Systemic Iron Regulation and Adipose Tissue Inflammation in Health and Disease.

Abstract

Iron dysregulation can lead to serious health concerns resulting from either too much or too little iron storage and availability. For example, iron deficiency anemia results in a reduced exercise tolerance, while chronic conditions such as obesity and type 2 diabetes may predispose individuals to tissue iron overload. The relatively recent discovery of hepcidin, the major iron-regulating hormone, has led to new hypotheses regarding conditions of iron dysregulation, including exercise-induced iron deficiency. A series of recent studies have suggested that exercise-induced iron deficiency might result from a transient increase in circulating hepcidin following acute exercise. However, it is unclear whether there is a cumulative effect of multiple acute excursions of hepcidin in response to everyday training. On the opposite end of the iron dysregulation spectrum, excess iron deposition is a potential contributor to the pathology of obesity-related metabolic complications. However, the underlying mechanisms are still unclear. The major findings from my dissertation studies include: in STUDY#1, the iron-regulating hormone, hepcidin, is not chronically elevated with sustained training in competitive collegiate runners, who have a high risk of iron deficiency (p>0.05); In STUDY#2, a high level of iron in the epididymal adipose tissue was accompanied by a robust adipose tissue remodeling, characterized by increased macrophages, fibrosis, cell death and elevated inflammation; In Study#3, five weeks voluntary exercise reduced weight, improved glucose intolerance and altered adipose tissue inflammatory gene expression in female polygenic obese KK mice. Contrary to our hypothesis, in STUDY#3, exercise did not improve the serum iron levels in KK mice and in STUDY#2 we observed no relationship between adipose tissue iron deposition and glucose homeostasis. Together the three projects enhanced our understanding of the underlying cause of exercise-induced iron deficiency anemia in female athletes as well as the relationship among the risks of diabetes, iron overload and exercise.