Faculty Bibliography

CONTEXT/BACKGROUND:Overweight and obesity are associated with relative growth hormone (GH) deficiency, which has been implicated in the development of nonalcoholic fatty liver disease (NAFLD). NAFLD is a progressive disease without effective treatments. OBJECTIVE:We hypothesized that GH administration would reduce hepatic steatosis in individuals with overweight/obesity and NAFLD. METHODS:In this 6-month randomized, double-blind, placebo-controlled trial of low-dose GH administration, 53 adults aged 18 to 65 years with BMI ≥25 kg/m2 and NAFLD without diabetes were randomized to daily subcutaneous GH or placebo, targeting insulin-like growth factor 1 (IGF-1) to the upper normal quartile. The primary endpoint was intrahepatic lipid content (IHL) by proton magnetic resonance spectroscopy (1H-MRS) assessed before treatment and at 6 months. RESULTS:Subjects were randomly assigned to a treatment group (27 GH; 26 placebo), with 41 completers (20 GH and 21 placebo) at 6 months. Reduction in absolute % IHL by 1H-MRS was significantly greater in the GH vs placebo group (mean ± SD: -5.2 ± 10.5% vs 3.8 ± 6.9%; P = .009), resulting in a net mean treatment effect of -8.9% (95% CI, -14.5 to -3.3%). All side effects were similar between groups, except for non-clinically significant lower extremity edema, which was more frequent in the GH vs placebo group (21% vs 0%, P = .02). There were no study discontinuations due to worsening of glycemic status, and there were no significant differences in change in glycemic measures or insulin resistance between the GH and placebo groups. CONCLUSION/CONCLUSIONS:GH administration reduces hepatic steatosis in adults with overweight/obesity and NAFLD without worsening glycemic measures. The GH/IGF-1 axis may lead to future therapeutic targets for NAFLD.

CONTEXT/BACKGROUND:Obesity is associated with nonalcoholic fatty liver disease (NAFLD). Sleeve gastrectomy (SG) is an effective means of weight loss and improvement of NAFLD in adults; however, data regarding the efficacy of SG in the early stages of pediatric NAFLD are sparse. OBJECTIVE:To assess the impact of SG on hepatic fat content 1 year after SG in youth with obesity compared with nonsurgical controls with obesity (NS). DESIGN/METHODS:A 12-month prospective study in 52 participants (mean age, 18.2 ± .36 years) with obesity, comprising 25 subjects who underwent SG (84% female; median body mass index [BMI], 44.6 [42.1-47.9] kg/m2) and 27 who were NS (70% female; median BMI, 42.2 [38.7-47.0] kg/m2). MAIN OUTCOME MEASURES/METHODS:Hepatic fat content by computed tomography (liver/spleen ratio), abdominal fat by magnetic resonance imaging. RESULTS:Mean 12-month decrease in BMI was greater in SG vs NS (-12.5 ± .8 vs -.2 ± .5 kg/m2, P < .0001). There was a within-group increase in the liver-to-spleen (L/S) ratio in SG (.13 ± .05, P = .014) but not NS with a trend for a difference between groups (P = .055). All SG participants with an L/S ratio <1.0 (threshold for the diagnosis of NAFLD) before surgery had a ratio of >1.0 a year after surgery, consistent with resolution of NAFLD. Within SG, the 12-month change in L/S ratio was negatively associated with 12-month change in visceral fat (ρ = -.51 P = .016). CONCLUSIONS:Hepatic fat content as assessed by noncontrast computed tomography improved after SG over 1 year in youth with obesity with resolution of NAFLD in all subjects. This was associated with decreases in visceral adiposity.

Sleeve gastrectomy (SG) has many metabolic benefits and leads to improvements in testosterone levels, which means improvement in the Leydig cell function of the testis. However, data about the effects of SG on Sertoli cell function (as assessed by inhibin B) are not available. In this preliminary study, we evaluate, for the first time, the effect of SG in adolescents after SG. We evaluate 16 adolescent and young adult males, six of whom underwent SG and followed them for 2 years. We report that Leydig cell function (as assessed by testosterone levels) improved and was associated with degree of weight loss. Sertoli cell function improved only slightly in SG group and did not change compared to the nonsurgical controls, and these changes were not associated with degree of weight loss. Thus, we conclude that larger and long-term follow-up studies are required to evaluate the changes in Sertoli cell function after SG as that is integral to male fertility.Clinical Trial Registration: NCT02557438.

PURPOSE/UNASSIGNED:To develop a deep learning algorithm capable of extracting pectoralis muscle and adipose measurements and to longitudinally investigate associations between these measurements and incident heart failure (HF) in participants from the Multi-Ethnic Study of Atherosclerosis (MESA). MATERIALS AND METHODS/UNASSIGNED:MESA is a prospective study of subclinical cardiovascular disease characteristics and risk factors for progression to clinically overt disease approved by institutional review boards of six participating centers (ClinicalTrials.gov identifier: NCT00005487). All participants with adequate imaging and clinical data from the fifth examination of MESA were included in this study. Hence, in this secondary analysis, manual segmentations of 600 chest CT examinations (between the years 2010 and 2012) were used to train and validate a convolutional neural network, which subsequently extracted pectoralis muscle and adipose (intermuscular adipose tissue (IMAT), perimuscular adipose tissue (PAT), extramyocellular lipids and subcutaneous adipose tissue) area measurements from 3031 CT examinations using individualized thresholds for adipose segmentation. Next, 1781 participants without baseline HF were longitudinally investigated for associations between baseline pectoralis muscle and adipose measurements and incident HF using crude and adjusted Cox proportional hazards models. The full models were adjusted for variables in categories of demographic (age, race, sex, income), clinical/laboratory (including physical activity, BMI, and smoking), CT (coronary artery calcium score), and cardiac MRI (left ventricular ejection fraction and mass (% of predicted)) data. RESULTS/UNASSIGNED:In 1781 participants (median age, 68 (IQR,61, 75) years; 907 [51%] females), 41 incident HF events occurred over a median 6.5-year follow-up. IMAT predicted incident HF in unadjusted (hazard ratio [HR]:1.14; 95% CI: 1.03-1.26) and fully adjusted (HR:1.16, 95% CI: 1.03-1.31) models. PAT also predicted incident HF in crude (HR:1.19; 95% CI: 1.06-1.35) and fully adjusted (HR:1.25; 95% CI: 1.07-1.46) models. CONCLUSION/UNASSIGNED:The study demonstrates that fast and reliable deep learning-derived pectoralis muscle and adipose measurements are obtainable from conventional chest CT, which may be predictive of incident HF.©RSNA, 2023.

OBJECTIVE:To determine mechanisms contributing to impaired bone health in youth 24 months following sleeve gastrectomy (SG). DESIGN/METHODS:Twenty-four-month longitudinal observational study. METHODS:Participants included 23 youth undergoing SG and 30 non-surgical controls (NS) 13-25 years old with moderate-to-severe obesity. Subjects underwent fasting labs for bone turnover markers (N-terminal propeptide of type 1 procollagen, C-telopeptide (CTX)), sex hormones, sex hormone binding globulin (SHBG), and enteric peptides, DXA for areal bone mineral density (aBMD) and body composition, high-resolution peripheral quantitative CT for volumetric BMD (vBMD) at the distal radius and tibia, and microfinite element analysis for strength estimates. RESULTS:Groups did not differ for mean age or BMI z-scores. Over 24 months, compared to NS, SG had greater reductions in BMI z-scores, and spine, hip, and femoral neck aBMD Z-scores (P ≤ .012), greater increases in serum CTX and SHBG (P ≤ .039), and greater decreases in estrone and ghrelin (P ≤ .021). Among females, estrone and free androgen index (FAI) decreased (P ≤ .022) in SG vs NS groups. After controlling for age and sex, decreases in BMI and lean mass were associated with decreases in total hip and femoral neck aBMD Z-scores, and decreases in radial total and trabecular vBMD and failure load, and tibial total and trabecular vBMD. Among females, after controlling for age, decreases in estrone were associated with decreases in spine aBMD Z-scores and radial total and trabecular vBMD, and decrease in FAI with decreases in radial failure load. CONCLUSION/CONCLUSIONS:Reductions in BMI, lean mass, and sex steroids over 24 months post-SG are associated with bone loss and could be targeted for preventative or therapeutic interventions. Clinical trial registration number: The study is registered in ClinicalTrials.gov (NCT02557438).

Adults with obesity have a reduction in branched-chain amino acid (BCAA) levels following metabolic and bariatric surgery (MBS), which is hypothesized to contribute to the metabolic advantages of MBS. We examined this relationship in 62 youth 13-24 years old with severe obesity (47 female) over 12 months. Thirty had sleeve gastrectomy (SG) and 32 were non-surgical controls (NS). We measured fasting insulin, glucose, glycated hemoglobin (HbA1c), isoleucine, leucine, and valine concentrations, and post-prandial insulin and glucose, following a mixed meal tolerance test. Twenty-four-hour food recalls were collected. At baseline, groups did not differ in the intake or the serum levels of BCAAs, HbA1C, HOMA-IR, Matsuda index, insulinogenic index, or oral Disposition index (oDI). Over 12 months, SG vs. NS had greater reductions in serum BCAAs, and SG had significant reductions in BCAA intake. SG vs. NS had greater reductions in HbA1c and HOMA-IR, with increases in the Matsuda index and oDI. In SG, baseline leucine and total BCAA concentrations were negatively correlated with the baseline Matsuda index. Reductions in serum leucine were positively associated with the reductions in HOMA-IR over 12 months. These associations suggest a potential role of BCAA in regulating metabolic health. Reducing dietary intake and serum BCAA concentrations may reduce insulin resistance.