Calreticulin and PDIA3, two markers of endoplasmic reticulum stress, are associated with metabolic alterations and insulin resistance in pediatric obesity: A pilot study

Abstract

Our aim was to evaluate the markers of endoplasmic reticulum (ER) stress among children and adolescents with obesity in relation to metabolic alterations. Calreticulin (CALR) and PDIA3 circulating levels were assessed on 52 pediatric subjects-26 patients with obesity and 26 normal weight controls (4-18 years)-enrolled in a pilot study. Clinical and metabolic evaluations were performed (BMI-SDS, insulin, and glucose at fasting and during an oral glucose tolerance test, lipid profile, blood pressure), and metabolic syndrome was detected. PDIA3 was higher (p < 0.02) and CALR slightly higher in children with obesity than in controls. PDIA3 was related positively to the Tanner stages. Both PDIA3 and CALR were positively associated with insulin resistance, cholesterol, and triglycerides and the number of criteria identifying metabolic syndrome and negatively with fasting and post-challenge insulin sensitivity. Our preliminary findings suggest the existence of a link between ER stress and metabolic changes behind obesity complications even at the pediatric age. CALR and PDIA3 could be early markers of insulin resistance and dyslipidemia-related ER stress useful to stratify patients at high risk of further complications.

Keywords: ER stress; insulin; lipids; obesity; pediatrics.

Figure 1

Some of the main mechanisms underlying the relationship between obesity, insulin resistance al URP-related chaperones activity. Nutrients intake, when is higher than cellular needs, causes an overproduction of unfolded proteins that require to be processed by ER. In these situations, ER activates multiple mechanisms to reduce stress sources. First, Insulin resistance is provoked by the cell to reduce the insulin-mediated protein transcription, lately being ad additional factor for the development of obesity. Secondly, ER activates UPR, increasing the activity of several enzymes such as caspases that are responsible of apoptotic processes in addition to ROS and inflammatory cytokines production. URP has also the role of increasing protein degradation (ERAD) and contemporarily of boosting folding capacity through oxidative protein folding, which is partially performed by the activation of the PDIA3/Calreticulin/Calnexin chaperones complex..