Objectives : Iron regulatory protein 1 (IRP1) plays a key regulator of cellular iron metabolism, systemic oxygen sensing, and erythropoiesis. Deletion of IRP1 leads to profound HIF2a-dependent abnormalities in erythropoiesis and iron metabolism. Previously, we demonstrated that modulation of adipose tissue iron metabolism is necessary for adipose tissue browning. However, the role of IRP1 in adipose tissue browning and its metabolic consequences are uncertain. This study aimed to investigate the role of IRP1 in regulating adipose tissue browning in a mouse model of genetic ablation of IPR1 (IRP1-/-).
Methods : The IRP1-/- mice and wildtype (WT) controls were kept either at room (25°C) or cold (6°C) temperature for 7 days. Adipose tissue browning was evaluated by UCP1 expression and prevalence of beige-like structure in inguinal fat. Thermogenic heat release captured by infrared camera and core body temperature was measured by a rectal thermometer. The modulation of iron metabolism was assessed by serum levels of ferritin, hematocrit, and erythropoietin levels by ELISA. To investigate the role of IRP1 on energy metabolism, IRP1-/- and WT controls were fed a high-fat diet (45%) for 14 weeks. Insulin sensitivity was determined by glucose and insulin tolerance test and HOMA-IR score. [3H]-2-deoxyglucose (DOG) was injected to determine the distribution of 3H-radioactivity was quantified.
Results : IRP1-/- mice dramatically increased serum levels of erythropoietin but decreased hepcidin. IRP1-/- developed polycythemia and reticulocytosis, which was not affected by cold exposure. IRP1-/- were completely blunted in cold-induced browning in the inguinal fat showing no changes in UCP1 and adipocyte morphology. Unexpectedly, IRP1-/- showed higher core body temperature and heat release than control independent of UCP1 expression. Chronic intake of HF diet paradoxically increased the insulin sensitivity regardless of obesity. 2-DOG distribution was significantly increased in red blood cells, suggesting that red blood cell-dependent energy expenditure significantly contributed to rapid glucose disposal.
Conclusions : Disruption of IRP1 blunted adipose tissue browning. The paradoxical rise in insulin sensitivity in IRP1-/- is likely due to red blood cells-mediated energy expenditure.
Funding Sources : No funding