Circulatory levels of lysophosphatidylcholine species in obese adolescents: Findings from cross-sectional and prospective lipidomics analyses.

BACKGROUND AND AIMS: Obesity has reached epidemic proportions, emphasizing the importance of reliable biomarkers for detecting early metabolic alterations and enabling early preventative interventions. However, our understanding of the molecular mechanisms and specific lipid species associated with childhood obesity remains limited. Therefore, the aim of this study was to investigate plasma lipidomic signatures as potential biomarkers for adolescent obesity. METHODS AND RESULTS: A total of 103 individuals comprising overweight/obese (n = 46) and normal weight (n = 57) were randomly chosen from the baseline ORANGE (Obesity Reduction and Noncommunicable Disease Awareness through Group Education) cohort, having been followed up for a median of 7.1 years. Plasma lipidomic profiling was performed using the UHPLC-HRMS method. We used three different models adjusted for clinical covariates to analyze the data. Clustering methods were used to define metabotypes, which allowed for the stratification of subjects into subgroups with similar clinical and metabolic profiles. We observed that lysophosphatidylcholine (LPC) species like LPC.16.0, LPC.18.3, LPC.18.1, and LPC.20.3 were significantly (p < 0.05) associated with baseline and follow-up BMI in adolescent obesity. The association of LPC species with BMI remained consistently significant even after adjusting for potential confounders. Moreover, applying metabotyping using hierarchical clustering provided insights into the metabolic heterogeneity within the normal and obese groups, distinguishing metabolically healthy individuals from those with unhealthy metabolic profiles. CONCLUSION: The specific LPC levels were found to be altered and increased in childhood obesity, particularly during the follow-up. These findings suggest that LPC species hold promise as potential biomarkers of obesity in adolescents, including healthy and unhealthy metabolic profiles.

Plausible diagnostic value of urinary isomeric dimethylarginine ratio for diabetic nephropathy.

Altered circulatory asymmetric and symmetric dimethylarginines have been independently reported in patients with end-stage renal failure suggesting their potential role as mediators and early biomarkers of nephropathy. These alterations can also be reflected in urine. Herein, we aimed to evaluate urinary asymmetric to symmetric dimethylarginine ratio (ASR) for early prediction of diabetic nephropathy (DN). In this cross-sectional study, individuals with impaired glucose tolerance (IGT), newly diagnosed diabetes (NDD), diabetic microalbuminuria (MIC), macroalbuminuria (MAC), and normal glucose tolerance (NGT) were recruited from Dr. Mohans' Diabetes Specialties centre, India. Urinary ASR was measured using a validated high-throughput MALDI-MS/MS method. Significantly lower ASR was observed in MIC (0.909) and MAC (0.741) in comparison to the NGT and NDD groups. On regression models, ASR was associated with MIC [OR: 0.256; 95% CI: 0.158-0.491] and MAC [OR 0.146; 95% CI: 0.071-0.292] controlled for all the available confounding factors. ROC analysis revealed ASR cut-point of 0.95 had C-statistic of 0.691 (95% CI: 0.627-0.755) to discriminate MIC from NDD with 72% sensitivity. Whereas, an ASR cut-point of 0.82 had C-statistic of 0.846 (95% CI: 0.800 - 0.893) had 91% sensitivity for identifying MAC. Our results suggest ASR as a potential early diagnostic biomarker for DN among the Asian Indians.

High molecular weight adiponectin reduces glucolipotoxicity-induced inflammation and improves lipid metabolism and insulin sensitivity via APPL1-AMPK-GLUT4 regulation in 3T3-L1 adipocytes.

BACKGROUND AND AIMS: Although the importance of adipokines in modulating the disease process of type 2 diabetes is well recognized, there is dearth of data on the specific role of high molecular weight adiponectin (HMW Ad) on insulin resistance and obesity. Therefore, we tested the effects of HMW Ad on glucolipotoxcity-induced inflammation and insulin resistance in 3T3-L1 adipocytes. METHODS: 3T3-L1 adipocytes were subject to glucolipotoxicity with and without HMW Ad treatment. Real-time PCR and Western-blot experiments were performed to analyse gene and protein expressions, respectively. Lipolysis, adipored staining, and glucose uptake assay were performed to evaluate alterations in lipid and glucose metabolism. RESULTS: Adipocytes subject to glucolipotoxicity showed significantly (p < 0.05) decreased mRNA expression of adiponectin, AdipoR2, GLUT4, and increased inflammation, lipid accumulation as well as lipolysis. Treatment with HMW Ad beneficially modulated lipid metabolism, reduced inflammation and improved glucose uptake in adipocytes. HMW Ad also beneficially regulated APPL1 and AMPK signaling in adipocytes. Silencing of APPL1 gene in adipocytes significantly reduced the effects of HMW Ad on pAMPK protein expression, indicating that HMW Ad plays an important role in regulating AMPK phosphorylation via APPL1 in 3T3-L1 adipocytes. CONCLUSIONS: HMW Ad treatment improved glucose homeostasis and resulted in reduced lipolysis, inflammation and insulin resistance in adipocytes subject to glucolipotoxicity. The beneficial modulation and regulation of APPL1 and AMPK signals by HMW Ad observed in this study represent a novel mechanism. Raising endogenous HMW Ad levels either by pharmacological or lifestyle modification could have a therapeutic value.