Roles of the calcium-binding protein sorcin in obesity and metabolism

Abstract

The Ca2+ binding protein sorcin has been shown to modulate pancreatic β-cell function, likely through prevention of ER stress. Overexpression of sorcin under control of the rat insulin 2 gene promoter (RIP7), or whole body sorcin deletion in 129S1/SvImJ mice, improves or impairs β-cell function respectively. Preliminary results also demonstrated changes in body weight, consistent with a role of sorcin in protecting against diet induced obesity. This thesis explores the mechanism by which sorcin functions and determine whether this underlies protection against diet induced obesity. Using apFRET studies, we found an interaction between sorcin and the cytoprotective ER stress sensor ATF6 at the protein level in-vitro. Given the role of hypothalamic ER stress on leptin resistance, we investigated whether altered leptin sensitivity is responsible for the body weight effects observed in Sri-/- mice. Our results challenge the role of sorcin in modulating body weight, demonstrating non-significant effects of sorcin deletion on body weight or leptin sensitivity in C57BL/6 mice. Sri-/- C57BL/6 mice also show non-significant differences in glucose tolerance, suggesting background specific effects of sorcin deletion. We also explored the role of sorcin in the liver, investigating whether its documented interaction with ChREBP in the pancreatic β-cell extends to the liver. We show a tendency towards increased ChREBP activity and increased hepatic triglyceride concentration in Sri-/- mice, associated with impaired insulin sensitivity. Deletion of sorcin in HEK293 cells increased ChREBP nuclear accumulation, whilst overexpression of sorcin in HepG2 cells led to reduced expression of glucose induced ChREBP target genes Acc and ChREBPβ. Altogether, our results challenge the role of sorcin in regulation of body weight but raise interesting questions regarding its role in the liver, and modulation of insulin sensitivity. These findings should be further investigated to determine the physiologic relevance of sorcin in insulin resistance and NAFLD progression.