Adipose Tissue Transferrin and Insulin Resistance

Abstract

Iron is an important micronutrient involved in several metabolic processes, and excessive iron is a risk factor for insulin resistance (IR) and diabetes. To define the genetic regulation of iron metabolism and its role in IR, we used gene expression, genotype, and insulin sensitivity data from an African American cohort (AAGMEx, N=256). Among the genes in a manually curated list of 62 transcripts representing iron homeostasis genes, expression of 32 in adipose tissue showed significant correlation with SI (p<0.01). The expression levels of transferrin (TF, β= 0.29, p=7.84 x 10-6) and ferritin heavy chain 1 (FTH1, β= -1.2, p=3.75 x 10-13) in adipose tissue were the most positively and negatively associated with SI, respectively. Observations were replicated in independent adipose tissue data sets from individuals of European ancestry (ARCA, N=99; METSIM, N=720). Among these SI-associated transcripts, the strongest cis-regulatory genetic variant (cis-eSNP) was for TF (rs6785596, β= 0.962, p=7.84 x 10-18) in adipose, but not in muscle or liver. To identify the role of TF in adipocytes, we downregulated its expression in a human adipocyte cell model (SGBS). Gene specific shRNA knockdown of TF caused differential expression (log2FC +/-0.4, probability>70%) of 465 genes, involved in mitochondrial function (CPT1B, UCP2), glucose transport (GLUT4), Wnt-pathway/insulin sensitivity (SFRP4, SFRP1), chemokine activity/cell-cell interaction (CXCL1, CXCL12, ICAM1), and genes with possible roles in obesity (CES1, RARRES2). Knockdown of TF mRNA in differentiated SGBS cells impaired mitochondrial respiration (49±10% reduction of maximal oxygen consumption rate) and caused a 34±4% reduction in maximal insulin-stimulated glucose uptake (p<0.05). In summary, genetic regulation of transferrin expression in adipose tissue plays a novel role in regulating insulin sensitivity. Disclosure D. McClain: None. N.K. Sharma: None. F. Lorenzo: None. S. Jain: None. C.D. Langefeld: None. M.E. Comeau: None. L. Salaye: None. S.K. Das: None.

Same role but different actors: genetic regulation of post-translational modification of two distinct proteins

“…Finally, our findings are not only relevant for unravelling the genetic mechanisms behind N-glycosylation PTM but also contribute to understanding changes in N-glycan patterns involved in disease. The most strongly N-glycosylation-associated variant for the TF gene, rs6785596, was suggested by McClain et al 36 to regulate TF expression in adipose tissue (also evident in GTEx v7) and consequently modulating insulin sensitivity. Excessive body iron stores represent a risk factor for decreased insulin sensitivity and diabetes 51 .…”

“…Excessive body iron stores represent a risk factor for decreased insulin sensitivity and diabetes 51 . McClain et al 36 argue that genetic downregulation of TF expression in adipocytes has functional consequences for these cells′ iron homeostasis and is sufficient to cause insulin resistance in humans and in a cell culture model. However, this SNP has so far not been associated with diabetes or diabetes-related traits, suggesting that this relationship needs to be explored further.…”

“…Transferrins are blood plasma glycoproteins regulating the level of iron in an organism. Iron plays a central role in many essential biochemical processes of human physiology: the cells’ need for iron in the face of potential danger as an oxidant has given rise to a complex system that tightly regulates iron levels, tissue distribution, and bioavailability 36 . Human transferrin has two N-glycosylation sites – at the N432 and N630 residues, with biantennary disialylated digalactosylated glycan structure without fucose being the most abundant glycan attached 37,38 .…”

Developmental programming: Transcriptional regulation of visceral and subcutaneous adipose by prenatal bisphenol-A in female sheep

“…The transcription factor CUX1 is involved in expression of FTO alpha-ketoglutarate dependent dioxygenase and retinitis pigmentosa GTPase regulatorinteracting protein-1 like (RPGRIP1L) (Stratigopoulos et al, 2011), which is strongly associated with adiposity (Frayling et al, 2007;Baker and Beales, 2009). Although these gene expression patterns are consistent with the negative role VAT plays in regulating lipid storage and metabolic homeostasis, paradoxically genes involved in maintaining insulin sensitivity, specifically TF (McClain et al, 2018) and adipogenesis, such as glycerol-3-phosphate acyltransferase 3 (GPAT3) (Shan et al, 2010), were also upregulated in VAT in this study. As GPAT3 knockout mouse are protected from diet induced obesity (Cao et al, 2014), the increased expression of GPAT3 and CUX1 raises the possibility that VAT manifest a gene expression profile that favors increase in visceral adiposity under conditions of positive energy such as overfed state.…”