Increased adipose tissue heme levels and exportation are associated with altered systemic glucose metabolism

Abstract

Abstract Iron status is known to be associated with the physiology of adipose tissue (AT). We aimed to investigate AT heme and expression of heme exporter (FLVCR1) in association with obesity and type 2 diabetes (T2D). Substantial amounts of FLVCR1 mRNA and protein levels were detected in AT, being significantly increased in subjects with T2D, and positively correlated with fasting glucose, fasting triglycerides and with circulating markers of iron stores (serum ferritin, blood hemoglobin and hematocrit). In both visceral (VAT) and subcutaneous AT (SAT), increased heme levels were found in subjects with T2D. Reinforcing these associations, FLVCR1 mRNA levels were positively linked to fasting glucose in an independent cohort. Longitudianlly, the percent change of FLVCR1 positively correlated with the percent change in fasting glucose (r = 0.52, p = 0.03) after bariatric surgery-induced weight loss. High-fat diet-induced weight gain in rats did not result in significant changes in AT Flvcr1 mRNA but, remarkably, the expression of this gene positively correlated with fasting glucose and negatively with insulin sensitivity (QUICKI). Altogether, these findings showed a direct association between FLVCR1 mRNA levels and hyperglycemia, suggesting that increased adipose tissue heme exportation might disrupt, or is the consequence of, impaired systemic glucose metabolism during the progression to T2D.