, both Hispanic and African-American youth showed higher intermyocellular lipid in skeletal muscle compared with non-Hispanic Whites, independent of body size. CONCLUSIONS: Racial/ethnic minorities experience higher overall adiposity, and may also have an increased risk for early development of metabolic syndrome relative to non-Hispanic White youth, beyond their increased obesity risk.

Exposure to maternal fuels during pregnancy and offspring hepatic fat in early childhood: The healthy start study.

BACKGROUND: Intrauterine overnutrition has been associated with paediatric nonalcoholic fatty liver disease (NAFLD), but the exact mechanisms involved remain unclear. OBJECTIVE: To examine whether maternal fuels and metabolic markers during pregnancy are associated with offspring hepatic fat in childhood. METHODS: This analysis included 286 mother-child pairs from the Healthy Start Study, a longitudinal pre-birth cohort in Colorado. Fasting blood draws were collected in early pregnancy (~17 weeks) and mid-pregnancy (~27 weeks). Offspring hepatic fat was assessed by magnetic resonance imaging (MRI) at ~5 years. RESULTS: In early pregnancy, maternal triglycerides (TGs) and free fatty acids (FFAs) were positively associated with offspring hepatic fat [Back-transformed ß (95% CI): 1.15 (1.05, 1.27) per 1 standard deviation (SD) TGs; 1.14 (1.05, 1.23) per 1 SD FFAs]. Maternal total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were also associated with offspring hepatic fat, but only among boys [1.22 (1.08, 1.37) per 1 SD TC; 1.21 (1.07, 1.37) per 1 SD LDL-C]. In mid-pregnancy, only maternal TGs remained associated with offspring hepatic fat. Adjusting for potential confounders or mediators did not affect associations. CONCLUSIONS: Maternal lipid concentrations, especially in early pregnancy, are associated with higher offspring hepatic fat, and may, therefore, be targeted in future interventions among pregnant women.

Childhood nutrient intakes are differentially associated with hepatic and abdominal fats in adolescence: The EPOCH study.

OBJECTIVE: The aim of this study was to examine whether nutrient intakes in childhood are associated with abdominal and hepatic fat depots later in adolescence. METHODS: Using data from 302 participants in the longitudinal Exploring Perinatal Outcomes among CHildren (EPOCH) study, energy partition and nutrient density models were constructed to examine associations of nutrient intakes in childhood (~10 years of age), assessed by food frequency questionnaire, with abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and hepatic fat in adolescence (~16 years of age). RESULTS: In energy partition models (energy intake not held constant), total, monounsaturated, and polyunsaturated fat intakes in childhood were associated with higher SAT in adolescence (ß [95% CI]: 8.5 [0.1-17.1], 25.1 [2.1-48.1], and 59.7 [16.1-103.3] mm2 per 100 kcal/d), higher starch intake was associated with log-hepatic fat (back-transformed ß [95% CI]: 1.07 [1.01-1.15] per 100 kcal/d), and, in boys only, higher animal protein intake was associated with VAT (ß [95% CI]: 5.3 [0.3-10.3] mm2 per 100 kcal/d). Most associations were unchanged when adjusted for energy intake in nutrient density models. CONCLUSIONS: Childhood nutrient intakes were differentially associated with adolescent body fats; specifically, unsaturated fat intake predicted abdominal SAT, animal protein intake predicted VAT, and starch intake predicted hepatic fat. These nutrient intakes may, therefore, be targets for intervention studies aiming to modify adolescent body fat distribution.

Pancreatic fat relates to fasting insulin and postprandial lipids but not polycystic ovary syndrome in adolescents with obesity.

OBJECTIVE: Adolescents with polycystic ovary syndrome (PCOS) and obesity can have insulin resistance, dysglycemia, and hepatic steatosis. Excess pancreatic fat may disturb insulin secretion and relate to hepatic fat. Associations between pancreatic fat fraction (PFF) and metabolic measures in PCOS were unknown. METHODS: This secondary analysis included 113 sedentary, nondiabetic adolescent girls (age = 15.4 [1.9] years), with or without PCOS and BMI ≥ 90th percentile. Participants underwent fasting labs, oral glucose tolerance tests, and magnetic resonance imaging for hepatic fat fraction (HFF) and PFF. Groups were categorized by PFF (above or below the median of 2.18%) and compared. RESULTS: Visceral fat and HFF were elevated in individuals with PCOS versus control individuals, but PFF was similar. PFF did not correlate with serum androgens. Higher and lower PFF groups had similar HFF, with no correlation between PFF and HFF, although hepatic steatosis was more common in those with higher PFF (≥5.0% HFF; 60% vs. 36%; p = 0.014). The higher PFF group had higher fasting insulin (p = 0.026), fasting insulin resistance (homeostatic model assessment of insulin resistance, p = 0.032; 1/fasting insulin, p = 0.028), free fatty acids (p = 0.034), and triglycerides (p = 0.004) compared with those with lower PFF. ß-Cell function and insulin sensitivity were similar between groups. CONCLUSIONS: Neither PCOS status nor androgens related to PFF. However, fasting insulin and postprandial lipids were worse with higher PFF.

Body composition trajectories from birth to 5 years and hepatic fat in early childhood.

BACKGROUND: Adiposity is an established risk factor for pediatric nonalcoholic fatty liver disease (NAFLD), but little is known about the influence of body composition patterns earlier in life on NAFLD risk. OBJECTIVES: We aimed to examine associations of body composition at birth and body composition trajectories from birth to early childhood with hepatic fat in early childhood. METHODS: Data were from the longitudinal Healthy Start Study in Colorado. Fat-free mass index (FFMI), fat mass index (FMI), percentage body fat (BF%), and BMI were assessed at birth and/or ∼5 y in >1200 children by air displacement plethysmography and anthropometrics. In a subset (n = 285), hepatic fat was also assessed at ∼5 y by MRI. We used a 2-stage modeling approach: first, we fit body composition trajectories from birth to early childhood using mixed models with participant-specific intercepts and linear slopes (i.e., individual deviations from the population average at birth and rate of change per year, respectively); second, associations of participant-specific trajectory deviations with hepatic fat were assessed by multivariable-adjusted linear regression. RESULTS: Participant-specific intercepts at birth for FFMI, FMI, BF%, and BMI were inversely associated with log-hepatic fat in early childhood in models adjusted for offspring demographics and maternal/prenatal variables [back-transformed ß (95% CI) per 1 SD: 0.93 (0.88, 0.99), 0.94 (0.88, 0.99), 0.94 (0.89, 0.99), and 0.90 (0.85, 0.96), respectively]. Whereas, faster velocities for BF% and BMI from birth to ∼5 y were positively associated with log-hepatic fat [back-transformed ß (95% CI) per 1 SD: 1.08 (1.01, 1.15) and 1.08 (1.02, 1.15), respectively]. These latter associations of BF% and BMI velocities with childhood hepatic fat were attenuated to the null when adjusted for participant-specific intercepts at birth. CONCLUSIONS: Our findings suggest that a smaller birth weight, combined with faster adiposity accretion in the first 5 y, predicts higher hepatic fat in early childhood. Strategies aiming to promote healthy body composition early in life may be critical for pediatric NAFLD prevention.This study was registered voluntarily at clinicaltrials.gov as NCT02273297.

Association of PNPLA3 with non-alcoholic fatty liver disease in a minority cohort: the Insulin Resistance Atherosclerosis Family Study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition, particularly among Hispanic Americans. A genetic variant in PNPLA3 (rs738409) has been identified as a strong predictor of hepatic fat content. AIMS: To confirm the association of this variant with NAFLD in two minority cohorts, Hispanic Americans and African Americans, in whom liver density was quantified by computed tomography (CT). METHODS: This analysis was conducted in the Insulin Resistance Atherosclerosis (IRAS) Family Study. Participants were recruited from the general community and included 843 Hispanic American and 371 African American adults aged 18-81 years. A single variant in PNPLA3 (rs738409) was genotyped. Liver density was calculated in Hounsfield Units from abdominal CT scans. RESULTS: Single nucleotide polymorphism (SNP) rs738409 was strongly associated with reduced liver density (i.e. NAFLD) in Hispanic Americans (1.18 × 10⁻9) and in African Americans (P=4.99 × 10⁻6). The association followed an additive genetic model with the G allele conferring risk. The allele was two times more common in Hispanic Americans than in African Americans (40 vs 19%), consistent with the greater prevalence of NAFLD in Hispanic Americans (24 vs 9%). The SNP explained 4.4 and 5.6% of the variance of the adjusted liver density outcome in Hispanic Americans and African Americans, respectively. CONCLUSIONS: We confirmed the association of a PNPLA3 variant with NAFLD in Hispanic Americans and African Americans, suggesting that PNPLA3 contributes to the variation in NAFLD across multiple ethnicities. This study adds to the growing evidence that some of the ethnic variation in NAFLD is genetic.

Hepatic Fat in Early Childhood Is Independently Associated With Estimated Insulin Resistance: The Healthy Start Study.

BACKGROUND: Fatty liver disease is a common metabolic abnormality in adolescents with obesity but remains understudied in early childhood. OBJECTIVES: To describe hepatic fat deposition in prepubertal children and examine cross-sectional associations with metabolic markers and body composition. METHODS: Data were from 286 children ages 4 to 8 years old in the Healthy Start Study, a longitudinal prebirth cohort in Colorado (USA). Assessments included magnetic resonance imaging to quantify hepatic and abdominal fats, fasting blood draws to measure metabolic markers, and air displacement plethysmography to measure body composition (fat mass and fat-free mass). RESULTS: The median (interquartile range) for hepatic fat was 1.65% (1.24%, 2.11%). Log-transformed hepatic fat was higher in Hispanic [mean (95% CI): 0.63 (0.52, 0.74)] vs non-Hispanic white children [0.46 (0.38, 0.53), P = 0.01] and children with overweight/obesity [0.64 (0.49, 0.79)] vs normal-weight [0.47 (0.40, 0.53), P = 0.02]. Higher log-hepatic fat was associated with higher insulin [ß (95% CI): 1.47 (0.61, 2.33) uIU/mL, P = 0.001] and estimated insulin resistance (homeostatic model assessment) [0.40 (0.20, 0.60), P < 0.001] in the full sample and glucose [5.53 (2.84, 8.21) mg/dL, P < 0.001] and triglycerides [10.92 (2.92,18.91) mg/dL, P = 0.008] in boys, in linear regression models adjusted for sociodemographics, maternal/perinatal confounders, and percentage body fat. Log-hepatic fat was also associated with abdominal subcutaneous adipose tissue [SAT; 7.37 (1.12,13.60) mm2, P = 0.02] in unadjusted models, but this was attenuated and insignificant after adjusting for confounders. CONCLUSIONS: While hepatic fat was low in children 4 to 8 years old, it was independently associated with estimated insulin resistance and exhibited sex-specific associations with glucose and triglycerides, suggesting hepatic fat may be an early indicator of metabolic dysfunction in youth.

A Prudent dietary pattern is inversely associated with liver fat content among multi-ethnic youth.

OBJECTIVES: To identify dietary patterns associated with hepatic fat fraction (HFF), a measure of liver fat content and risk factor for non-alcoholic fatty liver disease, in a prospective study of 397 multi-ethnic youth. METHODS: We obtained information on habitual dietary intake via the Block Kids Food Frequency Questionnaire at age 6 to 15 years ('T1') and 12 to 19 years ('T2'), and measured HFF using magnetic resonance imaging at T2. We derived dietary patterns via principal components analysis and examined associations with ln-transformed HFF using linear regression models that accounted for maternal education, gestational diabetes exposure and smoking habits; and child pubertal status, BMI and physical activity. RESULTS: At T1, none of the dietary patterns identified were associated with HFF measured at T2. At T2, a Prudent dietary pattern characterized by high fruit and vegetable intake was inversely associated with HFF (-0.08 [95% CI: -0.16, -0.00]). Similarly, increased adherence to the Prudent pattern across T1 and T2 corresponded with lower ln-HFF (-0.11 [-0.18, -0.04] units). On the other hand, adherence to a Western pattern comprising fried foods and refined carbohydrates at T2 correlated with higher HFF among non-Hispanic White participants (0.16 [0.06, 0.26]). These findings persisted after accounting for child BMI. CONCLUSIONS: Even in healthy youth, a diet high in fruits and vegetables is associated with lower HFF, whereas a diet high in fried foods and refined carbohydrates is related to higher HFF. Dietary changes may serve as an early preventive measure to mitigate liver fat accrual.

Tesamorelin improves fat quality independent of changes in fat quantity.

OBJECTIVES: Fat quality and quantity may affect health similarly or differently. Fat quality can be assessed by measuring fat density on CT scan (greater density = smaller, higher quality adipocytes). We assessed the effects of tesamorelin, a growth hormone-releasing hormone analogue that reduces visceral fat (VAT) quantity in some people living with HIV (PWH), on fat density. DESIGN: Participants from two completed, placebo-controlled, randomized trials of tesamorelin for central adiposity treatment in PWH were included if they had either a clinical response to tesamorelin (VAT decrease ≥8%, ≈70% of participants) or were placebo-treated. METHODS: CT VAT and subcutaneous fat (SAT) density (Hounsfield Units, HU) were measured by a central blinded reader. RESULTS: Participants (193 responders, 148 placebo) were 87% male and 83% white. Baseline characteristics were similar across arms, including VAT (-91 HU both arms, P = 0.80) and SAT density (-94 HU tesamorelin, -95 HU placebo, P = 0.29). Over 26 weeks, mean (SD) VAT and SAT density increased in tesamorelin-treated participants only [VAT: +6.2 (8.7) HU tesamorelin, +0.3 (4.2) HU placebo, P < 0.0001; SAT: +4.0 (8.7) HU tesamorelin, +0.3 (4.8) HU placebo, P < 0.0001]. The tesamorelin effects persisted after controlling for baseline VAT or SAT HU and area, and VAT [+2.3 HU, 95% confidence interval (4.5-7.3), P = 0.001) or SAT (+3.5 HU, 95% confidence interval (2.3-4.7), P < 0.001] area change. CONCLUSION: In PWH with central adiposity who experienced VAT quantity reductions on tesamorelin, VAT and SAT density increased independent of changes in fat quantity, suggesting that tesamorelin also improves VAT and SAT quality in this group.