Context: Excessive body iron stores are a risk factor for decreased insulin sensitivity (SI) 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 SI, we used gene expression, genotype, and SI 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 SI. Transferrin (TF) and ferritin heavy polypeptide were most positively and negatively associated with SI, 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 × 10-18) 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/ SI, 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 SI.
Context: Excessive body iron stores are a risk factor for decreased insulin sensitivity (SI) 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 SI, we used gene expression, genotype, and SI 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 SI. Transferrin (TF) and ferritin heavy polypeptide were most positively and negatively associated with SI, 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 × 10-18) 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/ SI, 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 SI.
Authors: Robert C Cooksey; Deborah Jones; Scott Gabrielsen; Jingyu Huang; Judith A Simcox; Bai Luo; Yudi Soesanto; Hugh Rienhoff; E Dale Abel; Donald A McClain Journal: Am J Physiol Endocrinol Metab Date: 2010-03-30 Impact factor: 4.310
Authors: José María Moreno-Navarrete; Francisco Ortega; María Moreno; Wifredo Ricart; José Manuel Fernández-Real Journal: Diabetologia Date: 2014-06-29 Impact factor: 10.122
Authors: Neeraj K Sharma; Satria P Sajuthi; Jeff W Chou; Jorge Calles-Escandon; Jamehl Demons; Samantha Rogers; Lijun Ma; Nicholette D Palmer; David R McWilliams; John Beal; Mary E Comeau; Kristina Cherry; Gregory A Hawkins; Lata Menon; Ethel Kouba; Donna Davis; Marcie Burris; Sara J Byerly; Linda Easter; Donald W Bowden; Barry I Freedman; Carl D Langefeld; Swapan K Das Journal: J Clin Endocrinol Metab Date: 2016-01-20 Impact factor: 5.958
Authors: Mete Civelek; Ying Wu; Calvin Pan; Chelsea K Raulerson; Arthur Ko; Aiqing He; Charles Tilford; Niyas K Saleem; Alena Stančáková; Laura J Scott; Christian Fuchsberger; Heather M Stringham; Anne U Jackson; Narisu Narisu; Peter S Chines; Kerrin S Small; Johanna Kuusisto; Brian W Parks; Päivi Pajukanta; Todd Kirchgessner; Francis S Collins; Peter S Gargalovic; Michael Boehnke; Markku Laakso; Karen L Mohlke; Aldons J Lusis Journal: Am J Hum Genet Date: 2017-03-02 Impact factor: 11.025
Authors: Judith A Simcox; Thomas Creighton Mitchell; Yan Gao; Steven F Just; Robert Cooksey; James Cox; Richard Ajioka; Deborah Jones; Soh-Hyun Lee; Daniel King; Jingyu Huang; Donald A McClain Journal: Diabetes Date: 2014-10-14 Impact factor: 9.461
Authors: Jeb S Orr; Arion Kennedy; Emily K Anderson-Baucum; Corey D Webb; Steve C Fordahl; Keith M Erikson; Yaofang Zhang; Anders Etzerodt; Søren K Moestrup; Alyssa H Hasty Journal: Diabetes Date: 2013-10-15 Impact factor: 9.461