Title | Adipocyte iron regulates leptin and food intake. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Gao Y, Li Z, J Gabrielsen S, Simcox JA, Lee S-hyun, Jones D, Cooksey B, Stoddard G, Cefalu WT, McClain DA |
Journal | J Clin Invest |
Volume | 125 |
Issue | 9 |
Pagination | 3681-91 |
Date Published | 2015 Sep |
ISSN | 1558-8238 |
Keywords | 3T3-L1 Cells, Adipocytes, Animals, Cyclic AMP Response Element-Binding Protein, Dietary Supplements, Eating, Ferritins, Gene Expression Regulation, Hemochromatosis, Iron, Leptin, Mice, Mice, Mutant Strains, Response Elements |
Abstract | Dietary iron supplementation is associated with increased appetite. Here, we investigated the effect of iron on the hormone leptin, which regulates food intake and energy homeostasis. Serum ferritin was negatively associated with serum leptin in a cohort of patients with metabolic syndrome. Moreover, the same inverse correlation was observed in mice fed a high-iron diet. Adipocyte-specific loss of the iron exporter ferroportin resulted in iron loading and decreased leptin, while decreased levels of hepcidin in a murine hereditary hemochromatosis (HH) model increased adipocyte ferroportin expression, decreased adipocyte iron, and increased leptin. Treatment of 3T3-L1 adipocytes with iron decreased leptin mRNA in a dose-dependent manner. We found that iron negatively regulates leptin transcription via cAMP-responsive element binding protein activation (CREB activation) and identified 2 potential CREB-binding sites in the mouse leptin promoter region. Mutation of both sites completely blocked the effect of iron on promoter activity. ChIP analysis revealed that binding of phosphorylated CREB is enriched at these two sites in iron-treated 3T3-L1 adipocytes compared with untreated cells. Consistent with the changes in leptin, dietary iron content was also directly related to food intake, independently of weight. These findings indicate that levels of dietary iron play an important role in regulation of appetite and metabolism through CREB-dependent modulation of leptin expression. |
DOI | 10.1172/JCI81860 |
Alternate Journal | J. Clin. Invest. |
PubMed ID | 26301810 |
PubMed Central ID | PMC4588289 |
Grant List | 1U54 GM104940 / GM / NIGMS NIH HHS / United States R01 DK081842 / DK / NIDDK NIH HHS / United States I01 BX001140 / BX / BLRD VA / United States U54 GM104940 / GM / NIGMS NIH HHS / United States 1R01 DK081842 / DK / NIDDK NIH HHS / United States P50 AT002776 / AT / NCCIH NIH HHS / United States P50AT002776 / AT / NCCIH NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:11pm