Adipocyte iron regulation and the effects of iron on the regulation of adiponectin and leptin

The incidence and prevalence of obesity and type 2 diabetes are increasingrapidly worldwide. There has been considerable interest in the factors contributing to both obesity and diabetes. While adipocytes were previously thought to be inert storage depots for excess calories, recent studies have demonstrated that adipose tissue is an important endocrine organ. Adipose tissue-produced hormones are involved in regulating a wide range of metabolic and behavioral processes. Two of these hormones are adiponectin and leptin. Adiponectin has been causally linked to insulin sensitivity while leptin is involved in the regulation of food intake and energy balance. Recently, the role of micronutrients in the regulation of adiposity and insulin sensitivity has started to be investigated. Dietary iron overload is associated with insulin resistance and increased diabetes risk. In this dissertation, I have investigated the regulation of iron in adipocytes and the role of iron in the regulation of adiponectin and leptin. I demonstrate that serum ferritin-a marker of body iron stores-is negativelyassociated with both serum adiponectin and serum leptin levels in humans. Theferritin-adiponectin and ferritin-leptin relationships are independent of body mass index (BMI) and inflammation. I also demonstrate that serum adiponectin and serum leptin levels are decreased in a mouse model of dietary iron overload. Furthermore, iron treatment decreases luciferase activity of the adiponectin promoter in a FOXO1- dependent manner In contrast to dietary iron overload, however, humans and mice with hereditary hemochromatosis (HH), a genetic form of iron overload, have increased serum adiponectin levels. To understand this apparent paradox, I investigated iron regulation in adipocytes. I demonstrate that adipocytes express the iron export protein, ferroportin, and actively regulate intracellular iron levels. The pathogenic mechanism of HH results in unregulated ferroportin expression. As a result, adipocytes are functionally iron underloaded in HH despite total body iron overload. Thus, high serum adiponectin levels in HH reflect low intracellular adipocyte iron levels in the same manner as low adiponectin reflects high adipocyte iron in dietary iron overload. These findings demonstrate an important role for adipocytes in modulating metabolism in response to iron store.