Excess iron has been strongly implicated in many diseases including diabetes and nonalcoholic steatohepatitis (NASH). At the other extreme, iron deficiency, the most common nutritional disorder in the world, contributes to obesity. Understanding the effects of iron on metabolism has important implications for all of these conditions. First, iron may play a fundamental, causal role in their pathogenesis, as has been demonstrated by interventional studies in human diabetes, NASH, and to a lesser degree vascular disease. This would support treating the disorders by manipulating iron stores (e.g. by blood donation); we need to understand the full ramifications of doing so to establish rational treatment goals of optimal iron. Second, understanding mechanisms underlying iron's effects will open doors to other druggable pathways. The need to define the effects of iron and their dose-responsiveness is illustrated by the effects on hepatic lipid metabolism. High iron is an established risk factor for the progression of nonalcoholic fatty liver disease (NAFLD) to NASH, but iron deficiency is a risk factor for NAFLD and obesity. Thus, there should be an existing intermediate level of iron that fully supports fuel oxidation and does not contribute to obesity bu that is also not in the range to contribute to the hepatic inflammation and scarring of NASH. Understanding the dose-responsiveness for the metabolic effects of iron is especially needed given the very wide range of normal iron, which is ~15-fold. In our previous work, we have demonstrated in mice that dietary iron, within the range of normal diets and without overt iron deficiency or iron toxicity, has major effects on carbohydrate metabolism. Preliminary data demonstrate that iron also regulates key aspects of lipid metabolism including hepatic de novo lipogenesis, fatty acid (FA) oxidation, and leptin synthesis. This proposal is to study the effects of iron on these processes, with the aims of describing a fuller phenotype of lipid metabolism as a function of tissue iron and of determining the mechanism for these effects. Our overall hypothesis is that iron levels can contribute oth to NAFLD, NASH, and obesity, and that manipulating these over a much narrower range than the normal one of the US population will have significant health implications.

Public Health Relevance

We have seen uniform improvement in glucose tolerance in individuals with diabetes whose serum ferritin (a marker of tissue iron) was reduced from the upper to the lower quartile of normal by phlebotomy. This suggests that large segments of the population might benefit from manipulation of their iron stores by, for example, donating blood, an intervention that is easy, safe, inexpensive, and even carries societal benefits. This project will extend this work also to the associated conditions of obesity, fatty liver, and NASH.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Laughlin, Maren R
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Wake Forest University Health Sciences
Internal Medicine/Medicine
Schools of Medicine
United States
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McClain, Donald A; Sharma, Neeraj K; Jain, Shalini et al. (2018) Adipose Tissue Transferrin and Insulin Resistance. J Clin Endocrinol Metab 103:4197-4208
Nagpal, Ravinder; Wang, Shaohua; Solberg Woods, Leah C et al. (2018) Comparative Microbiome Signatures and Short-Chain Fatty Acids in Mouse, Rat, Non-human Primate, and Human Feces. Front Microbiol 9:2897
Nam, Hyeyoung; Jones, Deborah; Cooksey, Robert C et al. (2016) Synergistic Inhibitory Effects of Hypoxia and Iron Deficiency on Hepatic Glucose Response in Mouse Liver. Diabetes 65:1521-33
Simcox, Judith A; Mitchell, Thomas Creighton; Gao, Yan et al. (2015) Dietary iron controls circadian hepatic glucose metabolism through heme synthesis. Diabetes 64:1108-19
Gao, Yan; Li, Zhonggang; Gabrielsen, J Scott et al. (2015) Adipocyte iron regulates leptin and food intake. J Clin Invest 125:3681-91
Ge, Ri-Li; Simonson, Tatum S; Gordeuk, Victor et al. (2015) Metabolic aspects of high-altitude adaptation in Tibetans. Exp Physiol 100:1247-55
Abbas, Mousa Al; Abraham, Deveraprabu; Kushner, James P et al. (2014) Anti-obesity and pro-diabetic effects of hemochromatosis. Obesity (Silver Spring) 22:2120-2
Creighton Mitchell, T; McClain, Donald A (2014) Diabetes and hemochromatosis. Curr Diab Rep 14:488
McClain, Donald A; Abuelgasim, Khadega A; Nouraie, Mehdi et al. (2013) Decreased serum glucose and glycosylated hemoglobin levels in patients with Chuvash polycythemia: a role for HIF in glucose metabolism. J Mol Med (Berl) 91:59-67
Huang, Jingyu; Simcox, Judith; Mitchell, T Creighton et al. (2013) Iron regulates glucose homeostasis in liver and muscle via AMP-activated protein kinase in mice. FASEB J 27:2845-54

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