Balagopal, Prabhakaran

Abstract Background Prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), and its sequelae of more severe forms such as metabolic dysfunction‐associated steatohepatitis (MASH) is rapidly increasing in children with the rise in obesity. Successful and sustainable treatments for MASLD are lacking in children. We determined the therapeutic effect of N ‐acetyl cysteine (NAC) on biomarkers of oxidative stress, inflammation and insulin resistance (IR), liver enzymes, liver fat fraction (LFF) and liver stiffness (LS) in children with obesity and biopsy‐confirmed MASLD. Methods Thirteen children ( n = 13; age: 13.6 ± 2.8 years; NAS score >2) underwent a double‐blind, placebo‐controlled trial of NAC (either 600 or 1200 mg NAC/day) or placebo for 16 weeks. Measurements included LFF (magnetic resonance imaging), LS (ultrasound elastography), and body composition. Erythrocyte glutathione (GSH), liver enzymes, insulin, glucose, adiponectin, high‐sensitivity c‐reactive protein (hs‐CRP), and interleukin‐6 (IL‐6) were also measured. homeostasis model assessment for insulin resistance (HOMA‐IR) was calculated. Results Sixteen‐week NAC treatment improved (baseline adjusted between‐group p < .05 for all) markers of inflammation (IL‐6 and hs‐CRP), oxidative stress (GSH), and IR (HOMA‐IR) and reduced liver enzymes, LFF and LS. Body weight and body composition did not show beneficial changes. Conclusions Sixteen‐week NAC treatment was well tolerated in children with obesity and MASLD and led to improvements in oxidative stress, inflammation and IR and liver outcomes. The results from this pilot study support further investigation of NAC as a therapeutic agent in children with MASLD.

Abstract Context Elevated concentrations of branched-chain amino acids (BCAA) are strong predictors of type 2 diabetes mellitus (T2DM). Their association with cardiovascular disease (CVD) remains uncertain, particularly in youth. Objective We investigated the role of BCAA and aromatic amino acids (AAA) in obesity, their relationships with novel biomarkers of CVD, and response to a physical activity-based lifestyle intervention (PAL-I) in a randomized controlled study in youth with normal weight (NW) and obesity (OB). Methods Age (14-18 years) and Tanner stage (≥IV) matched youth (OB, n = 15 and NW, n = 6) were studied; the 15 participants with OB underwent a 3-month randomized controlled PAL-I. Circulating amino acid profile, glucose, insulin, lipids, adiponectin, retinol binding protein-4, fibrinogen, high-sensitivity C-reactive protein, interleukin-6, and 25-hydroxy vitamin-D, along with body composition, were measured at baseline and after PAL-I. Independent t tests, analysis of covariance, and mixed-effect models were used for analysis of the data. Results Compared with NW, the concentration of various amino acids, including BCAA and AAA, were altered in OB (P &lt; 0.05). BCAA and AAA showed baseline correlations with body composition and novel biomarkers of CVD, particularly inflammatory factors (all P &lt; 0.05). The PAL-I produced only negligible effects (P &gt; 0.05) on BCAA and AAA. Glutamine, glycine, and aspartic acid decreased with PAL-I (all P &lt; 0.05). Conclusion The novel finding of the BCAA–inflammation relationship, along with strong correlations with nontraditional biomarkers of CVD, may raise the prospect of BCAA as a biomarker of CVD and evoke a potential link between obesity, T2DM, and CVD.

Abstract Low-grade inflammation associated with metabolic syndrome (MS) triggers alterations in several organs, but its effects on pulmonary functional and immunological response in older adults are unknown. This cross-sectional study investigated such responses in older adults with and without MS. The study consisted of 77 older adults with MS (68 ± 3 years old) and without MS (67 ± 3 years old). Impulse oscillometry (IOS) was used to evaluate airway and tissue resistance and reactance. Biomarkers of systemic and pulmonary inflammation and fibrosis were studied. Total resistance of respiratory system (R5Hz; p < 0.009), and resistance of proximal (R20Hz; p < 0.001) and distal (R5Hz-R20Hz; p < 0.004) airways were impaired in MS individuals compared to those without MS. The levels of pro-inflammatory (leptin; IL-1beta; IL-8, p < 0.001; TNF-alpha, p < 0.04) and pro-fibrotic (VEGF, p < 0.001) factor increased in MS, while reduced levels of anti-inflammatory cytokines (adiponectin; IL-1ra; IL-10; p < 0.001), and anti-fibrotic (relaxin 1; relaxin 3; Klotho, p < 0.001) factors were found. We conclude that MS accelerates lung function and mechanics impairment in older adults in detriment of an imbalance between pro and anti-inflammatory and fibrotic mediators. Furthermore, this study shows that the lungs also are a target organ in MS, deserving clinical assessment in older adults’ population.

Background: The sustainability of health benefits in response to lifestyle-based interventions remains unclear in children with overweight and obesity, and cardiometabolic disease (CMD). We determined the changes in novel biomarkers of CMD in a 1-year family-based intervention (FBI) program, during 6-month active monitoring phase and at 12-month follow-up. Methods: Children with an age-adjusted body mass index (BMI) percentile ≥85 ( N = 130; age 8–11 years) were recruited for a 1-year (6-month monitored and 6-month unmonitored) randomized controlled FBI program. Anthropometry and selected biomarkers of CMD were measured in 87 participants, randomly allocated to intervention (INT) and education-only (EDU) groups, at baseline, immediately after a 6-month active intervention or control period, and at 12-month unmonitored follow-up. Results: Samples from 87 participants (age 10.00 ± 0.11 years and Tanner stage ≤3) with obesity (BMI%ile = 97.45 ± 0.15) were available. Overall intervention effect (between groups), was observed for total (T) and high molecular weight (HMW) adiponectin, ratio of total to HMW adiponectin, fibrinogen, and interleukin (IL)-6 ( P < 0.05 for all). However, between-group beneficial changes after adjusting for baseline levels were limited to BMI percentile, T and HMW adiponectin and their ratio, IL-6, and fibrinogen ( P < 0.05 for all) mainly during the 6-month period of monitored intervention. Changes in traditional risk factors such as lipids and triglycerides were inconsistent. During the 6-month follow-up period, the changes in biomarkers leveled-off, except for T and HMW adiponectin, IL-6, and fibrinogen that continued to show benefits ( P < 0.05) from the 6- to 12-month follow-up. Conclusions: The FBI program beneficially altered novel biomarkers of CMD during the monitored intervention phase in school-age children with obesity, but they mostly moved back toward baseline during the unmonitored follow-up phase. The changes in novel biomarkers of CMD appear to be more sensitive compared to the traditional risk factors. The study implies the need for refinements in lifestyle-based approaches in the preservation of cardiovascular health and calls for robust biomarkers to monitor the changes. The study was registered at ClinicalTrials.gov (NCT01146314).

The aim of the study was to evaluate the effect of severe short‐term nutritional deprivation (ND) on the fractional synthesis rates (FSR) specific proteins and protein pools in the diaphragm muscle (DiaM). Male rats were divided into two groups: 20% of usual food intake for 4 days (ND) with water provided at libitum and free‐eating control (Ctl). [U‐13‐C] leucine was continuously infused through the jugular vein for 3–3.5 h after a priming dose of the isotope. Blood samples were collected from the carotid artery at baseline and every 30 min at precursor pool plateau. DiaM was excised at the end of the isotope infusion. Mixed muscle protein (MMP), myosin heavy chain (MHC), sarcoplasmic (Sarco) and mitochondrial (Mito) proteins were extracted from DiaM and the incorporation of the label into each protein(s) was determined using mass spectrometry. The FSR of MMP, MHC, Sarco and Mito in the rat DiaM were calculated using the precursor‐product relationship. ND resulted in the reduction of the FSRs of MMP (71%), MHC (69%), Sarco (44%) and Mito (55%) in DiaM. In summary, short‐term ND is associated with a global decrease in the synthetic rate of DiaM proteins, suggesting a compromise in the ability of the DiaM to synthesize functionally important proteins in the ND state. The underlying mechanisms for this depressed state of protein synthesis in DiaM related to ND remain to be elucidated.