Enhanced expression of lipogenic genes may contribute to hyperglycemia and alterations in plasma lipids in response to dietary iron deficiency

Abstract

Iron deficiency (ID) remains a public health concern affecting ~25% of the world's population. Metabolic consequences of ID include elevated plasma glucose concentrations consistent with increased reliance on glucose as a metabolic substrate, though the mechanisms controlling these responses remain unclear. To further characterize the metabolic response to ID, weanling male Sprague-Dawley rats were fed either a control (C; 40 mg Fe/kg diet) or iron-deficient (ID; 3 mg Fe/kg diet) diet or were pair-fed (PF) the C diet to the level of intake of the ID group for 21 days. In addition to reductions in hemoglobin, hematocrit, and plasma iron, the ID group also exhibited higher percent body fat and plasma triglycerides compared to the PF group. Steady-state levels of both plasma glucose and insulin increased 40 and 45%, respectively, in the ID group compared to the PF group. Plasma cortisol levels were decreased 67% in the ID group compared to the PF diet group. The systematic evaluation of the expression of genes involved in insulin signaling, glucose metabolism, and fatty acid metabolism in the liver and skeletal muscle revealed significant alterations in the expression of 48 and 52 genes in these tissues, respectively. A significant concurrent increase in lipogenic gene expression and decrease in gene expression related to β-oxidation in both the liver and skeletal muscle, in combination with differential tissue expression of genes involved in glucose metabolism, provides novel insight into the adaptive metabolic response in rodent models of severe iron deficiency anemia.

Lack of hepcidin expression attenuates steatosis and causes fibrosis in the liver

“…Furthermore, the deletion of Hamp1 alleles did not alter their basic expression levels. Iron-deficient rodents have been reported to display elevated lipogenic gene expression, which indirectly supports our findings [55][56][57] . Hepatic lipid homeostasis is also regulated by lipid export via VLDL secretion.…”

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

“…An independent study recently confirmed these findings, showing enhanced expression of lipogenic genes and alterations in levels of plasma lipids in response to dietary iron deficiency (52). The precise mechanisms responsible for the relative hyperglycemia associated with ferropenic anemia remain unclear (53,54).…”

PPARα, PPARγ and SREBP-1 pathways mediated waterborne iron (Fe)-induced reduction in hepatic lipid deposition of javelin goby Synechogobius hasta

“…In rats, Fe deficiency reduced β-oxidation of fatty acids, allowing the fatty acids to be diverted towards TG synthesis (Bartholmey and Sherman, 1985). Davis et al (2012) also reported that Fe deficiency reduced gene expression related to hepatic β-oxidation.…”

“…Similarly, Chen et al (2016) found that higher concentration of Fe exposure tended to reduce the lipogenic enzymatic activity and gene expression (G6PD and FAS). In rats, Davis et al (2012) reported that Fe deficiency increased hepatic lipogenesis by up-regulating gene expression related to lipogenesis. Our study indicated that the reduced FAS activity was attributable to the reduction in its mRNA expression, suggesting that FAS was regulated by Fe mainly at the transcriptional level, similar to the study by Chen et al (2016).…”