Many previous studies have demonstrated that obese people are prone to iron deficiency, but the specific pathophysiological mechanism of this phenomenon remains incomplete. Some researchers have suggested that it is due to the intake of nutritionally unbalanced foods by obese patients. They tend to eat high-fat, high-calorie, low-nutrient foods, which can cause unbalanced intake of nutrients, including insufficient uptake of iron, thus aggravating the problem of iron deficiency. In addition, obese patients have thicker subcutaneous fat, which expands the capillary beds and leads to increased blood volume, which can also result in iron deficiency [33]. Systemic chronic inflammation is a factor of interest to a wide range of researchers, and it can decrease iron absorption by increasing the levels of hepcidin [34]. Iron homeostasis was improved in obese patients undergoing bariatric surgery, and they had significantly lower concentrations of C-reactive protein (CRP) and iron-regulated hormone in comparison to previous concentrations, presumably due to reduction in the inflammation that may have been hindering iron absorption [35].
The duodenum is one of the major sites of iron absorption. DMT1 expressed in the duodenum is one of the key transporter proteins involved in iron uptake and the expression of duodenal DMT1 is reduced when the concentration of hepcidin is too high. At the same time, iron absorption at the tip of the intestine is inhibited, but the expression level of FPN is not altered [36, 37]. We found lower protein and mRNA expression levels of duodenal DMT1 in obese mice, but no statistically significant difference in mRNA expression of duodenal FPN between the two groups. This alteration may be due to chronic inflammation caused by obesity that increases hepcidin levels, which leads to decreased expression of duodenal DMT1, while FPN expression is not affected. Four AAs, Asp, Gln, Glu, and Gly, can increase iron absorption by increasing DMT1 expression [38], suggesting that in addition to bariatric surgery, we may also be able to prevent obesity-related iron deficiency through pharmacological interventions.
Obesity, inflammation, and iron deficiency are closely related [34]. Inflammation and iron deficiency are important causes of impaired reproductive function in obese men [39–41]. Inflammation reduces the number of Leydig cells and spermatozoa, decreases sperm viability and affects the synthesis of testicular steroid hormones [42, 43]. In addition to altering the microbiota, iron deficiency interferes with the expression of genes involved in spermatogenic activity, resulting in impairment of male reproductive function [44]. Iron deficiency also increases oxidative stress in the testes, and iron supplementation can mitigate oxidative damage and repair testicular dysfunction [45].
MiR-135b expression has previously been found to be higher in the sperm of obese subjects [46], and it is strongly associated with both inflammation and embryonic development. Previously, researchers found that sperm from obese patients had higher numbers of miRNAs associated with both inflammation and iron metabolism. We found higher miR-135b expression in the spermatozoa of obese mice and performed bioinformatics analyses. The results of GO analysis showed that miR-135b affected reproductive function in obese male mice.
Cilia are organelles present on the cell surface, and the movement of epithelial cell cilia is involved in the movement of extracellular fluids, such as the transport of mucus in the respiratory tract. In males, motile cilia ensure that sperm can be smoothly transported from the testis to the epididymis for further functional maturation [47]. Fatty acid metabolism plays a very important role in sperm energy production, and fatty acid β-oxidation is an important source of energy during sperm maturation. Solute carrier family 22 member 14 (SLC22A14) regulates long-chain fatty acid β-oxidation and thus maintains energy homeostasis within spermatozoa; mutations in this gene can lead to male infertility disorders [48]. Protein phosphorylation and dephosphorylation are among the primary molecular mechanisms of sperm signaling and regulatory expression of enzymes, and are also linked to sperm and egg cell signal recognition and completion of fertilization [49]. In addition, sperm capacitation cannot be achieved without tyrosine phosphorylation [50]. Sperm-egg cell fusion is one of the main processes of fertilization, and the movement of the male pronucleus to the female pronucleus of the oocyte, a process known as inward movement, is dependent on actin nucleation, which is one of the mechanisms of pronucleus migration of fertilized mouse eggs [51]. It has been shown that β-alanine, a taurine transport inhibitor, decreased reproductive hormone levels, significantly reduced sperm motility, and increased the incidence of abnormal sperm [52]. Phosphatidic acid (PA), a common phospholipid and a component of cell membranes, plays a very important role in the later stages of spermatogenesis, and phosphatidic acid levels have been associated with male infertility[53]. Glutamine and L-arginine have been proven to reduce sperm motility [54–56]. Thus, miR135b mainly affects sperm function in obese mice, including but not limited to sperm motility, sperm capacitation, sperm count and fertilization.
We explained the cause of iron deficiency due to dietary obesity and revealed the role of iron deficiency and inflammation in the regulation of reproductive disorders.