Body Mass Index From Early to Late Childhood and Cardiometabolic Measurements at 11 to 12 Years.

OBJECTIVES: To examine how overweight and obesity at specific ages and overall BMI growth patterns throughout childhood predict cardiometabolic phenotypes at 11 to 12 years. METHODS: In a population-based sample of 5107 infants, BMI was measured every 2 years between ages 2 to 3 and 10 to 11 years. We identified 5 BMI trajectories using growth curve models. At ages 11 to 12 years, 1811 children completed assessments for metabolic syndrome risk scores, carotid-femoral pulse wave velocity, and carotid intima-media thickness. Multivariable regression models were used to estimate associations, adjusted for potential confounders (eg, age, sex, smoking exposure, and small for gestational age). RESULTS: Overweight and obesity from early childhood onward were strongly associated with higher cardiometabolic risk at 11 to 12 years of age. At age 6 to 7 years, compared with those with a healthy weight, children with overweight had higher metabolic syndrome risk scores by 0.23 SD units (95% confidence interval 0.05 to 0.41) and with obesity by 0.76 SD units (0.51-1.01), with associations almost doubling by age 10 to 11 years. Obese (but not overweight) children had higher outcome pulse wave velocity (0.64-0.73 SD units) from ages 6 to 7 years and slightly higher outcome carotid intima-media thickness (0.20-0.30 SD units) at all ages. Cumulative exposure to high BMI from 2 to 3 years of age carried the greatest cardiometabolic risk, with a gradient of risk across trajectories. CONCLUSIONS: High early-childhood BMI is already silently associated with the development of cardiometabolic risk by 11 to 12 years, highlighting the urgent need for effective action to reduce overweight and obesity in early childhood.

Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in SH-SY5Y neuroblastoma cells.

Amyloid precursor protein (APP) undergoes post-translational modification, including O- and N-glycosylation, ubiquitination, and phosphorylation as it traffics through the secretory pathway. We have previously reported that copper promotes a change in the cellular localization of APP. We now report that copper increases the phosphorylation of endogenous APP at threonine 668 (Thr-668) in SH-SY5Y neuronal cells. The level of APPT668-p (detected using a phospho-site-specific antibody) exhibited a copper-dependent increase. Using confocal microscopy imaging we demonstrate that the phospho-deficient mutant, Thr-668 to alanine (T668A), does not exhibit detectable copper-responsive APP trafficking. In contrast, mutating a serine to an alanine at residue 655 does not affect copper-responsive trafficking. We further investigated the importance of the Thr-668 residue in copper-responsive trafficking by treating SH-SY5Y cells with inhibitors for glycogen synthase kinase 3-ß (GSK3ß) and cyclin-dependent kinases (Cdk), the main kinases that phosphorylate APP at Thr-668 in neurons. Our results show that the GSK3ß kinase inhibitors LiCl, SB 216763, and SB 415286 prevent copper-responsive APP trafficking. In contrast, the Cdk inhibitors Purvalanol A and B had no significant effect on copper-responsive trafficking in SH-SY5Y cells. In cultured primary hippocampal neurons, copper promoted APP re-localization to the axon, and this effect was inhibited by the addition of LiCl, indicating that a lithium-sensitive kinase(s) is involved in copper-responsive trafficking in hippocampal neurons. This is consistent with APP axonal transport to the synapse, where APP is involved in a number of functions. We conclude that copper promotes APP trafficking by promoting a GSK3ß-dependent phosphorylation in SH-SY5Y cells.