Adipose tissue transferrin and insulin resistance

Abstract

Context: Excessive body iron stores are a risk factor for decreased insulin sensitivity (S I ) and diabetes. We hypothesized that transcriptional dysregulation of genes involved in iron metabolism in adipocytes causes insulin resistance. Objective and Design: To define the genetic regulation of iron metabolism and its role in S I , we used gene expression, genotype, and S I data from an African American cohort (N = 256). Replication studies were performed in independent European ancestry cohorts. In vitro studies in human adipocytes were performed to define the role of a selected gene in causing insulin resistance. Results: Among 62 transcripts representing iron homeostasis genes, expression of 30 in adipose tissue were correlated with S I . Transferrin (TF) and ferritin heavy polypeptide were most positively and negatively associated with S I , respectively. These observations were replicated in two independent European ancestry adipose data sets. The strongest cis-regulatory variant for TF expression (rs6785596; P = 7.84 3 10 218 ) was identified in adipose but not muscle or liver tissue. Variants significantly affected the normal relationship of serum ferritin to insulin resistance. Knockdown of TF in differentiated Simpson-Golabi-Behmel syndrome adipocytes by short hairpin RNA decreased intracellular iron, reduced maximal insulin-stimulated glucose uptake, and reduced Akt phosphorylation. Knockdown of TF caused differential expression of 465 genes, including genes involved in glucose transport, mitochondrial function, Wnt-pathway/ S I , chemokine activity, and obesity. Iron chelation recapitulated key changes in the expression profile induced by TF knockdown. Conclusion: Genetic regulation of TF expression in adipose tissue plays a novel role in regulating S I .