1755-P: Transferrin Role in Systemic Iron Influence on Insulin Sensitivity and Adipocyte Function

Systemic iron overload is associated with decreased insulin sensitivity (Si) and diabetes. We previously characterized the genetic regulation of iron and its effect on Si in humans, which demonstrated that expression of the iron transport protein transferrin (Tf) in adipose tissue plays a role in regulating insulin sensitivity. To further characterize this effect at the tissue and cellular levels, we generated heterozygous Tf knock out (KO) mice and human adipose cells (ASC52Telo) with knock down (KD) of Tf. Heterozygous Tf KO and wild type (WT) mice were fed a 40% fat “fast-food” diets, supplemented with glucose in the water, containing either 35mg or 2000mg iron per kg chow. Fasting glucose levels were not affected in the Tf KO mice compared to WT (p=0.3889) on the low iron diet, but increased in the KO mice on 2gm/kg iron (13% increase, p=0.0511) suggesting the attenuation of the protective effect of transferrin in blood sugar regulation at high iron diet. We previously reported that adipose cells transfected with TF shRNA compared to a control vector had decreased intracellular iron and exhibited insulin resistance. We also performed mitochondrial function studies (oxygen consumption analyzed by Seahorse) in these cells. Tf KD cells exhibited decreased maximal oxygen consumption compared to controls (p:0.0004). Iron treatment of the cells augmented respiration in the control cells but worsened maximal oxygen consumption in the Tf KD cells (p=0.0011). We conclude that transferrin-mediated iron transport in adipocytes plays an important role in determining insulin sensitivity, allowing beneficial responses to high iron, namely protection from hyperglycemia and augmented mitochondrial function.