Iron deficiency anemia (IDA) is an important public health problem in developing countries. The etiology of some of the symptoms seen in ID has not been clearly elucidated. Especially within the scope of our study, we hypothesized that the sensation of coldness observed in individuals with IDA might be associated with Ir levels. This hypothesis stems from previous findings in various studies (18, 19), which have demonstrated that Ir plays a crucial role in generating heat energy through the conversion of WAT into BAT. Irisin and FABP4 are peptide-structured hormones involved in both energy metabolism and thermoregulation processes (15). As known, iron acts as a cofactor in the enzymes required for energy metabolism, participating in thermoregulation processes. Therefore, we believe that there may be a connection between iron and these two hormones.
In our study, we found that the basal serum Ir levels of ID, LID and IDA groups were statistically low compared to the control group(p < 0.05). Ir, which is known to be synthesised in almost all biological tissues, leads to heat energy production instead of ATP synthesis by increasing UCP-1 proteins (20). An increase in the amount of Ir in biological fluids may be associated with increased heat production in the body. Ir is considered a hormone that regulates energy expenditure and promotes the conversion of WAT to BAT. In this context, elevated levels of Ir in biological fluids may contribute to increased thermogenesis and heat production in the body. There are factors outside the hypothalamus that influence thermogenesis in our body, and Ir is one of these pathways. Ir increases the expression of a protein called UCP1 in white fat cells. UCP1 stimulates thermogenesis by converting energy into heat in the mitochondria of the cell. This process redirects energy towards heat production rather than the normal function of energy storage in white We observed decreased levels of Ir in cases of diminished iron, even in the absence of anemia. Furthermore, there was an elevation in serum Ir levels following iron therapy. Based on this mechanism, we posit that the diminished Ir levels may underlie the heightened sensitivity to cold in individuals with ID.
As known, Ir is released from muscle tissue. In the case of ID, symptoms such as weakness and fatigue develop, and patients may move slowly and engage in less physical activity. As reported here, an increase in Ir levels was observed with iron supplementation. The likely reason for this increase is the normalization of physical activity in children, associated with a reduction in fatigue and weakness due to ID. Consequently, there may be an elevation in muscle tissue through this mechanism, leading to an increase in the levels of Ir released from the muscles. We hypothesized that the rise in Ir levels following the treatment of ID could be attributed to this mechanism.
In other studies, the correlations of Ir and FABP4 serum and urine levels with anthropometric measurements were analysed. In our study, we observed no correlation between the levels of serum and urine Ir and FABP4 and gender, as well as anthropometric measurement data.Similarly, Moreno et al,(21) Liuliu et al. (22) found no relationship between Ir concentrations and gender. However, Al-Delghri et al. (23) in a cohort study of 153 Saudi Arabian children found that circulating Ir levels in the blood were higher in girls than in boys. Siahanidou et al. (24) found no significant correlation between FABP4 levels and gender, body weight, height and BMI, but Ibarretxe et al. (25) found high FABP4 levels in females in a study.
In our study, we also investigated urine samples to establish a potential link between Ir and ID using a simpler and non-invasive approach. However, we did not find any correlation between the levels of Irisin in serum and urine samples. On the other hand, no difference was observed in the changes in urine depending on the treatment, and the possible reason for this was thought to be that there was no correlation between the circulating level of Ir and its excretion from urine.
As it is known, decreases in neurocognitive functions such as attention deficit, learning difficulties, behavioural disorders, decreased perceptual functions, retardation in motor and mental development tests are observed in ID. Studies in school children have shown that learning and various developmental tests are impaired in ID with or without anemia, but learning difficulty may improve with iron treatment (26). In our study, it was thought that the decline in cognitive functions might be related with Ir, which is known to be released from all biological tissues. FNDC5/irisin has been shown as a new therapeutic factor that can improve cognition, learning and memory function (27). FNDC5 has been found to reduce some factors that provide neuronal destruction, and it has also been found that FNDC5 administration with adenovirus increases neuroprotective factors (28, 29) Moon et al. (30) found that Ir at pharmacological concentrations increased STAT3 levels in H 19 − 7 hippocampal neuronal cells and STAT3 levels in mice, and low levels of Ir decreased differentiation in neuronal functions in mouse embryonic stem cells. Low levels of Ir in serum have been shown to reduce the level of FNDC5, an Ir precursor in the human brain. A direct relationship has been shown in hippocampal neurogenesis. Dun et al (31) showed in another immunohistochemical study that purkinje cells in rats and mice express Ir and also FNDC5 in recent days. It is known that the hippocampus is a critical region in learning and memory formation, and is a very important structure in spatial memory formation. According to our current knowledge, the cellular and molecular mechanisms of learning and memory formation are explained by long-term potentiation (LTP) in the hippocampus (32). Since Ir and hippocampus are especially related in learning, we think that decreased Ir level in ID may be related to the decrease in cognitive functions seen in ID. In addition, the fact that these symptoms are reversible with iron supplementation suggests that they may be directly related to the increased Ir level after iron treatment.