Adipocyte Iron Regulates Leptin and Food Intake

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Publication Type dissertation
School or College School of Medicine
Department Biochemistry
Author Gao, Yan
Title Adipocyte Iron Regulates Leptin and Food Intake
Date 2015-08
Description Iron overload has been proposed to be a component of the insulin-resistance syndrome. On the other hand, dietary iron supplementation is associated with growth and increased appetite in children. We found the concentration of circulating ferritin is associated with low serum adiponectin, the insulin-sensitizing adipokine, and leptin, the adipokine that is responsible for regulating food intake. Similarly, mice fed a high iron diet and 3T3-L1 adipocytes treated with iron exhibited decreased adiponectin and leptin mRNA and protein. Iron negatively regulates transcription of adiponectin promoter-driven luciferase activity in a FOXO1-dependent manner. However, iron decreases the inactivated form of FOXO1, acetyl-FOXO1, while leaving phosphorylated FOXO1 and total FOXO1 unaffected. The mechanism of iron's effect on adiponectin and promotion of metabolic syndrome is demonstrated via the binding affinity of multiple transcription factors in the adiponectin promoter using ChIP studies. The higher activation of FOXO1 in iron-treated cells contributes to more inactivation of PPARγ through direct interaction, leading to decreased adiponectin transcription and expression. These findings directly demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role for adipocytes in modulating metabolism through adiponectin in response to iron stores. We found iron negatively regulated leptin transcription via cAMP response element binding protein (CREB) activation. Two potential CREB-binding sites were identified in the mouse leptin promoter region. Mutation of both sites completely blocked the effect of iron on promoter activity. We also found enrichment of phospho-CREB iv binding to those two sites by ChIP in 3T3-L1 adipocytes treated with iron. CREB is modified and destabilized by O-GlcNAc modification. Iron also negatively regulates O-GlcNAc modification both in 3T3-L1 and epididymal fat, and mice heterozygous for deletion of the gene encoding the enzyme that removes O-GlcNAc, O-GlcNAcase, showed significantly increased serum leptin compared to wild-type mice. Glucosamine treatment rescued high iron-induced decrease of leptin promoter activity. These results suggest that the effects of iron on leptin may be via crosstalk of O-GlcNAcylation and phosphorylation of CREB. These findings indicate that levels of dietary iron play an important role in regulation of appetite and fat metabolism through CREB-dependent modulation of leptin expression.
Type Text
Publisher University of Utah
Subject MESH Iron, Dietary; Iron Overload; Leptin; Insulin Resistance; Adipocytes; PPAR gamma; Binding Sites; Adiponectin; Risk Factors; Metabolic Syndrome X; Phosphoenolpyruvate Carboxykinase (ATP); Phosphoenolpyruvate; Diabetes Mellitus, Type 2; Ferritins; Phosphorylation; Cyclic AMP Response Element-Binding Protein; Transcription, Genetic; Signal Transduction; Mitochondria; Oxidation-Reduction; Gluconeogenesis; Adipose Tissue
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital version of Adipocyte Iron Regulates Leptin and Food Intake
Rights Management Copyright © Yan Gao 2015
Format Medium application/pdf
Format Extent 24,285,078 bytes
Source Original in Marriott Library Special Collections
ARK ark:/87278/s6xw7t3s
Setname ir_etd
Date Created 2016-05-04
Date Modified 2021-05-06
ID 197359
Reference URL https://collections.lib.utah.edu/ark:/87278/s6xw7t3s
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