Poorer Muscle Quality and Quantity With ART Initiation Is Associated With Greater Inflammation and Immune Activation.

BACKGROUND: We have previously shown that the initiation of antiretroviral therapy (ART) is associated with a decrease in skeletal muscle density (greater fat accumulation), suggesting that gains in lean body mass seen in many ART studies may reflect gains in low quality, fatty muscle. Here, we explore whether skeletal muscle density and area are associated with markers of inflammation and immune activation. METHODS: ART-naïve people with HIV were randomized to raltegravir or ritonavir-boosted atazanavir or darunavir, each with tenofovir disoproxil fumarate/emtricitabine. Abdominal computed tomography scans from baseline and week 96 were reanalyzed for psoas density and area and correlations explored with inflammation [interleukin-6 (IL-6) and high-sensitivity C-reactive protein] and immune activation [soluble CD14 (sCD14), soluble CD163 (sCD163), and %CD38+HLADR+ on CD4+ or CD8+ T cells]. RESULTS: Two hundred twenty-two participants had available inflammation/immune activation markers and paired computed tomography scans. At baseline, lower psoas density (greater fat) correlated with higher IL-6 (r = -0.26, P < 0.001) and sCD163 (r -0.15, P = 0.03) and lower lean psoas area correlated with higher IL-6, high-sensitivity C-reactive protein, sCD14, sCD163, and %CD38+HLADR+ on CD4+ T cells (r = -0.30-0.13; all P ≤ 0.05). From baseline to week 96, greater percent decrease in total psoas density (more fat) correlated with greater increase in IL-6 (r = -0.14; P = 0.04); greater % decrease in lean psoas area correlated greater increases in IL-6, sCD14, sCD163, and %CD38+HLADR+ on CD8+ T cells (r = -0.15 to -0.18; all P < 0.04). CONCLUSIONS: Greater fat infiltration within the psoas muscle (lower density) and greater loss in lean psoas muscle area were associated with higher inflammation and immune activation, which may portend important effects on muscle function and cardiometabolic risk.

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.

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.

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.